CN104557726B - Aromatic heterocyclic derivatives and its application on drug - Google Patents

Aromatic heterocyclic derivatives and its application on drug Download PDF

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Publication number
CN104557726B
CN104557726B CN201410557556.0A CN201410557556A CN104557726B CN 104557726 B CN104557726 B CN 104557726B CN 201410557556 A CN201410557556 A CN 201410557556A CN 104557726 B CN104557726 B CN 104557726B
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alkyl
base
compound
group
disease
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CN104557726A (en
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金传飞
钟文和
张英俊
张
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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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

Abstract

The present invention provides some aromatic heterocyclic derivatives or its stereoisomer, tautomer, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or prodrug, for treating Alzheimer's disease.The invention also discloses the pharmaceutical composition containing such compound and use the method for the compounds of this invention or its medicine composite for curing Alzheimer's disease.

Description

Aromatic heterocyclic derivatives and its application on drug
Technical field
The invention belongs to drug field and it is related to compound for treating Alzheimer's disease, comprising the compound Composition and application thereof and application method.Particularly, compound of the present invention is to can be used as 5-HT6Receptor antagonist Aromatic heterocyclic derivatives.
Background technique
A variety of central nervous system diseases such as anxiety, depression etc. with neurotransmitter serotonin (5-HT) or thrombocytin Disorder it is related.As modulability neurotransmitter main in brain, the function of neurotransmitter serotonin (5-HT) be pass through by Referred to as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6And 5-HT7A large amount of receptor families mediate.Based on Gao Shui in brain Flat 5-HT6Receptor mrna, it has been suggested that 5-HT6Receptor may play in the pathology of central nervous system disorders and treatment Effect.Specifically, it has been determined that 5-HT6Selective ligands have potential treatment effect, such as Parkinson to certain CNS illnesss Disease, Huntington's chorea, anxiety disorder, depression, manic-depressive psychosis, mental disease, epilepsy, obsessive-compulsive disorder, migraine, Alzheimer Disease (cognition and memory enhancing), sleep disturbance, eating disorder such as anorexia and bulimia nerovsa, panic attack, ADHD, attention lack Fall into obstacle, drug abuse such as cocaine, ethyl alcohol, nicotine and benzodiazepineRecessiveness brain syndrome, essence are taken off caused by class Refreshing Split disease and illness such as hydrocephalus related with spinal trauma or head injury.It is expected that the compound can also be used to treat Certain stomach intestinal disease such as functional bowel disorders.(see, for example, Roth, B.L. etc., J.Pharmacol.Exp.Ther., 268, 1403-14120 pages of (1994), Sibley, D.R. etc., Mol, Pharmacol., 43,320-327 (1993), A.J.Sleight Deng, Neurotransmission, 11,1-5 (1995) and Sleight, A.J. etc., Serotonin ID Research Alert, 1997,2 (3), 115-8).The study found that known 5-HT6Selective antagonist significantly improves in cortex of frontal lobe The level of glutamic acid and aspartic acid removes hormone, dopamine or 5-HT on first kidney without improving6Level.It is this memory and The selectivity raising for the specific neurochemical noticed in cognitive process has strongly suggested that 5-HT6Ligand is in cognition Act on (Dawson, L.A.；Nguyen, H.Q.；Li, P., British Journal of Pharmacology, 2000,130 (1), 23-26).With known selectivity 5-HT6Research that the memory of antagonists in animals and study carry out have it is some actively Effect (Rogers, D.C.；Hatcher, P.D.；Hagan, J.J., Society of Neuroscience, Abstracts, 2000,26,680).5-HT6The related potential treatment purposes of ligand is to treat the attention deficit disorder of children and adult.Because 5-HT6Antagonist seems to improve the activity of nigrostriatal dopamine approach, and because ADHD with it is different in caudate nucleus Chang Youguan (Ernst, M；Zametkin, A.J.；Matochik, J.H.；Jons, P.A.；Cohen, R.M., Journal of Neuroscience, 1998,18 (5), 5901-5907), so, 5-HT6Antagonist can treat attention deficit disorder.Also Through determining 5-HT6Antagonist is the potentially useful compound for treating obesity.See, for example, Bentley etc., Br.J.Pharmac.1999, supplementary issue 126；Bentley etc., J.Psychopharmacol.1997, supplementary issue A64:255；Wooley Deng Neuropharmacology 2001,41:210-129 and WO02098878.
Summary of the invention
The present invention relates to the methods of new aromatic heterocyclic derivatives and treatment Alzheimer's disease.The compounds of this invention or packet Pharmaceutical composition containing the compound is to 5-HT6Receptor has a preferable affinity interaction, especially to Alzheimer's disease have compared with Good therapeutic effect.
On the one hand, the present invention relates to a kind of compounds, are the solid of structure shown in structure shown in formula (I) or formula (I) Isomers, tautomer, nitrogen oxides, 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；
WhenWhen for singly-bound, X is CH or N；WhenWhen for double bond, X C；
R1For H, D, C1-6Alkyl, C3-8Naphthenic base, C1-6Halogenated alkyl ,-C (=O) R6,-C (=O) OR6,-C (=O) NR6R6a, R6R6aN-S (=O)2, R6S (=O)2, R6aR7N-C1-6Alkylidene, R6S (=O)-C1-6Alkylidene, R6R6aN-C (= O)-C1-6Alkylidene, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl-C1-6Alkylidene or C1-9Heteroaryl-C1-6Alkylidene；
Each R2And R3It is separately H, D, F, Cl, Br, I, CN, NO2, OH, NH2, R6aR6N- ,-C (=O) R6,-C (= O)NR6R6a,-N (R6) C (=O)-R6a, R6R6aN-S (=O)2, R6S (=O)2, R6S (=O)2N(R6aWhat)-, hydroxyl replaced C1-6Alkyl, R6aR6N-C1-6Alkylidene, R6S (=O)-C1-6Alkylidene, R6R6aN-C (=O)-C1-6Alkylidene, R6aR6N-C1-6It is sub- Alkoxy, R6S (=O)-C1-6Alkylene oxide group, R6R6aN-C (=O)-C1-6Alkylene oxide group, C6-10Aryl, C1-9Heteroaryl, C1-6Alkane Oxygroup, C1-6Alkylamino, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-8Naphthenic base, C1-6Alkylthio group, C6-10Aryl-C1-6Alkyl or C1-9Heteroaryl-C1-6Alkylidene,；Or two adjacent R2With the carbon being attached thereto Atom forms the former molecular carbocyclic ring of 5-6 optionally replaced, heterocycle, aromatic rings or heteroaromatic；
Each R4It independently is H, D, F, Cl, Br, I, CN, oxo (=O), C1-6Alkyl, C3-8Naphthenic base, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy or C6-10Aryl-C1-4Alkylidene；
R5For H, D, F, Cl, Br, I, CN, OH, NH2, C1-6Alkyl, C1-6Halogenated alkyl, C3-8Naphthenic base, C1-6Alkoxy ,-C (=O) R6,-C (=O) OR6,-C (=O) NR6R6a, C6-10Aryl or C6-10Aryl-C1-6Alkylidene；
Each R6And R6aIt independently is H, D, OH, NH2, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy or C6-10Aryl.
In some of these embodiments, R1For H, D, C1-4Alkyl, C3-6Naphthenic base or C6-10Aryl-C1-4Alkylidene.
In some of these embodiments, each R2And R3It is separately H, D, F, Cl, Br, I, OH, NH2, C1-4Alkyl, C3-6Naphthenic base, C1-4Alkoxy, C2-4Alkenyl, C2-4Alkynyl or C6-10Aryl；Or two adjacent R2With the carbon atom being attached thereto Form the former molecular aromatic rings of 5-6 optionally replaced or heteroaromatic.
In some of these embodiments, each R4It independently is H, D, C1-4Alkyl, C3-6Naphthenic base, C1-4Halogenated alkyl or C1-4Alkoxy.
In some of these embodiments, R5For H, D, F, Cl, Br, I ,-COOH, C1-4Alkyl, C3-6Naphthenic base, C6-10Virtue Base or C6-10Aryl-C1-4Alkylidene.
In some of these embodiments, the present invention has the vertical of structure shown in the structure as shown in formula (II) or formula (II) Body isomers, tautomer, nitrogen oxides, 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；
R1For H, D, C1-4Alkyl, C3-6Naphthenic base, C1-4Halogenated alkyl ,-C (=O) R6,-C (=O) OR6,-C (=O) NR6R6aOr C6-10Aryl-C1-4Alkylidene；
Each R2And R3It is separately H, D, F, Cl, Br, I, CN, OH, NH2, C1-4Alkyl, C3-6Naphthenic base, C1-4Alcoxyl Base, C2-4Alkenyl, C2-4Alkynyl or C6-10Aryl；Or two adjacent R2The 5-6 optionally replaced is formed with the carbon atom being attached thereto The molecular aromatic rings of a original or heteroaromatic；
Each R4It independently is H, D, CN, C1-4Alkyl, C3-6Naphthenic base, C1-4Halogenated alkyl or C1-4Alkoxy；
R5For H, D, F, Cl, Br, I, C1-4Alkyl, C6-10Aryl or C6-10Aryl-C1-4Alkylidene；
Each R6And R6aIt independently is H, D, OH, NH2, C1-4Alkyl, C1-4Miscellaneous alkyl or C1-4Halogenated alkyl.
In some of these embodiments, R1For H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, uncle Butyl, cyclopropyl or cyclobutyl.
In other embodiments, each R2And R3It is separately H, D, F, Cl, Br, I, CN, OH, NH2, methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth Oxygroup, isobutoxy, tert-butoxy, cyclopropyl or cyclobutyl；Or two adjacent R2It is formed and is appointed with the carbon atom being attached thereto Choose the phenyl ring in generation.
On the other hand, the present invention relates to a kind of pharmaceutical composition, described pharmaceutical composition includes the compound of the present invention, with And pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium or their combination.
In some of these embodiments, pharmaceutical composition of the present invention further includes treatment A Er The drug of Ci Haimo disease, drug or their combination for nervous disorders.
In other embodiments, treat Alzheimer's disease drug be 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, galanthamine, Memantine, mitzapine, Wen Lafa It is pungent, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, pentoxifylline or he Combination.
On the other hand, the purposes the present invention relates to the compounds of this invention or pharmaceutical composition in medicine preparation, the medicine Object is for treatment or prevention and 5-HT6Related disease.
In some of these embodiments, the present invention relates to 5-HT6Related CNS illness are as follows: ADHD, anxiety, with essence Refreshing nervous relevant disease, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, nervous disorders, memory disorders, Attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea.
In other embodiments, the present invention relates to 5-HT6Related disease is disorder of gastrointestinal tract.
In other embodiments, the present invention relates to 5-HT6Related disease is obesity.
Another aspect of the present invention is related to the method for the preparation, separation and purifying of formula (I) compound represented.
Biological results show that compound provided by the invention can be used as preferable 5-HT6Antagonist.In noted earlier Appearance only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and otherwise content will be under Make more specific complete description in face.
Specific embodiment
Definition and general terms
The present invention will list in detail document corresponding to the content determining materialization, and embodiment is all accompanied by structure The diagram of formula and chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, these may be such as right Existing invention field is included in defined in it is required that like that.Those skilled in the art will identify it is many similar or equivalent to This described method and substance, these can be applied to the practice of the present invention.The present invention is limited to absolutely not method and substance Description.There are many documents and similar substance to distinguish or contradict with the present patent application including but not limited to term Definition, the usage of term, the technology of description or range as controlled by the present invention.
The present invention will be using defined below unless other aspects show.Purpose according to the present invention, chemical element is according to member Plain periodic table, CAS version and Chemical Physics handbook, 75thEd., 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 bibliography.
As described in the present invention, the compound of the present invention can be optionally replaced one or more substituent groups, such as General formula compound above, or such as example special inside embodiment, subclass, and a kind of compound that the present invention is included. It should be appreciated that this term can be used interchangeably " optionally replacing " this term with " substituted or unsubstituted ".In general, art Language " optionally " whether it is before the term " replaced ", indicates that one or more hydrogen atoms in given structure are specific Replaced substituent group.Unless otherwise indicated, an optional substituent group can have a substituent group group is each can Substituted position is replaced.When more than one position can be selected from the one or more of specific group in given structural formula Replaced substituent group, then substituent group can replace at various locations identical or differently.Wherein the substituent group can be, But it is not limited to, deuterium, hydroxyl, amino, fluorine, chlorine, bromine, iodine, cyano, azido, aryl, heteroaryl, alkoxy, alkylamino, alkane Sulfenyl, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, heteroaryloxy, oxo, carboxyl, halogenated alkyl, hydroxyl Substituted alkyl, the alkoxy that hydroxyl replaces, alkyl-C (=O)-, alkyl-C (=O)-, the alkyl-S (=O)-that hydroxyl replaces, Alkyl-S (=O)2, the alkyl-S (=O)-that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces2, Carboxyalkoxy etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointing out, describing mode as used throughout this document " each ... independently be " and " ... be each independently " and " ... independently be " can be interchanged, and shall be understood in a broad sense, Either referring among the different groups, does not influence mutually, can also be indicated between expressed specific option between the same symbol In the same group, it is not influenced mutually between specific option expressed between the same symbol, with R6For, structural formula "-N (R6) C (=O) NR6R6a" and structural formula "-OC (=O) OR6" R between the two6Specific option it is unaffected from each other, together When, in same chemical formula "-N (R6) C (=O) NR6R6a" in, multiple R6Specific option it is unaffected from each other.
Terminology used in the present invention " alkyl " indicates the saturated straight chain of 1-20 carbon atom or the univalence hydrocarbyl of branch.One In a little embodiments, alkyl group includes 1-6 carbon atom, and in further embodiments, alkyl group includes 1-4 carbon atom. The example of alkyl includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n-Pr ,- CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,-CH2CH (CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), tert-butyl (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl (- CH (CH3)CH2CH2CH3), 3- amyl (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl-1-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyl (- CH (CH3) CH2CH2CH2CH3), 3- hexyl (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), etc..
Term " alkyl " and its prefix " alkane " use here, all include the saturated carbon chains of straight chain and branch.
Terminology used in the present invention " alkylidene " can be used alone or as " aryl-alkylidene " or " heteroaryl-Asia Most of alkyl " indicates to eliminate the saturation divalent hydrocarbon that two hydrogen atoms obtain from linear chain or branched chain saturated hydrocarbon Base.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, and some of embodiments are that alkylidene group contains There is 1-6 carbon atom, other embodiment is that alkylidene group contains 1-4 carbon atom, and other embodiment is, sub- Alkyl group contains 1-3 carbon atom, and other embodiment is that alkylidene group contains 1-2 carbon atom.Alkylidene group Example include, but is not limited to, methylene (- CH2), ethylidene (- CH2CH2), propylidene (- CH2CH2CH2), ethylidine (-CH(CH3) -), secondary isopropyl (- CH (CH3)CH2) etc..Alkylidene can be further substituted, which is selected from, but simultaneously It is not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, azido, alkyl, halogenated alkyl, alkenyl, alkynyl, hydroxy alkyl, alkane Oxygroup alkyl, aminoalkyl, alkyl amino alkyl, cyanoalkyl, hydroxyl, alkoxy, sulfydryl, alkylthio group, amino, alkylamino, ammonia Base acyl group, alkylamino acyl group, aryl, heteroaryl etc..
Term " alkenyl " indicates the monovalent hydrocarbon of the linear chain or branched chain of 2-12 carbon atom, and wherein at least one position is not Saturation state, i.e. a C-C are sp2Double bond.In some embodiments, alkenyl group includes 2-6 carbon atom, in other realities It applies in example, alkenyl group includes 2-4 carbon atom.Wherein alkenyl group can be independently and optionally by one or more present invention Replaced described substituent group, including group has negation, " suitable " or " E ", the positioning of " Z ", wherein the specific example packet of alkenyl It includes, but is not limited to, vinyl (- CH=CH2), allyl (- CH2CH=CH2), etc..
Term " alkynyl " indicates the monovalent hydrocarbon of the linear chain or branched chain of 2-12 carbon atom, and wherein at least one position is not Saturation state, i.e. a C-C are tri- key of sp.In some embodiments, alkynyl group includes 2-6 carbon atom, in other realities It applies in example, alkynyl group includes 2-4 carbon atom.Wherein alkynyl group can be independently and optionally by one or more present invention Replaced described substituent group, wherein the specific example of alkynyl is included, but is not limited to, acetenyl (- C ≡ CH), propargyl (-CH2C ≡ CH), etc..
Term " H " indicates single hydrogen atom.Such atomic group can be connect with other groups, for example with oxygen atom phase Even, hydroxyl group is formed.
Term " D " or "2H " indicates single D-atom.One such atomic group is connected with a methyl, forms mono- deuterium For methyl (- CDH2), two D-atoms are connected with a methyl, form double-deuterated methyl (- CD2H) and three D-atoms with One methyl is connected, and forms tris-methyl (- CD3)。
Term " hetero atom " indicates one or more O, S, N, P and Si atom, including the form of any oxidation state of N, S and P； The form of primary, secondary, tertiary amine and quaternary ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N (such as 3,4- N in dihydro-2 h-pyrrole base), NH (such as NH in pyrrolidinyl) or NR (such as NR in the pyrrolidinyl of N- substitution).
Term " halogen " refers to F, Cl, Br or I.
" unsaturated " the expression structure division of term as used in the present invention contains one or more degrees of unsaturation.
Term " hydroxyl replace alkyl " indicate alkyl group replaced one or more hydroxyl groups, wherein alkyl base Group has meaning of the present invention.Such example includes, but is not limited to methylol, ethoxy, 1,2- dihydroxy ethyl Deng.
Terminology used in the present invention " halogenated alkyl " indicates alkyl group by one or more identical or different halogen atoms Replaced, wherein alkyl group has meaning as described in the present invention, halogen atom, that is, fluorine, chlorine, bromine or iodine.Some of embodiment party Case is C1-6Halogenated alkyl is the alkyl group of 1-6 carbon atom replaced one or more identical or different halogen atoms, Other embodiment is C1-4Halogenated alkyl is the alkyl group of 1-4 carbon atom by one or more identical or different Replaced halogen atom, such example includes, but is not limited to trifluoromethyl, trifluoroethyl, chloromethyl, methyl fluoride etc..
Term " alkoxy " can be used alone or as " halogenated alkoxy " or a part of " alkylene oxide group ", indicate Alkyl group is connected by oxygen atom with molecule rest part, and wherein alkyl group has meaning as described in the present invention.Unless In addition it is described in detail, the alkoxy base contains 1-20 carbon atom, and some of embodiments are that alkoxy base contains 1- 6 carbon atoms, other embodiment are that alkoxy base contains 1-4 carbon atom.The example of alkoxy base includes, but It is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,-OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,- OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,- OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- butoxy ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- Butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t-BuO, t- butoxy,-OC (CH3)3) etc..And it is described Alkoxy can be substituted or unsubstituted, and wherein substituent group can be, but be not limited to, hydroxyl, amino, halogen, cyano, alkane Oxygroup, alkyl, alkenyl, alkynyl, sulfydryl, nitro etc..
Terminology used in the present invention " halogenated alkoxy " indicates alkoxy base by one or more identical or different halogen Replaced atom, wherein alkoxy base has meaning as described in the present invention, halogen atom, that is, fluorine, chlorine, bromine or iodine.It is some of Embodiment is C1-6Halogenated alkoxy is that the alkoxy base of 1-6 carbon atom is former by one or more identical or different halogen Replaced son, such example includes, but is not limited to trifluoromethoxy, trifluoro ethoxy, chloromethane epoxide, fluorine methoxyl group etc..
Term " alkylthio group " includes C1-6The alkyl of linear chain or branched chain is connected on the sulphur atom of divalent.Some of them are implemented Scheme is that alkylthio group is the C of lower level1-4Alkylthio group, such example include, but is not limited to methyl mercapto (CH3S-)。
Term " alkylamino " includes " N- alkyl amino " and " N, N- dialkyl amido ", wherein amine groups separately by Replaced one or two alkyl group.Some of embodiments are that alkylamino is one or two C1-6Alkyl is connected to nitrogen The alkylamino group of lower level on atom.Other embodiment is that alkylamino is C1-4Lower level alkyl amino Group.Suitable alkylamino radicals can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but is not limited to, N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- lignocaine etc..
Term " ring " includes carbocyclic ring, heterocycle, aromatic rings, heteroaromatic, loop coil, spiroheterocyclic, condensed ring, condensed hetero ring etc., wherein institute Carbocyclic ring is stated, heterocycle, aromatic rings, heteroaromatic, loop coil, spiroheterocyclic, condensed ring, condensed hetero ring group is with meaning as described in the present invention.
Term " alicyclic group ", " annular aliphatic base ", " carbocyclic ring ", " carbocylic radical " refer to monovalence or multivalence, non-aromatic, Saturation or the unsaturated ring in part, and do not include hetero atom, monocycle including 3-6 carbon atom or 7-12 carbon atom Two rings.Bicyclic carbocyclic with 7-12 atom can be two rings [4,5], [5,5], and [5,6] or [6,6] system has simultaneously The bicyclic carbocyclic of 9 or 10 atoms can be two rings [5,6] or [6,6] system.Suitable annular aliphatic base includes, but simultaneously It is not limited to, naphthenic base, cycloalkenyl and cycloalkynyl radical.Some of embodiments are that " naphthenic base " is that 3-8 carbon atom forms Ring.The example of " annular aliphatic base " includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkenyl, 1- cyclopenta -2- alkenyl, 1- cyclopenta -3- alkenyl, cyclohexyl, 1- cyclohexyl -1- alkenyl, 1- cyclohexyl -2- alkenyl, 1- hexamethylene Base -3- alkenyl, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl etc..And " annular aliphatic base " or " carbocyclic ring ", " carbocylic radical ", " naphthenic base " can be substituted or unsubstituted, and wherein substituent group can be, but be not limited to, hydroxyl, amino, Halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, hydroxyl The alkoxy that base replaces, the alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O) that hydroxyl replaces2, Alkyl-the S (=O)-that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces2, Carboxyalkoxy etc..
Term " " heterocycle " ", " " heterocycle " ", " " heteroalicyclic " " or " " heterocycle " " are used interchangeably here, are all Refer to monocycle, bicyclic or three-ring system, one or more carbon atoms are independently and optionally replaced hetero atom in middle ring, institute Hetero atom is stated with meaning as described in the present invention, ring can be it is fully saturated or comprising one or more degrees of unsaturation, but Definitely not aromatic, only one tie point are connected to other molecules up.Hydrogen atom on one or more rings it is independent and Optionally replaced one or more substituent groups described in the invention.Some of embodiments are " " heterocycles " ", " " miscellaneous Ring group " ", " " heteroalicyclic " or " " heterocycle " " group be 3-8 former molecular monocycle (1-6 carbon atom and be selected from N, O, The 1-3 hetero atom of P, S optionally obtain such as SO, SO in this S or P replaced one or more oxygen atoms2, PO, PO2's Group, when the ring is a three-membered ring, only one of them hetero atom) or 7-10 former molecular bicyclic (4-9 carbon Atom and it is selected from N, O, P, the 1-3 hetero atom of S optionally obtain for example replaced one or more oxygen atoms in this S or P SO, SO2, PO, PO2Group), other embodiment is, " heterocycle " is 2-10 carbon atom and selected from N, O, P, and S's is miscellaneous Former molecular group, other embodiment are that " heterocycle " is 4-7 carbon atom and is selected from N, O, P, and S's is heteroatomic The group of composition.
Heterocycle can be carbon-based or heteroatom group." heterocycle " equally also includes heterocyclic group and saturation or part insatiable hunger With ring or heterocycle and conjunction is formed by group.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrofuran base, dihydro Furyl, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, Thiophene oxane base, thiazolidinyl, oxazolidinyl, piperazinyl, high piperazine base, azelidinyl, oxetanylmethoxy, thietanyl, Homopiperidinyl, glycidyl, azacycloheptyl, oxetane, thiocycloheptyl, 4- Methoxy-piperidin -1- base, 1,2,3, 6- tetrahydropyridine -1- base, oxygen azepineBase, diazaBase, sulphur azepineBase, pyrrolin -1- base, 2- pyrrolinyl, 3- pyrrole Cough up quinoline base, indolinyl, 2H- pyranose, 4H- pyranose, dioxacyclohexyl, 1,3- dioxymyl, pyrazolinyl, two thiophenes Alkyl, dithienyl group, dihydrothiophene, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4- tetrahydro isoquinolyl, 1, 2,6- thiadiazine alkane 1,1- dioxo -2- base, 4- hydroxyl-Isosorbide-5-Nitrae-azepine phosphine 4- oxide -1- base, 2- hydroxyl -1- (piperazine - 1- yl) ethyl ketone -4- base, 2- hydroxyl -1- (5,6- dihydros -1,2,4- triazine -1 (4H)-yl) ethyl ketone -4- base, 5,6- dihydro -4H- 1,2,4- oxadiazines -4- base, 2- hydroxyl -1- (- 1 (2H)-yl of 5,6- dihydropyridine) 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- tetrahydros-[1,2,4] three Azoles [1,5-c] pyrimidine -6- base, 4,5,6,7- tetrahydro isoxazole [4,3-c] pyridine -5- bases, 3H- indyl 2- oxygen -5- azepine are double Ring [2.2.1] heptane -5- base, 2- oxygen -5- azabicyclo [2.2.2] octane -5- base, quinazinyl and N- pyridyl urea.Heterocycle The example of group further includes that two carbon atoms are replaced oxygen atom as phonetic on 1,1- dioxothiomorpholinyl and its middle ring Pyridine diketo.And the heterocycle can be substituted or unsubstituted, and wherein substituent group can be, but be not limited to, oxo, Hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, virtue Oxygroup, the alkoxy that hydroxyl replaces, the alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-alkyl-S that hydroxyl replaces (=O)2, the alkyl-S (=O)-that hydroxyl replaces, the alkyl-S (=O) that hydroxyl replaces2, Carboxyalkoxy etc..
Term " aryl " can be used alone or as " aralkyl ", and one of " aralkoxy " or " aryloxy alkyl " Point, indicate the monocycle altogether containing 6-10 member ring, bicyclic and tricyclic carbocyclic ring system, wherein at least one ring system is aromatic series , wherein each ring system includes 3-7 member ring, and only one attachment point is connected with the rest part of molecule.Term " virtue Base " can be used interchangeably with term " aromatic rings ", if aromatic rings may include phenyl, naphthalene and anthryl.And the aryl can Optionally to replace, wherein substituent group be can be, but is not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkane Oxygroup, alkylamino, alkyl, alkenyl, alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy that hydroxyl replaces, hydroxyl replace Alkyl-C (=O)-, alkyl-C (=O)-, alkyl-S (=O)-, alkyl-S (=O)2, hydroxyl replace alkyl-S (= O)-, the alkyl-S (=O) that hydroxyl replaces2Carboxyalkoxy, etc..
Term " aralkyl ", " aryl-alkyl " include the alkyl group that aryl replaces.Some of embodiments are virtues Alkyl group refers to that " aralkyl of lower level " group, i.e. aryl group are connected to C1-6Alkyl group on.Other is implemented Scheme is that aromatic alkyl group refers to containing C1-4Alkyl " benzeme alkylene ".Wherein specific example includes benzyl, diphenyl methyl, benzene Ethyl.Aryl on aralkyl can be further by halogen, alkyl, alkoxy, replaced halogenated alkyl and halogenated alkoxy.
Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Indicate the monocycle altogether containing 5-10 member ring, bicyclic and three-ring system, wherein at least one ring system is aromatic, and at least One ring system includes one or more hetero atoms, and wherein hetero atom has meaning of the present invention, wherein each ring body System includes 3-7 member ring, and only one attachment point is connected with molecule rest part.Some of embodiments are " heteroaryl alkane Base " is 1-9 carbon atom and selected from N, O, P, the monocycle or bicyclic of the hetero atom composition of S.Term " heteroaryl " can be with term " heteroaromatic " or " heteroaromatics " is used interchangeably.And the heteroaryl can be it is substituted or unsubstituted, wherein replacing Base can be, but be not limited to, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, Alkynyl, heterocycle, sulfydryl, nitro, aryloxy group, the alkoxy that hydroxyl replaces, the alkyl-C (=O)-, alkyl-C that hydroxyl replaces (=O)-, alkyl-S (=O)-, alkyl-S (=O)2, hydroxyl replace alkyl-S (=O)-, hydroxyl replace alkyl-S (= O)2, Carboxyalkoxy etc..
Other embodiment is that heteroaromatic includes monocycle below, but is 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- isoxazole Base, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, 4- methylisoxazole -5- base, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- Pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine radicals, 4- pyrimidine radicals, pyrimidine -5- base, pyridazinyl (such as 3- pyridazinyl), 2- thiophene Oxazolyl, 4- thiazolyl, 5- thiazolyl, tetrazole radical (such as 5- tetrazole radical), triazolyl (such as 2- triazolyl and 5- triazolyl), 2- thiophene Base, 3- thienyl, pyrazolyl (such as 2- pyrazolyl), isothiazolyl, 1,2,3-oxadiazoles base, 1,2,5- oxadiazoles base, 1,2,4- Oxadiazoles base, 1,2,3-triazoles base, 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-triazines base, benzo [d] thiazol-2-yl, imidazo [1,5-a] pyrrole Pyridine -6- base；Also including below bicyclic, it is bicyclic that such example includes, but is not limited to these: benzimidazolyl, benzo furan It mutters base, benzothienyl, indyl (such as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinoline Base) and isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl or 4- isoquinolyl).
As described in the invention, substituent group draws one and is keyed to the ring system (as follows) formed on the ring at center Representing substituent group any substitutive position on ring can replace.For example, formula e represent it is any on A ring may be substituted Position, such as formula f1‐f4It is shown.
Unless otherwise indicated, structural formula described in the invention includes that (such as mapping is different for all isomeric forms Structure, diastereo-isomerism and geometrical isomerism (or conformational isomerism)): such as R, S configuration containing asymmetric center, (Z) of double bond, (E) isomers, and the conformer of (Z), (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or its is right Reflect isomers, the mixture of diastereoisomer or geometric isomer (or conformer) belongs to the scope of the present invention.
Term " prodrug " used in the present invention represents a compound and is converted into formula (I) compound represented in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is influenced through enzymatic conversion in blood or tissue.This hair Bright pro-drug compounds can be ester, and ester can be used as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, it can is acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are obtaining through the di on parent.It is completely begged for about pro-drug By following documents can be referred to: 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 otherwise indicated, all tautomeric forms of the compound of the present invention are included in the scope of the present invention Within.In addition, unless otherwise indicated, the structural formula of compound described in the invention includes one or more different originals The enriched isotope of son.
" metabolite " refers to specific compound or its salt product obtained by metabolic action in the body.One change The metabolite for closing object can be identified that activity can be retouched by such as the present invention by technology well-known in the art It adopts as stating and is experimentally characterized.Such product can be by, by aoxidizing, restoring, water to drug compound Solution, amidated, deamidation, esterification, degreasing, the methods of enzymatic lysis etc. obtain.Correspondingly, the present invention includes compound Metabolite, including the compound of the present invention and mammal are come into full contact with into metabolite caused by a period of time.
The definition of neutral body chemistry of the present invention and the use of convention are typically referenced to following documents: 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.The compound of the present invention may include asymmetric center or chiral centre, therefore There are different stereoisomers.All stereoisomeric forms in any ratio of the compound of the present invention, it is including but not limited to, diastereomeric Body, enantiomter, atropisomer and their mixture, such as racemic mixture constitute a part of the invention. Many organic compounds all exist with optical active forms, i.e. the plane of their capable Plane of rotation polarised lights.In description light When learning reactive compound, prefix D, L or R, S are used to indicate the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use Come name compound linearly polarized light rotate symbol, (-) or l refer to compound be it is left-handed, prefix (+) or d refer to chemical combination Object is dextrorotation.The chemical structure of these stereoisomers is identical, but their stereochemical structure is different.It is specific vertical Body isomers can be enantiomer, and the mixture of isomers is commonly referred to as enantiomeric mixture.The enantiomer of 50:50 is mixed It closes object and is referred to as racemic mixture or racemic modification, this, which may cause in chemical reaction process, does not have stereoselectivity or solid Directionality.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack Optical activity.
Term " tautomer " or " tautomeric form " refer to that the isomer of the structure of different-energy can be with Pass through the mutual inversion of phases of low energy barrier.Such as proton tautomer (i.e. prototropic tautomer) includes passing through proton transfer Interconversion, such as the isomerization of keto-enol and imine-enamine.Valence (chemical valence) tautomer includes Recombinate the interconversion of bonding electrons.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document: S.M.Berge et al., Documented by J.Pharmaceutical Sciences, 66:1-19,1977.The salt that pharmaceutically acceptable nontoxic acid is formed It including, but is not limited to, inorganic acid salt formed by reacting with amino groups to form has a hydrochloride, hydrobromate, phosphate, sulfate, Perchlorate and acylate such as acetate, oxalates, maleate, tartrate, citrate, succinate, malonic acid Salt, or these salt are obtained by other methods described in the books or literature such as ion-exchange.Other are pharmaceutically acceptable Salt include adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, boric acid Salt, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonic acid Salt, formates, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproic acid Salt, hydriodate, 2- hydroxy-ethanesulfonate salt, lactobionate, lactate, laruate, lauryl sulfate, malate, Malonate, mesylate, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, mistake Sulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, tosilate, Undecylate, valerate, etc..Salt obtained by an appropriate base includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4 Salt.The compound that the present invention is also intended to contemplate the group of any included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or Dispersion product can be obtained by quaternization.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmacy Upper acceptable salt further comprises appropriate, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenation Object, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitric acid compound, C1-8Sulphonic acid compound and aromatic sulphonic acid compound.
" solvate " of the invention refers to that one or more solvent molecules and the compound of the present invention are formed by association Object.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
When term " blocking group " refers to a substituent group and other reacted with functional groups, commonly used to block or protect Protect special functionality.For example, " blocking group of amino " refers to that a substituent group is connected to block or protect with amino group The functionality of amino in compound, suitable amido protecting group include acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC), Benzyloxycarbonyl group (CBZ) and 9- fluorenes methylene oxygen carbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to that the substituent group of hydroxyl is used to The functionality of hydroxyl is blocked or protects, suitable blocking group includes acetyl group and silicyl." carboxy protective group " refers to The substituent group of carboxyl is used to block or protect the functionality of carboxyl, and general carboxyl-protecting group includes-CH2CH2SO2Ph, cyano second Base, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- (p-toluenesulfonyl) ethyl, 2- are (right Nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..Description general for blocking group can be joined Examine document: 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 The mostly dynamic obstacle of defect, be it is a kind of childhood very common psychataxia.According to " the general disease in the world of the World Health Organization Classification manual " the tenth edition (ICD-10, WHO, 1992) this disease be referred to as " hyperactivity disorder " (Hyperkinetic Disorder), Classification number is F90, general to be commonly called as again as " hyperactive children ".
Term " schizophrenia " refers to schizophrenia, schizophrenia-like disorder, schizoaffective disorder and spirit Characteristic of disease phrenoblabia, wherein term " mental disease " refers to vain hope, apparent illusion, amorphous language or unorganized behavior or deadlock Straightization behavior.Referring to Diagnostic and Statistical Manual of Mental Disorder, fourth edition, American Psychiatric Association, Washington, D.C..
The description of the compounds of this invention
Aromatic heterocyclic derivatives of the present invention, pharmaceutically acceptable salt and its pharmaceutical preparation have antagonism 5- HT6, especially have potential purposes to the treatment of Alzheimer's disease.
On the one hand, the present invention relates to a kind of compounds, are the solid of structure shown in structure shown in formula (I) or formula (I) Isomers, tautomer, nitrogen oxides, 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；
WhenWhen for singly-bound, X is CH or N；WhenWhen for double bond, X C；
R1For H, D, C1-6Alkyl, C3-8Naphthenic base, C1-6Halogenated alkyl ,-C (=O) R6,-C (=O) OR6,-C (=O) NR6R6a, R6R6aN-S (=O)2, R6S (=O)2, R6aR7N-C1-6Alkylidene, R6S (=O)-C1-6Alkylidene, R6R6aN-C (= O)-C1-6Alkylidene, C6-10Aryl, C1-9Heteroaryl, C6-10Aryl-C1-6Alkylidene or C1-9Heteroaryl-C1-6Alkylidene；
Each R2And R3It is separately H, D, F, Cl, Br, I, CN, NO2, OH, NH2, R6aR6N- ,-C (=O) R6,-C (= O)NR6R6a,-N (R6) C (=O)-R6a, R6R6aN-S (=O)2, R6S (=O)2, R6S (=O)2N(R6aWhat)-, hydroxyl replaced C1-6Alkyl, R6aR6N-C1-6Alkylidene, R6S (=O)-C1-6Alkylidene, R6R6aN-C (=O)-C1-6Alkylidene, R6aR6N-C1-6It is sub- Alkoxy, R6S (=O)-C1-6Alkylene oxide group, R6R6aN-C (=O)-C1-6Alkylene oxide group, C6-10Aryl, C1-9Heteroaryl, C1-6Alkane Oxygroup, C1-6Alkylamino, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Halogenated alkoxy, C2-6Alkenyl, C2-6Alkynyl, C3-8Naphthenic base, C1-6Alkylthio group, C6-10Aryl-C1-6Alkyl or C1-9Heteroaryl-C1-6Alkylidene,；Or two adjacent R2With the carbon being attached thereto Atom forms the former molecular carbocyclic ring of 5-6 optionally replaced, heterocycle, aromatic rings or heteroaromatic；
Each R4It independently is H, D, F, Cl, Br, I, CN, oxo (=O), C1-6Alkyl, C3-8Naphthenic base, C1-6Halogenated alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy or C6-10Aryl-C1-4Alkylidene；
R5For H, D, F, Cl, Br, I, CN, OH, NH2, C1-6Alkyl, C1-6Halogenated alkyl, C3-8Naphthenic base, C1-6Alkoxy ,-C (=O) R6,-C (=O) OR6,-C (=O) NR6R6a, C6-10Aryl or C6-10Aryl-C1-6Alkylidene；
Each R6And R6aIt independently is H, D, OH, NH2, C1-6Alkyl, C1-6Halogenated alkyl, C1-6Alkoxy or C6-10Aryl.
In some of these embodiments, R1For H, D, C1-4Alkyl, C3-6Naphthenic base or C6-10Aryl-C1-4Alkylidene.
In some of these embodiments, each R2And R3It is separately H, D, F, Cl, Br, I, OH, NH2, C1-4Alkyl, C3-6Naphthenic base, C1-4Alkoxy, C2-4Alkenyl, C2-4Alkynyl or C6-10Aryl；Or two adjacent R2With the carbon atom being attached thereto Form the former molecular aromatic rings of 5-6 optionally replaced.
In some of these embodiments, each R4It independently is H, D, C1-4Alkyl, C3-6Naphthenic base, C1-4Halogenated alkyl or C1-4Alkoxy.
In some of these embodiments, R5For H, D, F, Cl, Br, I ,-COOH, C1-4Alkyl, C3-6Naphthenic base, C6-10Virtue Base or C6-10Aryl-C1-4Alkylidene.
In some of these embodiments, the present invention has the vertical of structure shown in the structure as shown in formula (II) or formula (II) Body isomers, tautomer, nitrogen oxides, 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；
R1For H, D, C1-4Alkyl, C3-6Naphthenic base, C1-4Halogenated alkyl ,-C (=O) R6,-C (=O) OR6,-C (=O) NR6R6aOr C6-10Aryl-C1-4Alkylidene；
Each R2And R3It is separately H, D, F, Cl, Br, I, CN, OH, NH2, C1-4Alkyl, C3-6Naphthenic base, C1-4Alcoxyl Base, C2-4Alkenyl, C2-4Alkynyl or C6-10Aryl；Or two adjacent R2The 5-6 optionally replaced is formed with the carbon atom being attached thereto A molecular aromatic rings of original；
Each R4It independently is H, D, CN, C1-4Alkyl, C3-6Naphthenic base, C1-4Halogenated alkyl or C1-4Alkoxy；
R5For H, D, F, Cl, Br, I, C1-4Alkyl, C6-10Aryl or C6-10Aryl-C1-4Alkylidene；
Each R6And R6aIt independently is H, D, OH, NH2, C1-4Alkyl, C1-4Miscellaneous alkyl or C1-4Halogenated alkyl.
In some of these embodiments, R1For H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, uncle Butyl, cyclopropyl or cyclobutyl.
In other embodiments, each R2And R3It is separately H, D, F, Cl, Br, I, CN, OH, NH2, methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth Oxygroup, isobutoxy, tert-butoxy, cyclopropyl or cyclobutyl；Or two adjacent R2It is formed and is appointed with the carbon atom being attached thereto Choose the phenyl ring in generation.
In some of these embodiments, the present invention includes the structure of one of:
Or its stereoisomer, tautomer, nitrogen oxides, solvate, metabolism produce Object, pharmaceutically acceptable salt or prodrug.
The present invention also includes the application of the compound of the present invention and its pharmaceutically acceptable salt, for producing medical product Alzheimer's disease is treated, it is described in the invention including those.The compound of the present invention is equally used for producing a kind of pharmaceuticals For mitigating, prevent, control or treatment 5-HT6The illness mediated, especially Alzheimer's disease.The present invention includes medicine group Object is closed, which includes compound representated by formula formula (I) or formula (II) and at least one pharmaceutically acceptable load Effective treatment dosage needed for the combination of body, adjuvant or diluent.
Unless otherwise indicated, the stereoisomer that the compound of the present invention is all, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug belong to model of the invention It encloses.
Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes substance or composition must Must be suitble to chemistry or toxicologically, it is related with the other components of composition preparation and mammal for treatment.
The salt of the compound of the present invention further includes the intermediate for being used to prepare or purifying compound shown in formula (I) or formula (II) Or the salt of the enantiomter of the separation of compound shown in formula (I) or formula (II), but it is not necessarily pharmaceutically acceptable salt.
If the compound of the present invention be it is alkaline, conceivable salt can be by provided in the literature any suitable Method is prepared, for example, using inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or using organic Acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid；Pyrans Saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Amino acid, such as asparatate and paddy Propylhomoserin；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, ethanesulfonic acid, etc..
If the compound of the present invention be it is acid, conceivable salt can be prepared by suitable method, e.g., Using inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide or alkaline earth metal hydroxide, etc. Deng.Suitable salt includes, but is not limited to, organic salt obtained from amino acids, such as glycine and arginine, ammonia, and such as primaquine, secondary Ammonia and tertiary ammonia and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium Inorganic salts.
The compounds of this invention and pharmaceutical composition, preparation and administration
When available for treatment, the formula (I) of therapeutically effective amount or formula (II) compound and its pharmaceutically acceptable salt can It is given as unprocessed chemicals, the active constituent for being alternatively arranged as pharmaceutical composition provides.Therefore, present disclosure also mentions For pharmaceutical composition, the pharmaceutical composition include therapeutically effective amount formula formula (I) formula (II) compound or its can pharmaceutically connect The salt and one or more pharmaceutically acceptable carriers, diluent or excipient received.
It further comprise carrying out other to patient to resist comprising the treatment method that the compounds of this invention or pharmaceutical composition are administered The administration of Alzheimer disease drug (combination therapy), wherein the drug of other anti-Alzheimer diseases is selected from donepezil, receives Mei Fen, Risperidone, vitamin e, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX- 8066, SB-742457, naluzaton, Lu-AE58054, Tacrine, Rivastigmine, galanthamine, Memantine, mitzapine, Venlafaxine, desipramine, nortriptyline, zolpidem, zopiclone, Nicergoline, Piracetam, selegiline, pentoxifylline Alkali or their combination.
Term as used herein " therapeutically effective amount " refers to each active group for being enough to show significant patient benefit The total amount divided.When using separate active ingredients for separate administration, which only refers to the ingredient.When combining applications, the term Then refer to the combined amount for regardless of combination, sequential or simultaneous administration all causing the active constituent of therapeutic effect.(I) or formula (II) Compound and its pharmaceutically acceptable salt are as described above.From meaning compatible with preparation other compositions and harmless to its recipient From justice, carrier, diluent or excipient must be acceptable.According to another aspect of the present disclosure, use is also provided In the method for preparing pharmaceutical preparation, this method includes by formula (I) or formula (II) compound or its pharmaceutically acceptable salt and one Kind or a variety of pharmaceutically acceptable carriers, diluent or excipient mix.Term used in the present invention is " pharmaceutically acceptable " refer to such compound, raw material, composition and/or dosage form, they within the scope of reasonable medical judgment, be suitable for Patient tissue contact and without excessive toxicity, irritation, allergy or other problems relative to a reasonable benefit/risk ratio And complication, and effective for given application.
In general, the compound of the present invention is by any conventional application method of the substance for playing similar effectiveness to treat Effective quantity is administered.Suitable dosage range is typically daily 1-500mg, preferably daily 1-100mg, most preferably daily 1- 30mg, this depends on many factors, such as age and the relative health, institute of the seriousness of treated disease, subject With the effect of compound, the approach of application and form, the preference of the targeted indication and related medical practitioner of application and Experience.The those of ordinary skill for treating the disease areas relies on personal knowledge and disclosure of this application without excessive experiment It can determine that the therapeutically effective amount of the compounds of this invention for giving disease.
In general, the compound of the present invention is applied with pharmaceutical preparation form, the pharmaceutical preparation includes that those are suitable for taking orally (including oral cavity and sublingual), rectum, nose, part, lung, vagina or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and vein It is interior) application pharmaceutical preparation or the pharmaceutical preparation suitable for sucking or being blown into administration form.Preferred method of application is usually to take orally, Using suitable daily dose plan, it can be adjusted according to illness degree.
One or more compounds of the invention can be placed in together with one or more conventional adjuvants, carrying agent or diluent In pharmaceutical composition and unit dosage form.Pharmaceutical composition and unit dosage form may include the conventional ingredient of conventional ratio, With or without other reactive compound or ingredient, unit dosage form can contain and applied planned daily dose range phase Any suitable a effective amount of active constituent claimed.The application form of pharmaceutical composition can be solid such as tablet or filling glue Wafer, semisolid, powder, sustained release preparation or liquid such as solution, suspension, emulsion, elixir or the filling glue being administered orally Wafer；Or for rectum or the suppository form of vaginal application；Or the sterile injectable solutions form for parenterally using. Therefore, in every containing about 1mg active constituent or more broadly, the preparation containing about 0.01 to about 100mg active constituent is suitable Representative unit dosage form.
The compound of the present invention can be configured to the dosage form of various oral administrations.Pharmaceutical composition and dosage form can Using comprising one or more compound or pharmaceutically acceptable salt thereofs of the invention as active constituent.Pharmaceutical carrying agent can be solid Or liquid.The preparation of solid form includes: tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carries Body can be one or more substances, be also used as diluent, corrigent, solubilizer, lubricant, suspending agent, adhesive, Preservative, tablet disintegrant or coating material.In powder, carrier is usually finely ground solid, with finely ground active constituent Form mixture.In tablets, active constituent is usually mixed simultaneously with having the carrying agent of required adhesive force with the ratio for being suitable for It is pressed into required shapes and sizes.Powder and tablet preferably comprise from about the reactive compound of 1% to about 70%.Suitable carrying agent Including but not limited to carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl Cellulose, sodium carboxymethylcellulose, low melt wax, cocoa butter etc..Terms " formulation ", which is intended to include house, has coating material as cultivation Body is to provide the preparation of the reactive compound of capsule, and the active constituent of with or without carrier is tied therewith in the capsule The carrying agent closed is surrounded.It similarly, further include cachet and pastille.Tablet, powder, capsule, pill, cachet and pastille It is adapted for the solid form being administered orally.
Other forms for being suitable for being administered orally include preparation (including emulsion, syrup, elixir, the aqueous solution of liquid form Agent, aqueous suspension) or it is intended to preparation using the preceding solid form for being changed into liquid form preparation at once.Emulsion can be molten Emulsifier such as lecithin, Sorbitan Monooleate or Arab are prepared or can contained in liquid such as aqueous solution of propylene glycol Glue.Active constituent can be by being dissolved in water and suitable colorant, corrigent, stabilizer and thickening being added by aqueous solution agent It is prepared by agent.Aqueous suspension can be by with for example natural or synthetic glue of stickum, resin, methylcellulose, carboxymethyl Finely ground active constituent is dispersed in water to prepare by sodium cellulosate and other well known suspending agent.The preparation of liquid form includes Solution, suspension and emulsion, it can also contain colorant, corrigent, stabilizer, buffer, people other than active constituent Sweetener make and natural, dispersing agent, thickener, solubilizer etc..
The compound of the present invention can be prepared for parenteral administration (for example, passing through injection such as bolus injection or continuous defeated Note application) and can be present in a unit ampoule, in advance filling syringe, in low capacity infusion or be present in It is added in the multi-dose container of preservative.The adoptable form of composition has suspension for example in oily or aqueous excipients Agent, solution or emulsion, such as solution in polyethylene glycol solution.Oiliness or non-aqueous carrying agent, diluent, solvent or The example of excipient includes propylene glycol, polyethylene glycol, vegetable oil (such as olive oil) and organic esters for injection (such as oleic acid second Ester), and formulating substances such as preservative, wetting agent, emulsifier or suspending agent, stabilizer and/or dispersing agent can be contained.Alternatively, Active constituent can be powder type, preparation method be by sterile solid carry out without mattress dispense or by by solution be lyophilized so as to Using preceding with suitable excipient is for example sterile, pyrogen-free water is constructed.
The compound of the present invention can be prepared in the form of ointment, cream or lotion or in a form of transdermal patch office Portion is applied to epidermis.Ointment and cream can be for example with being added to the aqueous or oily of suitable thickener and/or gelling agent Property matrix is prepared.Lotion can be prepared with water or oily matrix and usually also contain one or more emulsifying agents, steady Determine agent, dispersing agent, suspending agent, thickener or colorant.Preparation suitable for topical application in the mouth includes comprising in flavoring base The pastille of matter, usually sucrose and the active constituent in Arabic gum or tragacanth；Comprising in inert base such as gelatin and The pastille of active constituent in glycerol or sucrose and Arabic gum；And comprising being in a suitable liquid carrier active constituent Collutory.
The compound of the present invention can be prepared for applying with suppository form.It can be first by low melt wax such as fatty acid glycerine Ester admixture or cocoa butter fusing, and active constituent is for example dispersed evenly by stirring.Then by the homogeneous mixture of melting It pours into the mold of suitable size, be allowed to cool and solidify.
The compound of the present invention can be prepared for vaginal application.Also contain carrying agent known in this field in addition to the active ingredient (s Vaginal plug, tampon, milk agent, gelling agent, paste, foaming agent or spray are suitable.
The compound of the present invention can be prepared for nasal administration.Can by solution or suspension by conventional method, example Such as nasal cavity is directly applied to dropper, suction pipe or sprayer.Preparation can be single dose or multiple dose form.For dropper or suction The multiple dose form of pipe, this can be realized by solution that be suitable for by patient's application, predetermined volume or suspension.For Sprayer, this can for example be realized by metering atomizing pump.
The compound of the present invention can be prepared for aerosol application, especially be applied to respiratory tract and including intranasally applying With.Compound usually has a small granularity, such as the granularity of 5 microns or more decimal magnitude.The granularity can pass through this field Well known method for example passes through micronization acquisition.Active constituent is to contain suitable propellant such as chlorofluorocarbon (CFC) such as dichloro The pressurized package of difluoromethane, trichlorofluoromethane or dichlorotetra-fluoroethane or carbon dioxide or other suitable gas provides.Gas Mist agent can also suitably contain surfactant such as lecithin.Drug dose can be controlled by metering valve.Alternatively, active constituent can With with dry powdered form, for example in suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methyl cellulose and The mixture of powders form of compound in polyvinylpyrrolidone provides.Powder carrier will form gel in nasal cavity.Powder Composition can be in a unit for example with gelatine capsule agent or cylindrantherae or bubble army's packaged form presence ' inhalator can be passed through By wherein applying powder.
When needing, preparation can be prepared with the enteric coating for being suitable for sustained release or controlled release application active constituent.For example, this The compound of invention can be formulated into transdermal or subcutaneous drug delivery device.When it is necessary to release the compound and work as patient for treatment When the compliance of scheme is most important, these delivery systems are advantageous.Compound in transdermal delivery system is often attached to In skin adhesive solid carrying agent.Compound of interest can also be with penetration enhancer, such as laurocapram (hole 1- 12 Base azacyclo- hept- 2- ketone) it is applied in combination.It can be inserted subcutaneously into a sustained release delivery system by surgery or injection hypodermic layer.Subcutaneously Compound is encapsulated in liquid soluble membrane, such as silicon rubber or Biodegradable polymeric such as polylactic acid for implantation material.
Pharmaceutical preparation is preferably unit dosage form.In the form, preparation is subdivided into containing appropriate amount active constituent Unit dose.Unit dosage form can be the preparation of packaging kit, the preparation containing discrete magnitude in packaging, such as complete packet The tablet of dress, capsule and powder or ampulla agent in the vial.In addition, unit dosage form can be capsule, tablet, flat Wafer or pastille itself or its any one of these form that can be suitable number in package form.
Other suitable medicinal carriers and their preparation are in Remington:The Science and Practice of Pharmacy 1995Martin, E.W are edited, Mack Publishing Company, and the 19th edition, Easton, It is described in Pennsylvania.
The purposes of the compounds of this invention and pharmaceutical composition
The feature of pharmaceutical composition of the invention includes listed by formula formula (I) or formula (II) compound represented or the present invention Compound and pharmaceutically acceptable carrier, adjuvant or excipient.Can there is the amount of compound in composition of the invention Imitate ground detectably antagonism 5-HT6To treat obesity, enterogastric diseases, CNS illness, wherein the CNS illness are as follows: ADHD, anxiety, disease relating to mental stress, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, nerve Illness, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntingdon dance Step disease etc..
" effective quantity " or " effective dose " of the compound of the present invention or pharmaceutically acceptable composition refer to processing or Mitigate the effective quantity that one or more present invention are previously mentioned the severity of illness.According to the method for the present invention, compound and combination Object can be any dosage and any administration route to be efficiently used for handling or mitigate the severity of disease.Required standard True amount will change according to the case where patient, this is depending on ethnic, the age, the general condition of patient, the severity of infection, Special factor, administration mode, etc..Compound or composition can be administered in combination with one or more other therapeutic agents, such as What the present invention was discussed.
The general synthetic method of the compounds of this invention
Generally, the compound of the present invention described method can be prepared through the invention, unless there are further Explanation, wherein the definition of substituent group is as shown in formula (i) or formula (ii).Following reaction scheme and embodiment is for further lifting Example illustrates the contents of the present invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent purchase is in quotient Product supplier such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all without by not being further purified when use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Imperial chemistry examination is risen in factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, tianjin haoyuyu chemicals co., ltd., Qingdao Agent Co., Ltd and Haiyang Chemical Plant, Qingdao are commercially available.
Anhydrous tetrahydro furan is dried to obtain by sodium metal reflux.Anhydrous methylene chloride and chloroform are returned by calcium hydride Stream is dried to obtain.Ethyl acetate, petroleum ether, n,N-dimethylacetamide and n,N-Dimethylformamide are through anhydrous sodium sulfate thing It is first dry to use.
Reaction is usually to cover a drying tube under positive pressure of nitrogen or argon or on anhydrous solvents (unless other aspects below Show), reaction flask all squeezed by syringe beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is using silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC13,DMSO-d6, CD3OD or acetone-d6It (is reported as unit of ppm) for solvent, with TMS (0ppm) or chloroform (7.25 Ppm) it is used as reference standard.When there is multiplet, following abbreviation: s (singlet, unimodal), d will be used (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, with hertz (Hz) it indicates.
The determination condition of low resolution mass spectrometry (MS) data is: 6120 level four bars HPLC-M of Agilent (column model: ZorbaxSB-C18,2.1x30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase: 5%-95% (contains 0.1% first The CH of acid3CN) in (H containing 0.1% formic acid2O the ratio in)), using electrospray ionisation (ESI), at 210nm/254nm, use UV detection.
Pure compound uses Agilent 1260pre-HPLC or Calesep pump 250pre-HPLC (pillar type Number: NOVASEP 50/80mm DAC), detected in 210nm/254nm with UV.
The use of logogram word below is through the present invention:
HOAc acetic acid
NaOAc sodium acetate
MeCN, CH3CN acetonitrile
Cl3C2OCl trichloro-acetic chloride
CHCl3Chloroform
CDC13Deuterated chloroform
ClSO2OH chlorosulfonic acid
DMF N,N-dimethylformamide
EtOAc/EA ethyl acetate
HCl hydrochloric acid
MgSO4Magnesium sulfate
MgCl2Magnesium chloride
MeOH,CH3OH methanol
HCHO formaldehyde
CH2Cl2, DCM methylene chloride
ML, ml milliliters
PE petroleum ether (60-90 DEG C)
Na2CO3Sodium carbonate
NaHCO3Sodium bicarbonate
KOH potassium hydroxide
RT rt room temperature
Rt retention time
NaBH3CN sodium cyanoborohydride
NaCl sodium chloride
NaH sodium hydride
Na2SO4Sodium sulphate
THF tetrahydrofuran
C2H7.HCl dimethylamine hydrochloride
Et3N, TEA triethylamine
H2O water
CH3COCH3Acetone
PCl5Phosphorus pentachloride
TsCl paratoluensulfonyl chloride
EDTA ethylenediamine tetra-acetic acid
PEI polyethyleneimine
Pargyline Pargyline
Tris-HCl tri- (methylol) aminomethane-hydrochloric acid
Following synthetic schemes describes the step of preparation disclosed compound of present invention.Unless otherwise stated, each k, R1, R3With R5With definition as described in the present invention.
Synthetic method 1
With such as formula (3) and (4) shown in the disclosed compound of present invention of structure can be by one described in synthetic schemes 1 As synthetic method be prepared, specific steps can refer to embodiment.In synthetic schemes 1, formula (1) compound represented and sulphonyl Chlorine obtain in the presence of alkali formula (2) compound represented.Formula (2) compound represented formula is under the action of alkali (potassium hydroxide) Obtain formula (3) shown in remove tribromo-acetyl based products, formula (3) compound represented further obtains with aldehyde or halohydrocarbons reaction Formula (4) shown in alkylate.
Synthetic method 2
With such as formula (6) and (7) shown in the disclosed compound of present invention of structure can be by one described in synthetic schemes 1 As synthetic method be prepared, specific steps can refer to embodiment.In synthetic schemes 2, formula (1) compound represented and naphthalene sulphur Acyl chlorides obtain in the presence of alkali formula (5) compound represented.Formula (5) compound represented formula alkali (potassium hydroxide) effect Under obtain formula (6) shown in remove tribromo-acetyl based products, formula (6) compound represented further obtains with aldehyde or halohydrocarbons reaction To formula (7) shown in alkylate.With reference to embodiments to compound provided by the invention, pharmaceutical composition and its application It is further described.
Embodiment
The synthesis of 1 1- of embodiment ((4- methoxyl group -3- (piperazine -1- base) phenyl) sulfonyl) -1H- benzo [d] imidazoles
The synthesis of the chloro- 1- of step 1) 2,2,2- tri- (4- (2- methoxyphenyl) piperazine -1- base) ethyl ketone
1- (2- methoxyphenyl) piperazine hydrochloride (1.0g, 4.39mmol) and triethylamine (2.5mL, 17.70mmol) are added Enter in methylene chloride (15mL), under 0 DEG C of low temperature bath, trichloro-acetic chloride (1.0mL, 8.96mmol) is slowly added dropwise, after dripping, It is transferred at 25 DEG C and reacts 24 hours, stop reaction, 50mL methylene chloride is added, is washed with saturated sodium bicarbonate solution (40mL), Organic phase is dry with anhydrous sodium sulfate after liquid separation.Filtering, filtrate decompression is spin-dried for, crude product be purified by silica gel column chromatography (petroleum ether/ Ethyl acetate (v/v)=10/1), obtaining title compound is faint yellow solid (763mg, 52%).
MS(ESI,pos.ion)m/z:337.0[M+H]+；
1H NMR(400MHz,CDCl3)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).
The synthesis of step 2) 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride
The chloro- 1- of 2,2,2- tri- (4- (2- methoxyphenyl) piperazine -1- base) ethyl ketone (550mg, 1.63mmol) is dissolved in 5mL It in methylene chloride, then in the case where 0 DEG C of low temperature is bathed, is added drop-wise in 3mL chlorosulfonic acid, after reaction 1 hour, introduces the reaction solution to ice water In the mixed liquor of (30mL) and methylene chloride (50mL), it is vigorously stirred rear liquid separation, organic phase is dry with anhydrous magnesium sulfate.Filtering, Filtrate decompression is spin-dried for being faint yellow solid (548mg, 78.5%) to title compound.
MS(ESI,pos.ion)m/z:435.0[M+H]+；
1H NMR(400MHz,CDCl3) 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) 1- (4- (5- ((1H- benzo [d] imidazoles -1- base) sulfonyl) -2- methoxyphenyl) piperazine -1- base) - The synthesis of 2,2,2- trichloroacetone
Benzo [d] imidazoles (295mg, 2.5mmol) and sodium hydride (100mg, 2.5mmol) are added to DMF at 0 DEG C In (6mL), it is then slowly added into 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) benzene -1- sulfonic acid chloride (1.2g,2.75mmol).Reaction after ten minutes, is warming up to 25 DEG C, the reaction was continued 2 hours.100mL ethyl acetate is added, then (30mL x 3) is washed with saturated sodium chloride solution, organic phase is dry with anhydrous sodium sulfate after liquid separation.Filtering, filtrate decompression are spin-dried for, Crude product is purified by silica gel column chromatography (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,CDCl3)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).
The synthesis of step 4) 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- trichloroacetones (1.19g, 2.30mmol) are dissolved in tetrahydrofuran (20mL), are then slowly added into potassium hydroxide (281mg, 5.02mmol are made into 1mmol/ml aqueous solution).After reaction solution is stirred to react 24 hours, 60ml methylene chloride is added； Organic phase washes (30mL x 3) with saturated sodium chloride solution, and organic phase is dry with anhydrous sodium sulfate after liquid separation.Filtering, filtrate is subtracted Pressure is spin-dried for, and crude product is purified by silica gel column chromatography (methylene chloride/methanol (v/v)=20/1), obtains title compound as white Solid (291mg, 34%).
MS(ESI,pos.ion)m/z:373.2[M+H]+；
1H NMR(400MHz,CDCl3) 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,CDCl3)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。
2 1- of embodiment ((4- methoxyl group -3- (piperazine -1- base) phenyl) sulfonyl) -2- methyl-1 H- benzo [d] imidazoles Synthesis
The chloro- 1- of step 1) 2,2,2- tri- (4- (2- methoxyl group -5- ((2- methyl-1 H- benzo [d] imidazoles -1- base) sulphonyl Base) phenyl) piperazine -1- base) and ethyl ketone synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- methyl benzo miaow Azoles (290mg, 2.20mmol), sodium hydride (90mg, 2.25mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine Piperazine -1- base) benzene -1- sulfonic acid chloride (1.05g, 2.41mmol) reaction preparation in DMF (6mL), crude product is through silica gel column chromatography (stone Oily ether/ethyl acetate (v/v)=4/1) purifying, it is white solid (1.02g, 87%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:533.1[M+H]+；
1H NMR(400MHz,CDCl3) 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) 1- ((4- methoxyl group -3- (piperazine -1- base) phenyl) sulfonyl) -2- methyl-1 H- benzo [d] imidazoles Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (2- methoxyl group -5- ((2- methyl-1 H- benzo [d] imidazoles -1- base) sulfonyl) phenyl) piperazine -1- base) ethyl ketone (347mg, 0.65mmol), potassium hydroxide (80mg, 1.41mmol are made into 1mmol/ml aqueous solution) are in tetrahydrofuran (20mL) Reaction preparation, crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), and concentrate drying obtains titled Conjunction object is white solid (181mg, 72%).
MS(ESI,pos.ion)m/z:387.0[M+H]+；
1H NMR(400MHz,CDCl3) 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,CDCl3)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。
Embodiment 31- ((4- methoxyl group -3- (4- methylpiperazine-1-yl) phenyl) sulfonyl) -2- methyl-1 H- benzo [d] The synthesis of imidazoles
By 1- ((4- methoxyl group -3- (piperazine -1- base) phenyl) sulfonyl) -2- methyl-1 H- benzo [d] imidazoles (386mg, It 1mmol) is dissolved in methanol (10mL), two drop acetic acid is added.At 0 DEG C, by sodium cyanoborohydride (188.3mg, 3mmol) and first Aldehyde (40%, 225 μ L, 3mmol) is slowly added into reaction solution.Reaction after ten minutes, is warming up to 25 DEG C；The reaction was continued 5 hours Afterwards, 10mL water is added and sodium carbonate (370mg, 3.5mmol) is quenched, (50mL x 3) is then extracted with dichloromethane.It is associated with Machine phase, anhydrous sodium sulfate are dry；Filtering, filtrate decompression is spin-dried for, crude product through silica gel column chromatography (methylene chloride/methanol (v/v)= 50/1) it purifies, obtaining title compound is white solid (328mg, 82%).
MS(ESI,pos.ion)m/z:401.1[M+H]+；
1H NMR(600MHz,CDCl3) 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,CDCl3)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。
4 1- of embodiment ((3- (4- ethyl piperazidine -1- base) -4- methoxyphenyl) sulfonyl) -2- methyl-1 H- benzo The synthesis of [d] imidazoles
By 1- ((4- methoxyl group -3- (piperazine -1- base) phenyl) sulfonyl) -2- methyl-1 H- benzo [d] imidazoles (386mg, 1mmol)、K2CO3(276mg, 2mmol), bromoethane (3mmol, 224 μ L) are added in acetone (10mL), are continued at 25 DEG C anti- It answers 20 hours；Stop reaction, is added methylene chloride (40mL), is washed with saturated sodium chloride solution (40mL)；Organic phase is used after liquid separation Anhydrous sodium sulfate is dry；Filtering, filtrate decompression are spin-dried for, and crude product is through silica gel column chromatography (methylene chloride/methanol (v/v)=50/1) Purifying, obtaining title compound is white solid (360mg, 87%).
MS(ESI,pos.ion)m/z:415.0[M+H]+；
1H NMR(600MHz,CDCl3) 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,CDCl3)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。
5 1- of embodiment ((3- (4- cyclopropylpiperazin -1- base) -4- methoxyphenyl) sulfonyl) -2- methyl-1 H- benzo The synthesis of [d] imidazoles
By 1- ((4- methoxyl group -3- (piperazine -1- base) phenyl) sulfonyl) -2- methyl-1 H- benzo [d] miaow at 25 DEG C Azoles (386mg, 1mmol) is dissolved in methanol (10mL), is added acetic acid (5mmol, 300 μ L), then by sodium cyanoborohydride (188.3mg, 3mmol) and 1- ethyoxyl -1- trimethylsilyl cyclopropane (2mmol, 432 μ L) are slowly added into reaction solution； After the reaction was continued 12 hours, water (10mL) is added and sodium carbonate (370mg, 3.5mmol) is quenched, is then extracted with dichloromethane (50mL x 3).Merge organic phase, anhydrous sodium sulfate is dry；Filtering, filtrate decompression are spin-dried for, and crude product is through silica gel column chromatography (stone Oily ether/ethyl acetate (v/v)=3/1) purifying, obtaining title compound is white solid (128mg, 30%).
MS(ESI,pos.ion)m/z:427.1[M+H]+；
1H NMR(600MHz,CDCl3) 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,CDCl3)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。
6 2- ethyl -1- of embodiment ((4- methoxyl group -3- (piperazine -1- base) phenyl) sulfonyl) -1H- benzo [d] imidazoles Synthesis
The chloro- 1- of step 1) 2,2,2- tri- (4- (5- ((2- ethyl -1H- benzo [d] imidazoles -1- base) sulfonyl) -2- methoxy Base phenyl) piperazine -1- base) ethyl ketone synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- ethyl benzo [d] imidazoles (450mg, 3.1mmol), sodium hydride (128mg, 3.2mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) Piperazine -1- base) benzene -1- sulfonic acid chloride (1.48g, 3.4mmol) reaction preparation in DMF (6mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, it is white solid (1.25g, 74%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:547.1[M+H]+；
1H NMR(400MHz,CDCl3) 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) 2- ethyl -1- ((4- methoxyl group -3- (piperazine -1- base) phenyl) sulfonyl) -1H- benzo [d] imidazoles Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (5- ((2- ethyl -1H- benzo[d]Imidazoles -1- base) sulfonyl) -2- methoxyphenyl) piperazine -1- base) ethyl ketone (600mg, 1.09mmol), potassium hydroxide (130mg, 2.32mmol are made into 1mmol/ml aqueous solution) are at tetrahydrofuran (10mL) Middle reaction preparation, crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), and concentrate drying obtains title Compound is white solid (380mg, 87%).
MS(ESI,pos.ion)m/z:401.2[M+H]+；
1H NMR(CDCl3, 400MHz) δ 8.07-8.05 (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(CDCl3,100MHz):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 conjunction of 7 1- of embodiment ((4- methoxyl group -3- (piperazine -1- base) naphthalene -1- base) sulfonyl) -1H- benzo [d] imidazoles At
The synthesis of the chloro- 1- of step 1) 2,2,2- tri- (4- (1- methoxynaphthalene -2- base) piperazine -1- base) Acetolon
1- (1- methoxynaphthalene -2- base) piperazine (680mg, 2.81mmol) and triethylamine (1.12mL, 8.42mmol) are added Enter in methylene chloride (15mL), under 0 DEG C of low temperature bath, trichloro-acetic chloride (0.47mL, 4.21mmol) is slowly added dropwise, drips Afterwards, it is transferred at 25 DEG C and reacts 24 hours, stop reaction, 50mL methylene chloride is added, with saturated sodium bicarbonate solution (40mL) It washes, organic phase is dry with anhydrous sodium sulfate after liquid separation.Filtering, filtrate decompression is spin-dried for, crude product through silica gel column chromatography (petroleum ether/ Ethyl acetate (v/v)=20/1) purifying, obtaining title compound is faint yellow solid (788mg, 72.3%).
MS(ESI,pos.ion)m/z:387.9[M+H]+；
1H NMR(600MHz,CDCl3) 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)。
The synthesis of step 2) 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) naphthalene -1- sulfonic acid chloride
The chloro- 1- of 2,2,2- tri- (4- (1- methoxynaphthalene -2- base) piperazine -1- base) ethyl ketone (782mg, 2.02mmol) is dissolved in In methylene chloride (5mL), then in the case where 0 DEG C of low temperature is bathed, chlorosulfonic acid (352.9mg, 3.03mmol) is slowly added dropwise, then at 25 DEG C After reaction 24 hours, it is added phosphorus pentachloride (624mg, 3.0mmol), continues to be stirred to react 5 hours, introduce the reaction solution to ice water In the mixed liquor of (30mL) and methylene chloride (50mL), it is vigorously stirred rear liquid separation, organic phase is dry with anhydrous magnesium sulfate.Filtering, Filtrate decompression is spin-dried for being faint yellow solid (595mg, 60.7%) to title compound.
MS(ESI,pos.ion)m/z:486.9[M+H]+；
1H NMR(600MHz,CDCl3) 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) 1- (4- (4- ((1H- benzo [d] imidazoles -1- base) sulfonyl) -1- methoxynaphthalene -2- base) piperazine -1- Base) -2,2,2- trichloroacetone synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by benzo [d] imidazoles (100mg, 0.85mmol), sodium hydride (36mg, 0.90mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) piperazine - 1- yl) naphthalene -1- sulfonic acid chloride (453mg, 0.93mmol) reaction preparation in DMF (5mL), crude product is through silica gel column chromatography (petroleum Ether/ethyl acetate (v/v)=4/1) purifying, it is yellow solid (261mg, 54%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:569.0[M+H]+；
1H NMR(400MHz,CDCl3) 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)。
The synthesis of step 4) 1- ((4- methoxyl group -3- (piperazine -1- base) naphthalene -1- base) sulfonyl) -1H- benzo [d] imidazoles
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., by 1- (4- (4- ((1H- benzo[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 are made into 1mmol/ml aqueous solution) are in tetrahydrofuran (20mL) Reaction preparation, crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), and concentrate drying obtains titled Conjunction object is yellow solid (101mg, 52%).
MS(ESI,pos.ion)m/z:423.1[M+H]+；
1H NMR(400MHz,CDCl3) 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,CDCl3)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。
8 1- of embodiment ((4- methoxyl group -3- (piperazine -1- base) naphthalene -1- base) sulphonyl) -2- methyl-1 H- benzo [d] imidazoles Synthesis
The chloro- 1- of step 1) 2,2,2- tri- (4- (1- methoxyl group -4- ((2- methyl-1 H- benzo [d] imidazoles -1- base) sulphonyl Base) naphthalene -2- base) piperazine -1- base) and ethyl ketone synthesisThis step title compound method system referring to described in 1 step 3 of embodiment It is standby to obtain, i.e., by 2- methyl benzo [d] imidazoles (500mg, 3.79mmol), sodium hydride (160mg, 4.0mmol), 4- methoxyl group- The reaction in DMF (8mL) of 3- (4- (2,2,2- trichloroacetyl) piperazine -1- base) naphthalene -1- sulfonic acid chloride (1.84g, 3.79mmol) Preparation, crude product are purified through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1), and concentrate drying obtains title compound For yellow solid (1.68g, 76%).
MS(ESI,pos.ion)m/z:581.0[M+H]+；
1H NMR(400MHz,CDCl3) 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) 1- ((4- methoxyl group -3- (piperazine -1- base) naphthalene -1- base) sulphonyl) -2- methyl-1 H- benzo [d] imidazoles Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (4- (1- methoxyl group -4- ((2- methyl-1 H- benzo [d] imidazoles -1- base) sulphonyl) naphthalene -2- base) piperazine -1- base) ethyl ketone (1.6g, 2.75mmol), potassium hydroxide (308mg, 5.5mmol are made into 1mmol/ml aqueous solution) are in tetrahydrofuran (30mL) Reaction preparation, crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), and concentrate drying obtains titled Conjunction object is yellow solid (1.07g, 89%).
MS(ESI,pos.ion)m/z:438.1[M+H]+；
1H NMR(600MHz,CDCl3) 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,CDCl3)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。
9 1- of embodiment ((4- methoxyl group -3- (4- methylpiperazine-1-yl) naphthalene -1- base) sulfonyl) -2- methyl-1 H- benzene And the synthesis of [d] imidazoles
By 1- ((4- methoxyl group -3- (piperazine -1- base) naphthalene -1- base) sulphonyl) -2- methyl-1 H- benzo [d] imidazoles (437mg, 1mmol) is dissolved in methanol (10mL), and two drop acetic acid are added.At 0 DEG C, by sodium cyanoborohydride (188.3mg, 3mmol) it is slowly added into reaction solution with formaldehyde (40%, 225 μ L, 3mmol).Reaction after ten minutes, is warming up to 25 DEG C；Continue After reaction 5 hours, 10mL water is added and sodium carbonate (370mg, 3.5mmol) is quenched, (50mL x is then extracted with dichloromethane 3).Merge organic phase, anhydrous sodium sulfate is dry；Filtering, filtrate decompression are spin-dried for, and crude product is purified by silica gel column chromatography (dichloromethane Alkane/methanol (v/v)=50/1) purifying, obtaining title compound is yellow solid (436mg, 97%).
MS(ESI,pos.ion)m/z:451.1[M+H]+；
1H NMR(600MHz,CDCl3) 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,CDCl3)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。
10 1- of embodiment ((3- (4- ethyl piperazidine -1- base) -4- methoxynaphthalene -1- base) sulfonyl) -2- methyl-1 H- benzene And the synthesis of [d] imidazoles
By 1- ((4- methoxyl group -3- (piperazine -1- base) naphthalene -1- base) sulphonyl) -2- methyl-1 H- benzo [d] imidazoles (437mg,1mmol)、K2CO3(276mg, 2mmol), bromoethane (3mmol, 224 μ L) are added in acetone (10mL), at 25 DEG C It is lower that the reaction was continued 20 hours；Stop reaction, is added methylene chloride (40mL), is washed with saturated sodium chloride solution (40mL)；After liquid separation Organic phase is dry with anhydrous sodium sulfate；Filtering, filtrate decompression are spin-dried for, and crude product is through silica gel column chromatography (methylene chloride/methanol (v/ V) it=50/1) purifies, obtaining title compound is yellow solid (264mg, 57%).
MS(ESI,pos.ion)m/z:465.0[M+H]+；
1H NMR(600MHz,CDCl3) 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,CDCl3)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。
11 1- of embodiment ((3- (4- cyclopropylpiperazin -1- base) -4- methoxyphenyl) sulfonyl) -2- methyl-1 H- benzene And the synthesis of [d] imidazoles
By 1- ((4- methoxyl group -3- (piperazine -1- base) naphthalene -1- base) sulphonyl) -2- methyl-1 H- benzo [d] miaow at 25 DEG C Azoles (437mg, 1mmol) is dissolved in methanol (10mL), is added acetic acid (5mmol, 300 μ L), then by sodium cyanoborohydride (188.3mg, 3mmol) and 1-Ethyoxyl-1-Trimethylsilyl cyclopropane (2mmol, 432 μ L) is slowly added into reaction solution； After the reaction was continued 12 hours, 10mL water is added and sodium carbonate (370mg, 3.5mmol) is quenched, is then extracted with dichloromethane (50mL x 3).Merge organic phase, anhydrous sodium sulfate is dry；Filtering, filtrate decompression are spin-dried for, and crude product is through silica gel column chromatography (stone Oily ether/ethyl acetate (v/v)=3/1) purifying, obtaining title compound is white solid (233mg, 49%).
MS(ESI,pos.ion)m/z:477.1[M+H]+；
1H NMR(600MHz,CDCl3) 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,CDCl3)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。
12 2- ethyl -1- of embodiment ((4- methoxyl group -3- (piperazine -1- base) naphthalene -1- base) sulphonyl) -1H- benzo [d] miaow The synthesis of azoles
The chloro- 1- of step 1) 2,2,2- tri- (4- (4- ((2- ethyl -1H- benzimidazole -1- base) sulfonyl) -1- methoxyl group Naphthalene -2- base) piperazine -1- base) ethyl ketone synthesis
This step title compound method referring to described in 1 step 3 of embodiment is prepared, i.e., by 2- ethyl benzo [d] imidazoles (120mg, 0.82mmol), sodium hydride (36mg, 0.9mmol), 4- methoxyl group -3- (4- (2,2,2- trichloroacetyl) Piperazine -1- base) naphthalene -1- sulfonic acid chloride (400mg, 0.82mmol) reaction preparation in DMF (4mL), crude product is through silica gel column chromatography (petrol ether/ethyl acetate (v/v)=4/1) purifying, it is yellow solid (166mg, 34%) that concentrate drying, which obtains title compound,.
MS(ESI,pos.ion)m/z:595.1[M+H]+；
1H NMR(400MHz,CDCl3) 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) 2- ethyl -1- ((4- methoxyl group -3- (piperazine -1- base) naphthalene -1- base) sulfonyl) -1H- benzo [d] imidazoles Synthesis
This step title compound method referring to described in 1 step 4 of embodiment is prepared, i.e., chloro- by 2,2,2- tri- 1- (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 are made into 1mmol/ml aqueous solution) are at tetrahydrofuran (10mL) Middle reaction preparation, crude product are purified through silica gel column chromatography (methylene chloride/methanol (v/v)=10/1), and concentrate drying obtains title Compound is yellow solid (166mg, 71%).
MS(ESI,pos.ion)m/z:451.1[M+H]+；
1H NMR(400MHz,CDCl3) 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,CDCl3)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 carries out biologic test to formula (I) or formula (II) compound represented using following methods:
1. with radio ligand binding assay evaluation compound to the source of people 5-HT being expressed on CHO cells6The parent of receptor And power
The 32 μ g expression prepared there is into source of people 5-HT6The CHO cell membrane protein of receptor, 2nM radioactively labelled substance [3H] LSD, the compound of different test concentrations and test buffer are uniformly mixed, and 37 DEG C are incubated for 120 minutes；Test buffer ingredient Are as follows: 50mM Tris-HCl (pH 7.4), 10mM MgCl2, 0.5mM EDTA, 10 μM of Pargylines and 20mg/l protease inhibit Agent.
100 μM of 5-HT removal nonspecific binding sites are added.After incubation, above-mentioned mixed liquor is used under vacuum conditions Glass filter filtering, filter are first presoaked with 0.3%PEI before filtration.It is rinsed several times with 50mM Tris-HCl again after filtering. After the filter is dry, radioactivity is counted on the scintillometer with scintillation mixed solution.Standard reference compounds are 5-HT, each real Several concentration are tested in testing to obtain its competition inhibition curve and calculate IC50。
Radio ligand binding assay is carried out to compound provided in an embodiment of the present invention according to the method described above and evaluates chemical combination Object is to the source of people 5-HT being expressed on CHO cells6The affinity determination of receptor, as a result referring to table 1, table 1 is the embodiment of the present invention The affinity measurement result of offer.
The affinity measurement result of the compound provided in an embodiment of the present invention of table 1
Example No. IC50(nM) Example No. IC50(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 is thin in CHO to expressing in radio ligand binding assay evaluation compound Source of people 5-HT on born of the same parents6Higher activity is generally shown in the affinity test of receptor.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example " " is specifically shown The description of example " or " some examples " etc. means specific features described in conjunction with this embodiment or example, structure, material or feature It is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms need not It must be directed to identical embodiment or example.Moreover, the specific features of description, structure, material or feature can be any It can be combined in any suitable manner in a or multiple embodiment or examples.In addition, without conflicting with each other, the technology of this field The feature of different embodiments or examples described in this specification and different embodiments or examples can be combined by personnel And combination.
Although the embodiments of the present invention has been shown and described above, it is to be understood that above-described embodiment is example Property, it is not considered as limiting the invention, those skilled in the art within the scope of the invention can be to above-mentioned Embodiment is changed, modification, replacement and variant.

Claims (12)

1. a kind of compound is the pharmaceutically acceptable salt of structure shown in structure shown in formula (II) or formula (II),
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；
R1For H, D, C1-4Alkyl, C3-6Naphthenic base, C1-4Halogenated alkyl or-C (=O) R6；
Each R2It independently is methoxyl group；Or two adjacent R25-6 optionally replaced can be formed with the carbon atom being attached thereto Former molecular aromatic rings or heteroaromatic；
Each R3It independently is H, D, F, Cl, Br, I, CN, OH, NH2, C1-4Alkyl, C3-6Naphthenic base or C1-4Alkoxy；
Each R4It independently is H, D or C1-4Alkyl；
R5For H, D, F, Cl, Br, I or C1-4Alkyl；
Each R6It independently is C1-4Halogenated alkyl.
2. compound according to claim 1, wherein R1For H, D, methyl, ethyl, n-propyl, isopropyl, normal-butyl is different Butyl, tert-butyl, cyclopropyl or cyclobutyl.
3. compound according to claim 1, wherein each R2It independently is methoxyl group；Or two adjacent R2Phase therewith Carbon atom even can form the phenyl ring optionally replaced；
Each R3It independently is H, D, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, Tert-butyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, cyclopropyl or ring Butyl.
4. compound according to claim 1, the structure with one of:
Or its pharmaceutically acceptable salt.
5. a kind of pharmaceutical composition includes compound and pharmaceutically acceptable carrier described in claim 1-4 any one, Excipient or their combination.
6. pharmaceutical composition according to claim 5, wherein further including additional therapeutic agent, these additional treatments Agent is the drug for treating nervous disorders.
7. pharmaceutical composition according to claim 6, wherein the additional therapeutic 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), galanthamine (galantamine), Memantine (memantine), mitzapine (Mirtazapine), Venlafaxine (venlafaxine), desipramine (desipramine), Nortriptyline (nortriptyline), zolpidem (zolpidem), zopiclone (zopiclone), Nicergoline (nicergoline), Piracetam (piracetam), selegiline (selegiline), pentoxifylline (pentoxifylline) or their combination.
8. a kind of use medicine group described in compound described in claim 1-4 any one or claim 5-7 any one It closes object and is used for treatment or prevention and 5-HT to prepare6Purposes in the drug of related disease.
9. purposes according to claim 8, wherein described and 5-HT6Related disease is CNS illness.
10. purposes according to claim 9, wherein the CNS illness includes: ADHD, anxiety is related to stress Disease, schizophrenia, besetment and behavior disorder, manic-depressive psychosis, memory disorders, attention deficit disorder, pa gold Gloomy disease, amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's chorea.
11. purposes according to claim 8, wherein described and 5-HT6Related disease is disorder of gastrointestinal tract.
12. purposes according to claim 8, wherein described and 5-HT6Related disease is obesity.
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CN105085436B (en) 2014-04-19 2019-08-16 广东东阳光药业有限公司 Sulfonic acid amide derivatives and its application on drug
CN105541693B (en) 2014-07-08 2018-10-16 广东东阳光药业有限公司 Aromatic heterocyclic derivatives and its application on drug
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