CN101309905A - Substituted isoindolones and their use as metabotropic glutamate receptor potentiators - Google Patents
Substituted isoindolones and their use as metabotropic glutamate receptor potentiators Download PDFInfo
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- CN101309905A CN101309905A CNA2006800353774A CN200680035377A CN101309905A CN 101309905 A CN101309905 A CN 101309905A CN A2006800353774 A CNA2006800353774 A CN A2006800353774A CN 200680035377 A CN200680035377 A CN 200680035377A CN 101309905 A CN101309905 A CN 101309905A
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Abstract
Compounds of formula (I), wherein R<1> is a ring, n is 1 to 8, and uses of the compounds in therapy as metabotropic glutamate receptors modulators, particularly in neurological and psychiatric disorders.
Description
The cross reference of related application
The application is relevant with the PCT application PCT/US05/28760 that submitted on August 12nd, 2005, and it is attached to herein by reference in full.
Background of invention
The application relates to performance as new compound, its preparation method of the function of glutamate receptor potentiators, the medicinal compositions that contains them and the purposes in treatment thereof.
Metabotropic glutamate receptor (mGluR) belongs to GTP-conjugated protein (G-albumen) coupled receptor family, and it is activated by L-glutamic acid, and in central nervous system, comprises in the cynapse activity of neural plasticity, neurodevelopment and neurodegeneration aspect playing an important role.
The activation of mGluRs in intact mammalian nervous unit produces one or more following responses: the activation of Phospholipase C; The increase of phosphoinositide (PI) hydrolysis; Intracellular Ca2+ discharges; The activation of phosphatidase D; The activation of adenylate cyclase and inhibition; Increase or minimizing that 3'5'-AMP (cAMP) forms; The activation of guanylyl (guanylyl) cyclase; The increase that cyclic guanosine monophosphate one phosphoric acid (cGMP) forms; Phosphide enzyme A
2Activation; The increase that arachidonic acid discharges; And voltage-and the active of part-gated ion channel increase or reduce (Schoepp etc., 1993, Trends Pharmacol.Sci., 14:13; Schoepp, 1994, Neurochem.Int., 24:439; Pin etc., 1995, Neuropharmacology 34:1; Bordi ﹠amp; Ugolini, 1999, Prog.Neurobiol.59:55).
8 kinds of mGluR hypotypes have been identified.Connect and the pharmacology collection of illustrative plates according to original series similarity, information conduction, these hypotypes are divided into three groups.The I group comprises mGluR1 and mGluR5, and it activates the generation of Phospholipase C and intracellular calcium signal.II group (mGluR2 and mGluR3) and III group (mGluR4, mGluR6, mGluR7 and mGluR8) mGluRs regulate the restraining effect of adenylyl cyclase activity and ring AMP level.Be to look back, referring to Pin etc., 1999, Eur.J.Pharmacol., 375:277-294.
The activity of mGluR family receptors relates to a large amount of normal processes among the Mammals CNS and is the important target of the compound of multiple neurological of treatment and psychiatric disorders.Need to activate that mGluR strengthens with the long time-histories of inducing hippocampus and the long time-histories of cerebellum fails (Bashir etc., 1993, Nature, 363:347; Bortolotto etc., 1994, Nature, 368:740; Aiba etc., 1994, Cell, 79:365; Aiba etc., 1994, Cell, 79:377).Proved the effect of mGluR activated (Meller etc., 1993, Neuroreport, 4:879 in injury sensation and the analgesia; Bordi ﹠amp; Ugolini, 1999, Brain Res., 871:223).In addition, thought that mGluR activates in various other normal processes, comprise in the control of maincenter control, awakening, behavior control and vestibulo-ocular reflex of cynapse conduction, neuronal development, apoptotic neuronal death, synaptic plasticity, space learning, scent-memorizing, cardiomotility, play regulating effect (Nakanishi, 1994, Neuron, 13:1031; Pin etc., 1995, Neuropharmacology is on seeing; Knopfel etc., 1995, J.Med.Chem., 38:1417).
Nearest progress aspect the neurophysiology effect of illustrating mGluRs determined, these acceptors are as drug targets likely aspect and chronic neuropathic and psychiatric disorders and chronic and the acute pain disease acute in treatment.Because physiology and the physiopathology meaning of mGluRs need to regulate the new medicine and the compound of mGluR function.
Summary of the invention
We have identified the compound that a class is regulated the mGluR function.On the one hand, the invention provides formula I compound or its pharmacy acceptable salt, hydrate, solvate, optical isomer or its combination,
Wherein:
R
1Be to contain the first ring of the one or more heteroatomic 3-7 that independently is selected from N, O and S, wherein said ring can be replaced by one or more A;
R
2And R
3Independently be selected from H, C
1-6-alkyl, C
2-6-alkenyl, C
2-6-alkynyl, aryl, heteroaryl, Heterocyclylalkyl, C
3-8-cycloalkyl, C
1-6-alkyl-aryl, C
1-6-alkyl-heteroaryl, C
1-6-alkyl-Heterocyclylalkyl and C
1-6-alkyl-C
3-8-cycloalkyl, wherein R
2And R
3Can be replaced by one or more A;
R
4And R
6Independently be selected from H, hydroxyl, F, Cl, Br, I, nitro, cyano group, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, aryl, C
1-6-alkylaryl, OC
0-6-alkylaryl, (CO) R
10, O (CO) R
10, O (CO) OR
10, C (O) OR
10, O (CN R
10) OR
11, C
1-6-alkyl OR
10, OC
2-6-alkyl OR
10, C
1-6-alkyl (CO) R
10, OC
1-6-alkyl (CO) R
10, C
0-6-alkyl CO
2R
10, OC
1-6-alkyl CO
2R
10, C
1-6-alkyl cyano group, OC
2-6-alkyl cyano group, C
0-6-alkyl NR
10R
11, OC
2-6-alkyl NR
10R
11, C
1-6-alkyl (CO) NR
10R
11, OC
1-6-alkyl (CO) NR
10R
11, C
0-6-alkyl NR
10(CO) R
11, OC
2-6-alkyl NR
10(CO) R
11, C
0-6-alkyl NR
10(CO) N R
10R
11, C
0-6-alkyl SR
10, OC
2-6-alkyl SR
10, C
0-6-alkyl (SO) R
10, OC
2-6-alkyl (SO) R
10, C
0-6-alkyl SO
2R
10, OC
2-6-alkyl SO
2R
10, C
0-6-alkyl (SO
2) NR
10R
11, OC
2-6-alkyl (SO
2) NR
10R
11, C
0-6-alkyl NR
10(SO
2) R
11, OC
2-6-alkyl NR
10(SO
2) R
11, C
0-6-alkyl NR
10(SO
2) NR
10R
11, OC
2-6-alkyl NR
10(SO
2) NR
10R
11, (CO) NR
10R
11, O (CO) NR
10R
11, NR
10OR
11, C
0-6-alkyl NR
10(CO) OR
11, OC
2-6-alkyl NR
10(CO) OR
11, SO
3R
10With can contain the one or more heteroatomic 5-7 unit ring that independently is selected from N, O and S, wherein R
4And R
6Can be replaced by one or more A and wherein any cycloalkyl or aryl optional with can contain the one or more heteroatomic 5-7 unit that independently is selected from C, N, O and S and encircle and condense;
R
5Be selected from CN, OC
0-6-alkyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, C
0-6-alkylaryl, OC
0-6-alkylaryl, C
0-6-miscellaneous alkyl aryl, OC
0-6-miscellaneous alkyl aryl, Heterocyclylalkyl, C
1-6-alkyl heterocycle alkyl, OC
0-6-alkyl heterocycle alkyl and (CO) R
10, wherein any loop section can be replaced by one or more B;
R
7Be selected from H, F, Cl, Br, I, nitro, cyano group, OC
1-4-alkyl, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl and C
3-8-cycloalkyl;
R
8And R
9Independently be selected from H, F, Cl, Br, I, nitro, cyano group, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl and OC
2-6-alkynyl,
Perhaps, n wherein is greater than 1, the two or more R on the adjacent carbons
8And/or R
9May not exist, form alkenyl or alkynyl part;
R
10And R
11Independently be selected from H, hydroxyl, oxo, F, Cl, Br, I, nitro, cyano group, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, aryl, C
1-6-alkylaryl, OC
0-6-alkylaryl, C
0-6-alkyl-Heterocyclylalkyl, OC
1-6-alkyl-Heterocyclylalkyl, heteroaryl, C
1-6Miscellaneous alkyl aryl, Heterocyclylalkyl-C
1-6-alkylaryl and Heterocyclylalkyl-C
1-6-miscellaneous alkyl aryl, wherein any loop section is chosen wantonly and can be contained first ring of the one or more heteroatomic 5-7 that independently is selected from C, N, O and S and condenses and the optional substituting group replacement that is selected from alkyl, halogeno-group, hydroxyl, O alkyl, haloalkyl and O haloalkyl of any loop section;
A is selected from H, hydroxyl, F, Cl, Br, I, nitro, cyano group, oxo, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, aryl, C
1-6-alkylaryl, OC
0-6-alkylaryl, C
1-6-alkyl-heterocyclic radical, C
1-6-alkyl-Heterocyclylalkyl, OC
0-6-alkyl-Heterocyclylalkyl, (CO) R
10, O (CO) R
10, O (CO) OR
10, O (CNR
10) OR
11, C
1-6-alkyl OR
10, OC
2-6-alkyl OR
10, C
1-6-alkyl (CO) R
10, OC
1-6-alkyl (CO) R
10, C
0-6-alkyl CO
2R
10, OC
1-6-alkyl CO
2R
10, C
1-6-alkyl cyano group, OC
2-6-alkyl cyano group, C
0-6-alkyl NR
10R
11, OC
2-6-alkyl NR
10R
11, C
0-6-alkyl (CO) NR
10R
11, OC
1-6-alkyl (CO) NR
10R
11, C
0-6-alkyl NR
10(CO) R
11, OC
2-6-alkyl NR
10(CO) R
11, C
0-6-alkyl NR
10(CO) NR
10R
11, C
0-6-alkyl SR
10, OC
2-6-alkyl SR
10, C
0-6-alkyl (SO) R
10, OC
2-6-alkyl (SO) R
10, C
1-6-alkyl SO
2R
10, OC
2-6-alkyl SO
2R
10, C
0-6-alkyl (SO
2) NR
10R
11, OC
2-6-alkyl (SO
2) NR
10R
11, C
0-6-alkyl NR
10(SO
2) R
11, OC
2-6-alkyl NR
10(SO
2) R
11, C
0-6-alkyl NR
10(SO
2) NR
10R
11, OC
2-6-alkyl NR
10(SO
2) NR
10R
11, (CO) NR
10R
11, O (CO) NR
10R
11, NR
10OR
11, C
0-6-alkyl NR
10(CO) OR
11, OC
2-6-alkyl NR
10(CO) OR
11, SO
3R
10With can contain the one or more heteroatomic 5-7 unit ring that independently is selected from N, O and S, wherein said 5-7 unit ring is optional by one or more R
10And R
11Replace;
B is selected from C
0-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, C
0-6-alkylaryl, OC
0-6-alkylaryl, C
1-6-alkyl-Heterocyclylalkyl, OC
0-6-alkyl-Heterocyclylalkyl, C
1-6-miscellaneous alkyl aryl and OC
1-6-miscellaneous alkyl aryl, wherein any loop section is selected from halogeno-group, alkyl, haloalkyl, alkoxyl group, oxo, COR, CO
2R, SO
2At least one substituting group of R and CN replaces;
R is selected from H and alkyl;
With
N is selected from 1,2,3,4,5,6,7 and 8.
The present invention also provides formula I the preparation method of compound.
The present invention also provides the medicinal compositions according to the compound of formula I that contains with pharmaceutically acceptable carrier or vehicle; On the other hand, the invention provides L-glutamic acid dysfunction related neural disease of the animal for the treatment of or need preventing to treat like this and the method for psychiatric disorders.This method comprises the formula I compound that gives the treatment of animals significant quantity or the step of its medicinal compositions.
The present invention also provides formula I compound or its pharmacy acceptable salt or solvate to be used for the treatment of purposes in the medicine of any disease as herein described in preparation.In addition, the invention provides formula I compound or its pharmacy acceptable salt or the solvate that is used for the treatment of.
Detailed Description Of The Invention
The present invention is based on and show, particularly as the discovery of the active compound of metabotropic glutamate receptor modulators as medicine.More particularly, compound of the present invention shows the activity as the synergistic agent of mGluR2 acceptor, and is used for the treatment of, in particular for the treatment of sick of L-glutamic acid dysfunction related neural and psychiatric disorders.
Definition
Unless explanation is arranged in this application in addition, the nomenclature that is used for the application is generally according to organic chemistry nomenclature (Pergamon Press, Oxford, 1979) example and the rule described in A, B, C, D, E, F and the H chapter, the rule of its chemical structure name of giving an example and name chemical structure is incorporated into this paper by reference.Randomly, can adopt chemical name program: ACD/ChemSketch, September 5.09 editions/calendar year 2001, contemporary chemical developer, Inc., Toronto, Canada, the title of generation compound.
The term " alkyl " that is used for this paper refers to have, for example, and the straight or branched alkyl of 1-6 carbon atom, and comprise methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl etc.
The term " alkenyl " that is used for this paper refers to have, for example, and the straight or branched alkenyl of 2-6 carbon atom, and comprise vinyl, 1-propenyl, 1-butylene base etc.
The term " alkynyl " that is used for this paper refers to have, for example, and the straight or branched alkynyl of 2-6 carbon atom, and comprise 1-proyl (propargyl), 1-butylene base etc.
The term " cycloalkyl " that is used for this paper refers to have, for example, and the cyclic group of 3-7 carbon atom (it can be substituted), and comprise cyclopropyl, cyclohexyl, cyclohexenyl etc.
The term " Heterocyclylalkyl " that is used for this paper refers to for example, have the first cyclic group (it can be substituted) of at least one heteroatomic 3-7 that is selected from N, S and O, and comprise piperidyl, piperazinyl, pyrrolidyl, tetrahydrofuran base etc.
The term " alkoxyl group " that is used for this paper refers to have, for example, and the straight or branched alkoxyl group of 1-6 carbon atom, and comprise methoxyl group, oxyethyl group, propoxy-, isopropoxy, tert.-butoxy etc.
The term " halogeno-group " that is used for this paper refers to halogen, and comprises the fluoro that is radioactivity and on-radiation form, chloro, bromo, iodo etc.
The term " aryl " that is used for this paper refers to have, for example, and the aromatic group of 5-12 atom, and comprise phenyl, naphthyl etc.
Term " heteroaryl " refers to comprise at least one the heteroatomic aromatic group that is selected from N, S and O, and comprises several groups, and comprises pyridyl, indyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl etc.
The term " alkyloyl " that is used for this paper refers to have, for example, and the straight or branched alkyloyl of 2-7 atom, and comprise ethanoyl, propionyl, butyryl radicals etc.
The term " cycloalkenyl group " that is used for this paper refers to have, for example, and the unsaturated cycloalkyl of 4-7 carbon atom, and comprise ring penta-1-thiazolinyl, hexamethylene-1-thiazolinyl etc.
Term " alkylaryl ", " miscellaneous alkyl aryl " and " alkyl-cycloalkyl " refer to by the alkyl of aryl, heteroaryl or cycloalkyl substituted, and comprise 2-styroyl, 3-cyclohexyl propyl group etc.
Term " can contain the first ring of the one or more heteroatomic 5-7 that independently is selected from N, O and S " and comprise aromatics and heteroaromatic rings, and carbocyclic ring and heterocycle, it can be saturated or undersaturated, and comprises furyl, isoxazolyl, oxazolyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, thiazolyl, thienyl, imidazolyl, triazolyl, morpholinyl, piperazinyl, piperidyl, homopiperidinyl, THP trtrahydropyranyl, phenyl, cyclohexyl, suberyl, cyclopentyl, cyclohexyl etc.
Term " pharmacy acceptable salt " refers to be suitable for the acid salt or the base addition salt of patient treatment.
" pharmaceutically-acceptable acid addition " is the basic cpd represented by formula I or any non-toxic organic or the inorganic acid addition salt of its any intermediate.Form the exemplary inorganic acid that is suitable for salt and comprise spirit of salt, Hydrogen bromide, sulfuric acid and phosphoric acid and acid metal salt for example sodium hydrogen phosphate and sal enixum.Forming the exemplary organic acid that is suitable for salt comprises single, double and tricarboxylic acid.For example, this exemplary class acid has acetate, oxyacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, oxysuccinic acid, tartrate, citric acid, xitix, toxilic acid, hydroxymaleic acid, phenylformic acid, hydroxy-benzoic acid, phenylacetic acid, styracin, Whitfield's ointment, 2-phenoxy benzoic acid, tosic acid and other sulfonic acid, for example methylsulfonic acid and 2-ethylenehydrinsulfonic acid.Can form list or diacid salt, this class salt can hydration, solvation or substantially anhydrous form exist.Usually, compare with its free alkali form, the more soluble in water and various hydrophilic organic solvents of the acid salt of these compounds, and show higher fusing point usually.The choice criteria of suitable salt is known to those skilled in the art.For example, other non-pharmacy acceptable salt for example oxalate can be used for the separation of laboratory purposes or the follow-up formula I compound that is converted into pharmaceutically-acceptable acid addition.
" pharmaceutically acceptable base addition salt " is the acidic cpd represented of formula I or any non-toxic organic or the mineral alkali additive salt of its any intermediate.Form the oxyhydroxide that the exemplary inorganic alkali that is suitable for salt comprises lithium, sodium, potassium, calcium, magnesium or barium.Form the exemplary organic bases that is suitable for salt and comprise aliphatics, alicyclic or aromatics organic amine, for example methylamine, Trimethylamine 99 and picoline or ammonia.The selection of suitable salt can be important, so that the ester functional group (if there is) of other position in the molecule is not hydrolyzed.The choice criteria of suitable salt is known to those skilled in the art.
" solvate " refers to the pharmacy acceptable salt of formula I compound or formula I compound, and wherein the molecule of suitable solvents is incorporated in the lattice.Suitable solvents under the dosage that gives as solvate is can tolerate on the physiology.The example of the solvent that is suitable for has ethanol, water etc.When water was solvent, this molecule was called as hydrate.
Term " steric isomer " is the general term at distinguishing all isomer aspect its atoms in space location at unique molecular.It comprises mirror image isomer (enantiomer), how much (cis/trans) isomer and has more than one is not the isomer (diastereomer) of compound of the chiral centre of mutual mirror image.
Term " processing " or " treatment " refers to that the appearance of the symptom of specified illness or disease is perhaps prevented or slowed down to temporarily or for good and all relief of symptoms, symptomatolytic reason.
Term " treatment significant quantity " refers to effectively treat the amount of the compound of specified illness or disease.
Term " pharmaceutically acceptable carrier " refers to innoxious solvent, dispersion agent, vehicle, adjuvant or mixes so that medicinal compositions promptly, can give other raw material that patient's formulation forms with activeconstituents.An example of this class carrier is the pharmaceutically acceptable oil that generally is used as administered parenterally.
Compound:
The compounds of this invention meets formula I usually:
Wherein:
R
1Be to contain the first ring of the one or more heteroatomic 3-7 that independently is selected from N, O and S, wherein said ring can be replaced by one or more A;
R
2And R
3Independently be selected from H, C
1-6-alkyl, C
2-6-alkenyl, C
2-6-alkynyl, aryl, heteroaryl, Heterocyclylalkyl, C
3-8-cycloalkyl, C
1-6-alkyl-aryl, C
1-6-alkyl-heteroaryl, C
1-6-alkyl-Heterocyclylalkyl and C
1-6-alkyl-C
3-8-cycloalkyl, wherein R
2And R
3Can be replaced by one or more A;
R
4And R
6Independently be selected from H, hydroxyl, F, Cl, Br, I, nitro, cyano group, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, aryl, C
1-6-alkylaryl, OC
0-6-alkylaryl, (CO) R
10, O (CO) R
10, O (CO) OR
10, C (O) OR
10, O (CN R
10) OR
11, C
1-6-alkyl OR
10, OC
2-6-alkyl OR
10, C
1-6-alkyl (CO) R
10, OC
1-6-alkyl (CO) R
10, C
0-6-alkyl CO
2R
10, OC
1-6-alkyl CO
2R
10, C
1-6-alkyl cyano group, OC
2-6-alkyl cyano group, C
0-6-alkyl NR
10R
11, OC
2-6-alkyl NR
10R
11, C
1-6-alkyl (CO) NR
10R
11, OC
1-6-alkyl (CO) NR
10R
11, C
0-6-alkyl NR
10(CO) R
11, OC
2-6-alkyl NR
10(CO) R
11, C
0-6-alkyl NR
10(CO) N R
10R
11, C
0-6-alkyl SR
10, OC
2-6-alkyl SR
10, C
0-6-alkyl (SO) R
10, OC
2-6-alkyl (SO) R
10, C
0-6-alkyl SO
2R
10, OC
2-6-alkyl SO
2R
10, C
0-6-alkyl (SO
2) NR
10R
11, OC
2-6-alkyl (SO
2) NR
10R
11, C
0-6-alkyl NR
10(SO
2) R
11, OC
2-6-alkyl NR
10(SO
2) R
11, C
0-6-alkyl NR
10(SO
2) NR
10R
11, OC
2-6-alkyl NR
10(SO
2) NR
10R
11, (CO) NR
10R
11, O (CO) NR
10R
11, NR
10OR
11, C
0-6-alkyl NR
10(CO) OR
11, OC
2-6-alkyl NR
10(CO) OR
11, SO
3R
10With can contain the one or more heteroatomic 5-7 unit ring that independently is selected from N, O and S, wherein R
4And R
6Can be replaced by one or more A and wherein any cycloalkyl or aryl optional with can contain the one or more heteroatomic 5-7 unit that independently is selected from C, N, O and S and encircle and condense;
R
5Be selected from CN, OC
0-6-alkyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, C
0-6-alkylaryl, OC
0-6-alkylaryl, C
0-6-miscellaneous alkyl aryl, OC
0-6-miscellaneous alkyl aryl, Heterocyclylalkyl, C
1-6-alkyl heterocycle alkyl, OC
0-6-alkyl heterocycle alkyl and (CO) R
10, wherein any loop section can be replaced by one or more B;
R
7Be selected from H, F, Cl, Br, I, nitro, cyano group, OC
1-4-alkyl, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl and C
3-8-cycloalkyl;
R
8And R
9Independently be selected from H, F, Cl, Br, I, nitro, cyano group, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl and OC
2-6-alkynyl,
Perhaps, n wherein is greater than 1, the two or more R on the adjacent carbons
8And/or R
9May not exist, form alkenyl or alkynyl part;
R
10And R
11Independently be selected from H, hydroxyl, oxo, F, Cl, Br, I, nitro, cyano group, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, aryl, C
1-6-alkylaryl, OC
0-6-alkylaryl, C
0-6-alkyl-Heterocyclylalkyl, OC
1-6-alkyl-Heterocyclylalkyl, heteroaryl, C
1-6Miscellaneous alkyl aryl, Heterocyclylalkyl-C
1-6-alkylaryl and Heterocyclylalkyl-C
1-6-miscellaneous alkyl aryl, wherein any loop section is chosen wantonly and can be contained first ring of the one or more heteroatomic 5-7 that independently is selected from C, N, O and S and condenses and the optional substituting group replacement that is selected from alkyl, halogeno-group, hydroxyl, O alkyl, haloalkyl and O haloalkyl of any loop section;
A is selected from H, hydroxyl, F, Cl, Br, I, nitro, cyano group, oxo, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, aryl, C
1-6-alkylaryl, OC
0-6-alkylaryl, C
1-6-alkyl-heterocyclic radical, C
1-6-alkyl-Heterocyclylalkyl, OC
0-6-alkyl-Heterocyclylalkyl, (CO) R
10, O (CO) R
10, O (CO) OR
10, O (CNR
10) OR
11, C
1-6-alkyl OR
10, OC
2-6-alkyl OR
10, C
1-6-alkyl (CO) R
10, OC
1-6-alkyl (CO) R
10, C
0-6-alkyl CO
2R
10, OC
1-6-alkyl CO
2R
10, C
1-6-alkyl cyano group, OC
2-6-alkyl cyano group, C
0-6-alkyl NR
10R
11, OC
2-6-alkyl NR
10R
11, C
0-6-alkyl (CO) NR
10R
11, OC
1-6-alkyl (CO) NR
10R
11, C
0-6-alkyl NR
10(CO) R
11, OC
2-6-alkyl NR
10(CO) R
11, C
0-6-alkyl NR
10(CO) NR
10R
11, C
0-6-alkyl SR
10, OC
2-6-alkyl SR
10, C
0-6-alkyl (SO) R
10, OC
2-6-alkyl (SO) R
10, C
1-6-alkyl SO
2R
10, OC
2-6-alkyl SO
2R
10, C
0-6-alkyl (SO
2) NR
10R
11, OC
2-6-alkyl (SO
2) NR
10R
11, C
0-6-alkyl NR
10(SO
2) R
11, OC
2-6-alkyl NR
10(SO
2) R
11, C
0-6-alkyl NR
10(SO
2) NR
10R
11, OC
2-6-alkyl NR
10(SO
2) NR
10R
11, (CO) NR
10R
11, O (CO) NR
10R
11, NR
10OR
11, C
0-6-alkyl NR
10(CO) OR
11, OC
2-6-alkyl NR
10(CO) OR
11, SO
3R
10With can contain the one or more heteroatomic 5-7 unit ring that independently is selected from N, O and S, wherein said 5-7 unit ring is optional by one or more R
10And R
11Replace;
B is selected from C
0-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, C
0-6-alkylaryl, OC
0-6-alkylaryl, C
1-6-alkyl-Heterocyclylalkyl, OC
0-6-alkyl-Heterocyclylalkyl, C
1-6-miscellaneous alkyl aryl and OC
1-6-miscellaneous alkyl aryl, wherein any loop section is selected from halogeno-group, alkyl, haloalkyl, alkoxyl group, oxo, COR, CO
2R, SO
2At least one substituting group of R and CN replaces;
R is selected from H and alkyl;
With
N is selected from 1,2,3,4,5,6,7 and 8;
Or its pharmacy acceptable salt, hydrate, solvate, optical isomer or its combination; Prerequisite is that described compound is not selected from:
5-(4-benzyl-piperazine-1-carbonyl)-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
7-methyl-5-(4-pyridin-4-yl methyl-piperazine-1-carbonyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
7-methyl-5-[4-(2-pyridin-4-yl-ethyl) piperazine-1-carbonyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
4-{4-[7-methyl isophthalic acid-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-ylmethyl]-piperidines-1-ylmethyl }-benzonitrile,
2-benzyl-1-oxo-2,3-dihydro-1H-isoindole-5-nitrile,
7-chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-nitrile,
7-methyl isophthalic acid-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-nitrile,
7-methyl isophthalic acid-oxo-2-(4-chloro-benzyl)-2,3-dihydro-1H-isoindole-5-nitrile,
1-oxo-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-1H-isoindole-5-nitrile,
3-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4, the 6-dintrile,
7-iodo-5-methoxyl group-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
2-benzyl-5-methoxyl group-2,3-dihydro-isoindole-1-ketone and
7-chloro-5-methoxyl group-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone.
It will be readily apparent to those skilled in the art that when The compounds of this invention contains one or more chiral centre The compounds of this invention can be used as enantiomer or diastereomeric form, or as racemic mixture existence and separated.The present invention includes any possible enantiomer, diastereomer, racemic modification or their mixture of formula I compound.For example, can separate, by synthesizing by the optical activity starting raw material or, preparing the optical activity form of The compounds of this invention by asymmetric synthesis based on method described below by the chirality chromatography of racemic modification.
Those skilled in the art can be appreciated that also some The compounds of this invention can be used as geometrical isomer, and for example the E of alkene and Z isomer exist.The present invention includes any geometrical isomer of formula I compound.Be also to be understood that the present invention will comprise the tautomer of formula I compound.
Those skilled in the art also will appreciate that, some The compounds of this invention can solvation, and for example hydration and non-solvent form exist.Be also to be understood that all these kind solvent forms that the present invention includes formula I compound.
The salt of formula I compound also within the scope of the invention.Usually, adopt standard program well known in the art, for example, by making the compound of abundant alkalescence, for example alkylamine and suitable acid, for example, HCl or acetic acidreaction generate acceptable negatively charged ion on the physiology, obtain the pharmacy acceptable salt of The compounds of this invention.Also can be by in water-bearing media, handle with the basic metal of monovalent or alkaline earth metal hydroxides or alkoxide (for example ethylate or methylate) or the alkaline organic amine (for example choline or meglumine) that is suitable for and to have the proper sourness proton, the The compounds of this invention of carboxylic acid or phenol for example, through conventional purification technique, prepare corresponding alkali metal (for example sodium, potassium or lithium) or alkaline-earth metal (for example calcium) salt subsequently.
In one embodiment of the invention, formula I compound can be converted into its pharmacy acceptable salt or solvate, especially, acid salt, for example hydrochloride, hydrobromate, phosphoric acid salt, acetate, fumarate, maleate, tartrate, Citrate trianion, mesylate or tosilate.
In specific embodiments of the present invention, R
5Be selected from Heterocyclylalkyl and C
1-6-alkyl heterocycle alkyl.
In specific embodiments of the present invention, B is selected from C
0-6-alkylaryl, C
1-6-miscellaneous alkyl aryl and C
0-6-alkyl heterocycle alkyl.
Particular example of the present invention comprises the compound shown in the following table, their pharmacy acceptable salt, hydrate, solvate and optical isomer thereof.
Medicinal compositions:
Compound of the present invention can be mixed with conventional medicinal compositions, and it comprises formula I compound or its pharmacy acceptable salt or solvate with pharmaceutically acceptable carrier or mixed with excipients.Pharmaceutically acceptable carrier can be solid or liquid.But the solid form preparation includes, but not limited to powder, tablet dispersible granule, capsule, cachet and suppository.
Solid carrier can be one or more materials, and they can play the effect of thinner, correctives, solubilizing agent, lubricant, suspension agent, tackiness agent or tablet disintegrant.Solid carrier also can be encapsulated materials.
In the powder, carrier is finely divided solid, and it mixes with finely divided The compounds of this invention or active ingredient.In the tablet, active ingredient is mixed in the proper ratio with the carrier with the bond property that needs and is pressed into needed shape and size.
For the preparation suppository composition, at first melt low melt wax, for example the mixture of glycerin fatty acid ester and theobroma oil passes through again, for example stirs, and activeconstituents is scattered in wherein.The uniform mixture that will melt again injects the suitably mould of size, makes it cooling and curing.
The carrier that is suitable for includes, but not limited to magnesiumcarbonate, Magnesium Stearate, talcum, lactose, sucrose, pectin, dextrin, starch, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.
The term composition is also planned to comprise the preparation of the active ingredient with the capsular capsulation material that provides as carrier, and active ingredient wherein (having or do not have other carrier) is surrounded by such and its bonded carrier.Similarly, comprise cachet (cachets).
Tablet, powder, cachet and capsule can be used as and be suitable for oral solid dosage.
The liquid form composition comprises solution, suspensoid and emulsion.For example, the sterilized water of active compound or aqueous solution of propylene glycol can be the liquid preparation that is suitable for parenteral admin.Liquid composition also can be formulated into the solution in the polyoxyethylene glycol aqueous solution.
Can be by making solubilization of active ingredient in water, and add appropriate colouring agent, correctives, stablizer and thickening material when needed, prepare oral aqueous solution agent.Can be scattered in and the viscosity raw material by making the active ingredient of segmenting, for example, in other suspension agent water together known to natural synthetic gum, resin, methylcellulose gum, Xylo-Mucine and the medicinal preparations field, prepare oral aqueous suspensions.Oral exemplary composition can contain one or more tinting materials, sweeting agent, correctives and/or sanitas.
Depend on administering mode, medicinal compositions will comprise about 0.05% weight (weight percent)-Yue 99% weight, and more particularly, the The compounds of this invention of about 0.10% weight-50% weight, all weight percents are all based on the total weight of composition.
Adopt known standard, comprise the response of age, weight and individual patient, those of ordinary skill in the art can determine treatment significant quantity of the invention process, and is illustrated in the context of the disease of being treated or being prevented.
Medical usage:
We have found that compound of the present invention shows as medicine, especially as the activity of the conditioning agent of metabotropic glutamate receptor.More particularly, compound of the present invention shows the activity as the synergistic agent of mGluR2 acceptor, therefore is used for the treatment of, especially the treatment of sick of the L-glutamic acid dysfunction related neural of animal and psychiatric disorders.
More particularly, neurological and psychiatric disorders comprise, but be not limited to following disease, for example, the brain that causes after heart bypass operation and the transplanting is damaged, apoplexy, cerebral ischemia, spinal cord injuries receptor, wound, perinatal hypoxia, heart stopping collecting, hypoglycemic neuronal damage, dull-witted (comprising the dementia that AIDS brings out), presenile dementia, huntington's chorea, amyotrophic lateral sclerosis, ocular injury, retinopathy, cognitive disorder, spontaneous and drug-induced Parkinson's disease, muscle spasm and comprise with the muscle spasm diseases associated is trembled, epilepsy, faint from fear, the brain of epileptic state that is secondary to prolongation is damaged, migraine (comprising the migraine headache), the urinary incontinence, the material tolerance, material is given up disease and (is comprised that material is opium for example, Nicotine, tobacco product, alcohol, the benzodiazepine leather, Cocaine, tranquilizer, soporific etc.), psychosis, schizophrenia, anxiety disorder (comprises generalized anxiety disorder, paranoid fears, social phobia, obsession and post-traumatic stress disorder (PTSD)), mood disorder (comprises dysthymia disorders, mania, attention-deficient), circadian rhythm obstacle (comprising jet lag and shift work syndrome), trigeminal neuralgia, hearing disability, tinnitus, the eyes macular degeneration, vomiting, cerebral edema, pain (comprises acute and the chronic pain state, have an intense pain, refractory pain, neuropathic pain, pain after inflammatory pain and the wound), tardive dyskinesia, somnopathy (comprising hypnolepsy), attention-deficient/hyperfunction obstacle and behavior disorder.
Therefore, the invention provides according to the compound of formula I or its pharmacy acceptable salt or solvate and be used for the treatment of purposes in the medicine of above-mentioned any illness in preparation.
In addition, the invention provides the method that treatment suffers from the curee of above-mentioned any illness, thereby need compound or its pharmacy acceptable salt or the solvate according to formula I of patient's significant quantity of treatment like this.As indicated above such, the present invention also provides formula I compound or its pharmacy acceptable salt or the purposes of solvate in treatment.
In the application's context, term " treatment " also comprises " prevention " is unless there is opposite explanation in addition.Term " treatment " and " remedially " should be explained accordingly.Term in the context of the invention " treatment " further comprises the The compounds of this invention that gives significant quantity, alleviating acute or chronic already present morbid state, or alleviates the recurrence disease.This definition also is included as the prophylactic treatment of prevention of recurrence disease and to the continued treatment of chronic disease.
Warm-blooded animal, for example in people's the therepic use, can be by any approach, comprise in per os, intramuscular, subcutaneous, local, the nose, in the intraperitoneal, intrathoracic, intravenously, epidural, sheath, Intraventricular, with by being expelled in the joint, give compound of the present invention with the form of conventional medicinal compositions.In particular of the present invention, route of administration is per os, intravenously or intramuscular.
Dosage will depend on route of administration, severity of disease, age and patient's body weight and each dosage of definite particular patient and the common other factors of considering of attending doctor of dosage level.
Such as mentioned above, can be to be suitable for oral form, for example, provide or transmit compound as herein described with the form of tablet, lozenge, hard and soft capsule, aqueous solution agent, oily solution agent, emulsion and suspensoid.As selection, described compound can be configured to topical, for example, and as creme, ointment, gelifying agent, sprays or aqueous solution agent, oily solution agent, emulsion or suspensoid.Also can provide to be the form that is suitable for nose administration, for example, as the compound as herein described of nasal spray, nasal drop or dried powder.Can suppository form give described compound to vagina or rectum.Also can be through parenteral, for example, give compound as herein described through intravenously, intravesical (intravesicular), subcutaneous or intramuscularly or transfusion.Can give described compound through sucking (for example, as finely divided powder).Also can give described compound through transdermal or hypogloeeis.
Except they the purposes aspect the medicine, the formula I compound or its salt also exploitation of pilot system in vitro and in vivo and stdn aspect is used in the effect of estimating the inhibitor of mGluR related activity as the laboratory animal of the part of novel treatment research as pharmacological tool.This class animal comprises, for example, and cat, dog, rabbit, monkey, rat and mouse.
The preparation method:
Compound of the present invention can be by various synthetic method preparations.Prepare in the limit of power that is chosen in those skilled in the art of ad hoc approach of given compound.Therefore, certain structural features and/or substituent selection may influence selects a kind of method, and does not select another kind of method.
Under these total guilding principles, can adopt following method to prepare the exemplary subgroup of The compounds of this invention.Except as otherwise noted, the definition of given those variablees of following flow process and the variable described in the method and following formula I is identical.
In one approach, for example, at formula R
1(CR
8CR
9)
nNH
2The existence of amine under, make the cyclisation of formula Ia compound:
Obtain formula Ib compound:
Formula Ib compound again with contain R
5Suitable reagent cross-coupling, obtain compound according to formula Ic:
In an embodiment of present method, synthetic 5-replaces-7-methyl isoindolone as shown in following flow process 1.Under the Sandmeyer reaction conditions, 4-bromo-2, the 6-xylidine is converted into corresponding nitrile.Nitrile progressively is hydrolyzed to acid again.Can obtain acid amides by alkaline hydrolysis.Acid amides by nitrosyl-sulfuric acid diazotization and hydrolysis, obtains phenylformic acid again, is methyl esters with standard conditions with its protection subsequently.As radical initiator, the methyl of benzyl is by N-bromosuccinimide list bromination with benzoyl peroxide.Alkali for example salt of wormwood in the presence of, this resultant intermediate is an isoindolone by suitable amine cyclisation.Finally, adopt typical B uchwald, Suzuki or Stille cross-coupling reaction condition and reagent, with substituent R
5Be incorporated on the C5 of isoindolone.
Flow process 1:
(a) NaCN, CuCN, HCl; (b) NaOH; (c) nitrosyl-sulfuric acid; (d) MeI, K
2CO
3(e) NBS, (PhCO
2)
2(f) R1CH
2NH
2, K
2CO
3(g) R5H, BINAP, PdCl
2(dppf), NaOtBu or R5B (OH)
2, PdCl
2(dppf), K
2CO
3Or R5SnBu
3, Pd (PPh
3)
4
In another embodiment of this method, synthetic 5-replacement-7-chloro isoindolone as shown in following flow process 2.With N-chlorosuccinimide and palladium catalyst at the ortho position of acid chlorination 4-bromo-2-tolyl acid.In being similar to the above (flow process 1) method, this acid is esterified again, bromination and cyclisation, obtains the isoindolone intermediate.Introduce substituent R similarly
5
Flow process 2:
In another embodiment of present method, can as shown in following flow process 3, prepare the isoindolone that on C5, is replaced by acid amides.Therefore, in the presence of palladium catalyst, the 5-bromo isoindolone that will suitably replace with zinc cyanide is converted into corresponding nitrile.Under alkaline condition,, obtain phenylformic acid again, make itself and various amine coupling with method well known in the art again, obtain final compound the nitrile hydrolysis.
Flow process 3:
In another embodiment, can adopt aforesaid method to prepare amino-propargyl and amino-alkyl isoindolone.Therefore, at first as shown in Scheme 4, make suitable 5-bromo isoindolone and various propargyl amine experience Sonogashira coupling condition.Available then ordinary method makes the alkynes hydrogenation that obtains, and obtains the product that amino-alkyl replaces.In flow process 4, R and R ' corresponding to as at this paper to R
10And R
11The substituting group of definition.
Flow process 4
According to another method of the present invention, adopt some aforementioned synthetic method preparation to have the substituent compound of N-propargyl type.Therefore, in the presence of propargyl amine, formula Ia compound:
By cyclisation is formula Id compound:
Formula Id compound with contain R
1The reagent coupling, obtain formula Ie compound:
R
1Be preferably aryl.Make formula Ie compound then and contain R
5The crosslinked coupling of reagent, obtain formula If compound thus:
An embodiment of this method is shown in the following flow process 5.Make terminal alkyne and various aryl coupling with standard Sonogashira coupling condition.At last as shown in Scheme 5, adopt typical B uchwald, Suzuki or the crosslinked coupled reaction condition of Stille on C5, to introduce substituent R
5
Flow process 5
Another method of the present invention comprises preparation unsubstituted formula I compound on the isoindolone aromatic ring.This subgroup compound can directly prepare as shown in Scheme 6.Therefore, under acidic conditions, for example reduce phthalimide, obtain iso-dihydro-indole with tin.With this intermediate under alkaline condition with various electrophilic reagent alkylations, obtain required end product.In flow process 6, X can be any suitable leavings group, and halo for example is as bromo and iodo; And toluenesulphonic acids base (tosylate).
Flow process 6
Additive on many variablees of preceding method and its appears among subsequently the embodiment.Therefore, those of ordinary skill in the art can be appreciated that, can according to or adopt one or more methods disclosed herein, preparation The compounds of this invention.
By being intended to describe in detail the following example of several embodiments of the present invention, further specify the present invention.These embodiment neither plan, the scope that they can not be construed as limiting the invention.Should be clear and definite, the concrete narration of the available this paper of being different from such realizes the present invention.According to described herein, a large amount of modification of the present invention and variation are possible, thereby they all within the scope of the invention
Universal method:
All raw materials can obtain or narration more arranged in the literature through commercial approach.
Except as otherwise noted, in deuterate chloroform, adopt TMS or residual solvent signal in contrast as solvent,
1H and
13C NMR spectrum is recorded in respectively and exists
1On Bruker 300, the Bruker DPX400 or Varian+400 spectrometer that 300,400 and the 400MHz of H NMR moves down.All chemical shifts of report represent with the ppm on the δ scale, the trickle multiplicity of signal also appear in the record (s: unimodal, br s: wide unimodal, d: bimodal, t: three peaks, q: four peaks, m: multiplet).
Separate according to the liquid chromatography of the on-line analysis of mass spectrometric detection and to be embedded on the Waters LCMS that forms by Alliance2795 (LC) and the single quadrupole mass spectrometer of ZQ.This mass spectrograph is equipped with just and/or the electric spray ion source of negative ion mode operation.Ionspray voltage is ± 3kV that during sweep time, mass spectrograph is scanned from m/z 100 to 700 at 0.8s.Coupled columns, utilization X-Terra MS, Waters, C8,2.1 * 50mm, 3.5mm, linear gradient is in the 10mM ammonium acetate (aqueous solution) or the 5%-100% acetonitrile among the 0.1%TFA (aqueous solution).
The preparation reverse-phase chromatography moves on the automatic preparation HPLC of Gilson of band diode-array detector, adopts XTerra MS C8,19 * 300mm, and 7mm is as post.
Adopt TC Research 7924T chromatotron through the purifying of chromatotron through be coated with 1,2 or the rotation silica gel/gypsum (Merck, the 60PF-254 of band calcium sulfate) of 4mm coating layer sheet glass on carry out.
Also adopt Chem Elut column extractor (Varian, Cat#1219-8002), Mega BE-SI (Bond Elut Silica) SPE post (Varian, Cat# 12256018; 12256026; 12256034) or by the filling silica gel glass column in the flash chromatography method, purified product.
Be 2450MHz produce carry out in the Smith synthesizer single-mode microwave office of continuous gamma radiation microwave heating (individual's chemistry (Personal Chemistry) AB, Uppsala, Sweden).
Can adopt the pharmacological property of analyzing The compounds of this invention at the standard test of functionally active.For example, the example of glutamate receptor test such as Aramori etc., 1992, Neuron, 8:757; Tanabe etc., 1992, Neuron, 8:169; Miller etc., 1995, J.Neuroscience, 15:6103; Balazs, etc., 1997, J.Neurochemistry, 1997, described in the 69:151 like that, for known in the art.Method described in these publications is incorporated herein by reference.Expediently, can be by [the Ca in the cell of measuring intracellular Ca2+, expression mGluR2
2+] the test of moving, the research The compounds of this invention.
With the board-like reader of fluorescence imaging (FLIPR) analytical method, move detection mGluR2 allosteric activator through calcium.Employing is fused to and mixes the chimeric protein G of dwelling
α qi5, express clone HEK 293 clones that the chimeric mGluR2/CaR comprise people mGluR2 extracellular domain and membrane-spanning domain and people's calcium recipient cell intracellular domain constitutes thing.This constitutes thing by agonist or allosteric activator activation, causes stimulating the PLC approach and Ca in the follow-up cell of FLIPR analysis to measure
2+Move.In analysis preceding 24 hours, the cell trypsinize also was tiled among DMEM black limit, clear bottom, collagen I coating, in the 96-well culture plate with 100,000 cells/well.In 37 ℃, 5%CO
2Cultivate this culture plate down.Under the room temperature, with 6 μ M Fluo-3 acetoxyl methyl esters (molecular probe, Eugene Oregon) load cells 60 minutes.Containing 126mMNaCl, 5mM KCl, the 1mM MgCl that is supplemented with 1.0mg/ml D-glucose and 1.0mg/ml BSA flow point IV (pH 7.4)
2, 1mM CaCl
2, 20mM Hepes, 0.06 μ MDCG-IV (II group mGluR selective agonist) buffered soln in, carry out all tests.
Adopt 0.8W laser aid and 0.4 second CCD camera shutter speed to carry out the FLIPR experiment.Extracellular fluo-3 is by flush away, and cell is maintained in the 160 μ L damping fluids and is tiled among the FLIPR.After 10 seconds, adding test compounds (0.01 μ M-30 μ M, duplicate) with FLIPR record baseline fluorescence reading.After 75 seconds, note down fluorescent signal again, add DCG-IV (0.2 μ M) for the second time this moment, after 65 seconds, the record fluorescent signal.Fluorescent signal is measured as the peak heights of the response during sample.Calculate EC with Assay Explorer analytical data with four parameter logarithmic equations
50And E
MaxValue (with respect to maximum DCG-IV effect).
A[
35S]-GTP γ S is used to the receptor activation from function check mGluR2 in conjunction with test.With the film of the Chinese hamster ovary celI that is prepared in stably express people mGluR2, adopt [
35S]-GTP γ S is in conjunction with test, and the allosteric activator of mensuration compound is to the activity of people mGluR2 acceptor.This test is incorporated into the protein-coupled acceptor of G-based on agonist, to stimulate the principle of the proteic GDP-GTP exchange of G-.Since [
35S]-GTP γ S is the GTP analogue of non-hydrolysable, therefore, it can be used to provide the index of GDP-GTP exchange and receptor activation.Therefore, GTP γ S provides the quantitative assay of receptor activation in conjunction with test.
Film is by being prepared by the Chinese hamster ovary celI of people mGluR2 stable transfection.Under the room temperature, before adding 1 μ M L-glutamic acid, use test compounds (3nM-300 μ M) culture membrane (30 μ g albumen) 15 minutes, and containing 30 μ M GDP and 0.1nM[in 30 ℃
35S]-the 500 μ L of GTP γ S (1250Ci/mmol) test damping fluid (20mM HEPES, 100mM NaCl, 10mMMgCl
2) the middle cultivation 30 minutes.In 2mL polypropylene 96-well culture plate, carry out reaction repeated three times.With Packard 96-hole collector and Unifilter-96, GF/B strainer microtest plate, through the vacuum filtration termination reaction.With the ice-cold lavation buffer solution of 4 * 1.5mL (10mM sodium phosphate buffer, pH 7.4) washing filter culture plate.The device for drying and filtering culture plate adds 35 μ L scintillating liquids (Microscint 20) to each hole.By calculating culture plate, determine the amount of radioactivity boundary with Packard TopCount.With GraphPad Prism analytical data, calculate EC with non-linear regression
50And E
MaxValue (with respect to the effect of maximum valley propylhomoserin).
In general, in test as herein described, at concentration (or EC
50During value) less than 10 μ M, compound of the present invention is activated.For example, embodiment 8.3,10.4,11 and 13.7 has 75,230,84 and the EC of 28nM respectively
50Value.
Embodiment 1:4,4-difluoro cyclohexane carboxamide
With 4, (2500mg, 13mmol) (28%, 50ml) suspension in spends the night in 60 ℃ of stirrings 4-difluoro hexahydrobenzoic acid ethyl ester at ammonium hydroxide.Except that after desolvating, wash residue with water.Obtain for the throw out of product (white solid, 800mg).
1H?NMR(300MHz，CDCl
3)：δ5.31-5.45(br，2H)，2.02-2.27(m，3H)，1.92-2.02(m，2H)，1.72-1.87(m，4H)。With 1N HCl mother liquor is acidified to pH＜1.Extract this compound with EtOAc.Organic layer water, salt water washing through anhydrous sodium sulfate drying, are filtered, and concentrate.Obtain 4,4-difluoro hexahydrobenzoic acid is the 1200mg white solid, and it can further be converted into 4 by the following method, 4-difluoro cyclohexane carboxamide.
In-70 ℃, to 4,4-difluoro hexahydrobenzoic acid (1.35g, 8.22mmol) THF (50ml) solution in add 4-methylmorpholine (831mg, 8.22mmol), then add chlorocarbonic acid isobutyl (isobutyl chloridocarbonate) (1140mg, 8.22mmol).After 10 minutes, and adding ammonium hydroxide (28%, 10ml).Make the mixture that obtains be warmed to 0 ℃.After removing all solvents, residue water, hexane wash obtain the 1.06g white solid, and it is 4,4-difluoro cyclohexane carboxamide.Total recovery is 82%.
Embodiment 2:[(4,4-difluoro cyclohexyl) methyl] amine
Under nitrogen atmosphere, with 4,4-difluoro cyclohexane carboxamide (1.32g, 8.10mmol) (1M, 30ml) spend the night in the solution at lithium borohydride by stirring.Then, with reaction mixture refluxed 4 hours.After being cooled to room temperature, in its slow impouring frozen water.After the filtration, product extracts from filtrate with methylene dichloride.The organic layer water, the salt water washing that merge through anhydrous sodium sulfate drying, are filtered and are concentrated, and obtain 934mg colorless oil (82%). and δ 2.53 (d, 2H), 1.98-2.09 (m, 2H), 1.73-1.82 (m, 6H), 1.17-1.29 (m, 3H).
Embodiment 3:4-fluoro hexahydrobenzoic acid tertiary butyl ester
In 0 ℃, to 4-hydroxyl hexahydrobenzoic acid tertiary butyl ester (1500mg, methylene dichloride 7.45mmol) (anhydrous, 20ml) add in the solution DAST (1571mg, 22.4mmol).The mixture that obtains was stirred 3 hours in 0 ℃.This mixture dilutes with methylene dichloride, uses the sodium bicarbonate quencher.Separate organic layer, water extracts with EtOAc.The organic layer water, the salt water washing that merge are through anhydrous sodium sulfate drying.Purified product (flash chromatography, 10-20%EtOAc/ hexane) obtains 210mg yellow oil (25%).
1H?NMR(300MHz，CDCl
3)：δ5.60-5.80(m，1H)，4.99-5.09(m，2H)，4.73(d，2H)，3.34(br，2H)，2.29-2.32(m，2H)，1.44-1.46(m，9H)。
Embodiment 4:5-bromo-7-chloro-2-[(4,4-difluoro cyclohexyl) methyl] isoindoline-1-ketone
In 95 ℃, with 4-bromo-2-bromomethyl-6-chloro benzoic acid methyl ester (3.5g, 9.35mmol), (4,4-difluoro cyclohexyl) methylamine (1.7g, 11.39mmol) and K
2CO
3(3.15g 22.78mmol) stirred 12 hours in toluene (10mL).Make reactant distribution between ethyl acetate and water, organic layer salt water washing is through anhydrous Na
2SO
4Dry.Removal of solvent under reduced pressure, product obtains title compound through column chromatography purification (10-25%EtOAc/ hexane), is yellow foam thing (2.2g, 45%),
1H NMR (300MHz, CDCl
3): 7.58 (s, 1H), 7.50 (s, 1H), 4.36 (s, 2H), 3.48 (d, 2H), 2.10-2.14 (m, 2H), 1.64-1.82 (m, 5H), 1.35-1.447 (m, 2H)
Embodiment 5:7-chloro-2-[(4,4-difluoro cyclohexyl) methyl]-1-oxoisoindoline diindyl-5-nitrile
Under argon gas, with 5-bromo-7-chloro-2-[(4,4-difluoro cyclohexyl) methyl] (1.14g 3.01mmol) stirs in DMF (10mL) isoindoline-1-ketone, adds Zn (CN)
2(389mg, 3.31mmol) and Pd (PPh
3)
4(347mg, 0.3mmol).In 80 ℃ this reactant was stirred 1.5 hours.Make reactant distribution between ethyl acetate and water, organic layer salt water washing is through anhydrous Na
2SO
4Dry.Removal of solvent under reduced pressure, product obtains title compound through column chromatography purification (40%EtOAc/ hexane), is yellow foam thing (60mg, 80%).
1H?NMR(300MHz，CDCl
3)：7.72(s，1H)，7.65(s，1H)，4.45(s，2H)，3.53(d，2H)，2.11-2.15(m，2H)，1.66-1.91(m，5H)，1.41-1.50(m，2H)
Embodiment 6:7-chloro-5-[5-(chloro methyl)-1,2,4-oxadiazole-3-yl]-2-[(4,4-two fluoro-cyclohexyl) methyl] isoindoline-1-ketone
To 7-chloro-N-hydroxyl-1-oxo-2-[(4,4-difluoro cyclohexyl) methyl]-2, (450mg, (170mg 1.51mmol), then adds K to 3-dihydro-1H-isoindole-5-carbonamidine to add chloro-acetyl chloride in acetonitrile 1.26mmol) (10ml) solution
2CO
3(260mg, 1.89mmol).This mixture stirring is spent the night.After EtOAc (20ml) dilution, with its water, salt water washing,, filter and concentrate through anhydrous sodium sulfate drying, obtain yellow foam thing.In 140 ℃ this foam thing was stirred 3 hours in DMF (2ml).After being cooled to room temperature, with its water (5ml) dilution, product extracts with EtOAc.Organic layer water, salt water washing through anhydrous sodium sulfate drying, are filtered and are concentrated.Product obtains title compound through column chromatography purification (40-60%EtOAc is in hexane), is white solid
Embodiment 7.1:7-chloro-N-hydroxyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbonamidine (carboxamidine)
To 7-chloro-1-oxo-2-[4-(trifluoromethoxy) benzyl] isoindoline-5-nitrile (500mg, 1.36mmol) in the suspension of ethanol (2ml), add oxine (495mg, 3.41mmol), then add hydroxylamine hydrochloride (199mg, 2.86mmol) water (1ml) solution and yellow soda ash (230mg, water 2.2mmol) (1ml) solution.The mixture that obtains was refluxed 4 hours.Except that after desolvating, make residue through flash chromatography.Purified product (20%EtOAc/ hexane-2% ammonia is in MeOH/EtOAc) obtains 500mg light green foam thing (90%).
1H?NMR(300MHz，CDCl
3)：δ10.04(s，1H)7.48-7.61(m，2H)，7.28-7.36(m，2H)，7.17-7.21(m，2H)，6.04(br，1H)，4.77(s，2H)，4.22(s，2H)。
Make following compound in a similar manner:
Embodiment 8.1:7-chloro-5-[5-(4-hydroxy-piperdine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone
To 4-hydroxy piperidine (9.9mg, 0.098mmol), 7-chloro-5-chloro methyl-[1,2,4] oxadiazole-3-yl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone (30mg, 0.065mmol) and salt of wormwood (27mg adds acetonitrile (3.0mL) in mixture 0.195mmol).This mixture stirred under room temperature spend the night.Add entry (2.0mL), the product ethyl acetate extraction.Organic layer water, salt water washing through dried over sodium sulfate, are filtered and are concentrated.Column chromatography provides title compound, is yellow oil, 16.7mg (49%).
1H?NMR(300MHz，CDCl
3)：δ8.20(s，1H)，8.04(s，1H)，7.38-7.41(m，2H)，7.20-7.23(m，2H)，4.82(s，2H)，4.34(s，2H)，3.95(s，2H)，3.75(br，1H)，2.90-2.93(m，2H)，2.42-2.50(m，2H)，1.94-1.99(m，2H)，1.64-1.74(m，3H)
Make following compound in a similar manner:
Embodiment 9.1:4-(2-cyclopropyl methyl-7-methyl isophthalic acid-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl)-piperidines-1-carboxylic acid tertiary butyl ester
To the 4-methylene radical-piperidines-1-carboxylic acid tertiary butyl ester of purging (argon gas) (727mg, add in 3.68mmol) 9-BBN (11.32mL, 5.66mmol).This mixture was stirred 2 hours in 60 ℃.After being cooled to room temperature, this solution is joined 5-bromo-7-methyl-2-cyclopropyl methyl-2, and 3-dihydro-isoindole-1-ketone (794mg, 2.83mmol), Pd (dppf) Cl
2(115mg, 0.142mmol), (1.17g is 8.49mmol) and in the water (2.5mL) for DMF (25mL), salt of wormwood.This mixture was stirred 1.5 hours in 75 ℃.This mixture is cooled in room temperature and the impouring water (3mL) then.The product ethyl acetate extraction.The organic layer that merges washes with water 3 times, uses the salt water washing, through dried over sodium sulfate, filters and concentrates.Column chromatography (30% ethyl acetate/hexane) provides title compound, is light yellow oil (777mg, 53%).
1H?NMR(300MHz，CDCl
3)：δ7.01(s，1H)，6.94(s，1H)，4.39(s，2H)，3.42(d，2H)，2.68(s，3H)，2.57(s，2H)，2.54(d，2H)，1.70-1.62(m，4H)，1.43(s，9H)，1.09(d，1H)，1.01(m，1H)，0.56-0.5(m，2H)，0.31-0.29(m，2H)。
Make following compound in a similar manner:
Embodiment 10.1:2-cyclopropyl methyl-7-methyl-5-piperidin-4-yl methyl-2,3-dihydro-isoindole-1-ketone
Make 4-[7-methyl isophthalic acid-oxo-2-cyclopropyl methyl-2,3-dihydro-1H-isoindole-5-yl]-(777mg 1.95mmol) is dissolved in formic acid (10mL) to piperidines-1-carboxylic acid tertiary butyl ester, stirs 0.5 hour under room temperature.Decompression removes formic acid removal, product NaHCO
3CH is used in neutralization
2Cl
2Extract.Organic layer salt water washing is through anhydrous Na
2SO
4Drying is filtered and is concentrated, and obtains title compound (578mg, 99%), is brown oil.
1H?NMR(300MHz，CDCl
3)：δ7.02(s，1H)，6.95(s，1H)，4.40(s，2H)，3.43(d，2H)，3.07-3.03(d，2H)，2.69(s，3H)，2.56-2.38(m，4H)，2.38(br?s，1H)，1.64-1.61(m，4H)，1.19-1.15(m，2H)，1.02(m，1H)，0.57-0.53(m，2H)，0.34-0.30(m，2H)。
Make following compound in a similar manner:
Embodiment 11.2-cyclopropyl methyl-5-[1-(2-fluoro benzyl)-piperidin-4-yl methyl]-7-methyl-2,3-dihydro-isoindole-1-ketone
To 2-fluoro bromotoluene (47 μ L, 0.377mmol), 7-methyl-5-piperidin-4-yl methyl-2-cyclohexyl propyl group-2,3-dihydro-isoindole-1-ketone (75mg, 0.251mmol) and salt of wormwood (104mg adds acetonitrile (3.0mL) in mixture 0.753mmol).This mixture was stirred 4 hours in 80 ℃.Add 1 sodium tert-butoxide (～200mg), continue to stir in 80 ℃ and to spend the night.Make this mixture be cooled to room temperature, add entry (2.0mL), the product ethyl acetate extraction.Organic layer water, salt water washing through dried over sodium sulfate, are filtered and are concentrated.Column chromatography provides title compound, is yellow oil (6.6mg, 6%).
1H?NMR(300MHz，CDCl
3)：δ7.38(m，1H)，7.23-7.13(m，1H)，7.11-7.00(m，3H)，6.96(s，1H)，4.41(s，2H)，3.61(s，2H)，3.46-3.44(d，2H)，2.95-2.92(d，2H)，2.70(s，3H)，2.59-2.57(d，2H)，2.01-1.98(t，2H)，1.65-1.61(m，3H)，1.38-1.27(m，2H)，1.04(m，1H)，0.60-0.55(m，2H)，0.36-0.32(m，2H)。
Embodiment 12.1:2-cyclohexyl methyl-7-methyl-5-(1-pyrimidine-2-base methyl-piperidin-4-yl methyl)-2,3-dihydro-isoindole-1-ketone
To 2-chloro methylpyrimidine (32mg, 0.247mmol), 2-cyclohexyl methyl-7-methyl-5-piperidin-4-yl methyl-2,3-dihydro-isoindole-1-ketone (56mg, 0.164mmol) and cesium carbonate (160mg adds acetonitrile (3.0mL) in mixture 0.492mmol).This mixture stirred under room temperature spend the night.Add entry (2.0mL), the product ethyl acetate extraction.Organic layer water, salt water washing through dried over sodium sulfate, are filtered and are concentrated.Column chromatography provides title compound, is yellow oil (48mg, 69%).
1H?NMR(300MHz，CDCl
3)：δ8.76-8.72(d，2H)，7.18(t，1H)，6.99(s，1H)，6.95(s，1H)，4.30(s，2H)，3.78(s，2H)，3.40-3.37(d，2H)，2.97-2.93(d，2H)，2.70(s，3H)，2.58-2.56(d，2H)，2.10-2.05(t，2H)1.71-1.42(m，10H)，1.26-1.13(m，4H)，1.09-0.98(m，2H)。
Make following compound in a similar manner:
Embodiment 13.1:2-cyclopropyl methyl-5-[1-(3-fluoro-benzyl)-piperidin-4-yl methyl]-7-methyl-2,3-dihydro-isoindole-1-ketone
To 2-cyclopropyl methyl-7-methyl-5-piperidin-4-yl methyl-2, (30mg slowly adds acetate (1mL) to 3-dihydro-isoindole-1-ketone in methyl alcohol 0.101mmol) (2mL) solution.After stirring 5 minutes under the room temperature, be added dropwise to 3-fluoro-phenyl aldehyde (12.8L, 0.121mmol) and sodium cyanoborohydride (8L, 0.111mmol).This mixture was stirred under room temperature 2 hours, with saturated sodium bicarbonate (10mL) neutralization.Use the dichloromethane extraction aqueous mixture, organism filters and concentrates through anhydrous sodium sulfate drying.Column chromatography (the 10-40% ethyl acetate is in hexane) provides title compound, is yellow oil.
1H?NMR(300MHz，CDCl
3)：δ7.70-7.23(m，1H)，7.09-7.03(m，3H)，6.97-6.92(m，2H)，4.41(s，2H)，3.48-3.44(m，4H)，2.88-2.85(d，2H)，2.71(s，3H)，2.60-2.57(d，2H)，1.93(t，2H)，1.64-1.50(m，3H)，1.36-1.28(m，2H)，1.04(m，1H)，0.60-0.55(m，2H)，0.34-0.32(m，2H)
Make following compound in a similar manner:
Embodiment 14:2-cyclopropyl methyl-5-iodo-7-methyl-2,3-dihydro-isoindole-1-ketone
To 5-bromo-7-methyl-2-cyclopropyl methyl-2,3-dihydro-isoindole-1-ketone (1.0g, 3.56mmol) butanols (10ml) solution in add (1R, 2R)-N, N '-dimethyl cyclohexane-1, and the 2-diamines (204mg, 1.42mmol), cuprous iodide (I) (140mg, 0.714mmol) and sodium iodide (1.08g, 14.3mmol).The mixture that obtains is spent the night in 120 ℃ of stirrings.After the cooling, this mixture dilutes with ethyl acetate, and water, salt water washing through anhydrous sodium sulfate drying, are filtered, concentrated.Column chromatography (30%EtOAc/ hexane) provides title compound (1.07g, 92%), is colorless solid.
1H?NMR(300MHz，CDCl
3)：δ7.65(s，1H)，7.59(s，1H)，4.42(s，2H)，3.46-3.44(d，2H)，2.70(s，3H)，1.04-1.02(m，1H)，0.61-0.57(m，2H)，0.34-0.31(m，2H)
Embodiment 15:5-(1-benzyl-tetramethyleneimine-3-base is amino)-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone
Make 3-amino-1-benzyl-tetramethyleneimine (57mg, 0.325mmol), 5-bromo-7-methyl-2-(4-trifluoro-methoxybenzyl)-2,3-dihydro-isoindole-1-ketone (100mg, 0.25mmol), NaO
tBu (168mg, 1.75mmol), BINAP (16mg, 0.025mmol) and Pd
2(dba)
3(23mg 0.025mmol) is dissolved in dry toluene (5mL).This mixture is dipped in 110 ℃ of oil baths.After 18 hours, in cooling reactant and the impouring water, use ethyl acetate extraction.Organic phase salt water washing is through MgSO
4Drying is filtered and is concentrated.Through this compound of column chromatography (50%EtOAc/ hexane) purifying, obtain title compound, be yellow jelly (87mg, 70%).
1H NMR (300MHz, CDCl
3): δ 7.24-7.34 (m, 7H), 7.18 (d, 2H), 6.34 (d, 2H), 4.72 (s, 2H), 4.33 (d, 1H), 4.12 (s, 2H), 4.04 (m, 1H), 3.64 (lower (collapsed) dd, 2H), 2.75-2.83 (m, 2H), 2.66 (s, 3H), 2.58 (dd, 1H), 2.45 (ddd, 1H), 2.32-2.42 (m, 1H), 1.67-1.70 (m, 1H).
Embodiment 16.1:7-methyl-5-[5-(4-methyl-piperazine-1-ylmethyl)-pyridin-3-yl]-2-(4-trifluoro-methoxybenzyl)-2,3-dihydro-isoindole-1-ketone
Make methylsulfonic acid 5-[7-methyl isophthalic acid-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-yl]-(36mg 0.071mmol) is dissolved in THF (5mL) to the pyridin-3-yl methyl ester.(24uL 0.213mmol), stirs this mixture 18 hours in 50 ℃ to add N methyl piperazine.Cool off this mixture, dilute with water is used ethyl acetate extraction.Organic phase salt water washing through anhydrous sodium sulfate drying, is filtered and is concentrated.Column chromatography (5%2M NH
3In MeOH/CH
2Cl
2) title compound (24mg, 67%) is provided, be yellow oil.
1H?NMR(300MHz，CDCl
3)：δ8.73(s，1H)，8.56(s，1H)，7.86(s，1H)，7.42(d，2H)，7.37(d，2H)，7.19(d，2H)，4.82(s，2H)，4.32(s，2H)，3.60(s，2H)，2.85(s，3H)，2.52-2.42(br?s，8H)，2.30(s，3H)。
Make following compound in a similar manner:
Embodiment 17.1:4-{4-[7-chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-ylmethyl]-piperidines-1-ylmethyl }-benzonitrile
To 4-cyano group-bromotoluene (12mg, 0.06mmol), 7-chloro-5-piperidin-4-yl methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone (30.0mg, 0.06mmol) and salt of wormwood (42mg adds acetonitrile (3.0mL) in mixture 0.3mmol).This mixture stirred under room temperature spend the night.Add entry (2.0mL), the product ethyl acetate extraction.Organic layer water, salt water washing through dried over sodium sulfate, are filtered and are concentrated.Column chromatography provides title compound, is brown oil (39.0mg, 99%).
1H?NMR(300MHz，CDCl
3)：δ7.60(d，2H)，7.27-7.59(m，4H)，7.17-7.20(m，3H)，7.05(s，1H)，4.77(s，2H)，4.22(s，2H)，3.53(s，2H)，2.80-2.84(m，2H)，2.58-2.60(m，2H)，1.91(t，2H)，1.56-1.62(m，3H)，1.27-1.34(m，2H)。
Make following compound in a similar manner:
Embodiment 18.1:4-{4-[7-chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-ylmethyl]-piperazine-1-methyl }-the cigarette nitrile
Make 4-(piperazine-1-ylmethyl) benzonitrile (30mg, 0.094mmol) be dissolved in methylene dichloride (2.0mL), add 7-chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2, and 3-dihydro-1H-isoindole-5-formaldehyde (carbaldehyde) (20.0mg, 0.054mmol).This mixture was stirred 10 minutes, and (16.1mg 0.076mmol), spends the night this reactant stirring to add sodium triacetoxy borohydride.With the methylene dichloride dilution,,, filter and concentrate then through dried over sodium sulfate with saturated sodium bicarbonate and salt water washing.Column chromatography (20%MeOH/EtOAc) provide title compound, is yellow oil (17.9mg, 32%).
1H?NMR(300MHz，CDCl
3)：δ7.60-7.63(m，2H)，7.34-7.47(m，5H)，7.27-7.28(m，1H)，7.18-7.21(m，2H)，4.78(m，2H)，4.24(s，2H)，3.55-3.57(m，4H)，2.48-2.53(m，8H)。
Make following compound in a similar manner:
Embodiment 19:7-chloro-2-cyclopropyl methyl isophthalic acid-oxo-2,3-dihydro-1H-isoindole-5-nitrile
Under argon gas, with 5-bromo-7-chloro-2-cyclopropyl methyl-2, (360mg 1.20mmol) stirs in DMF (15mL) 3-dihydro-isoindole-1-ketone, adds Zn (CN)
2(154mg, 1.32mmol) and Pd (PPh
3)
4(139mg, 0.12mmol).In 80 ℃ of reaction stirred 1.5 hours.Make reactant distribution between ethyl acetate and water, organic layer salt water washing is through anhydrous Na
2SO
4Dry.Removal of solvent under reduced pressure, product obtain yellow solid (142.6mg, 82%) through column chromatography purification (40%EtOAc/ hexane).
1H?NMR(300MHz，CDCl
3)：δ7.53(s，2H)，7.36(d，2H)，7.22(s，2H)，4.80(s，2H)，4.30(s，2H)，2.81(s，3H)。
Embodiment 20:7-trifluoromethyl-5-methoxyl group-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone
With 7-trifluoromethyl-5-bromo-2-(4-trifluoromethoxy-benzyl)-2, (0.060g 0.15mmol) stirred 1 hour in 100 ℃ with the mixture of 30% sodium methylate-methyl alcohol (0.21mL) in methyl alcohol (4mL) 3-dihydro-isoindole-1-ketone.Aftertreatment and through silica gel column chromatography with 30% ethyl acetate/hexane wash-out, obtains 7-trifluoromethyl-5-methoxyl group-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone (0.043g, 70%).
1H?NMR(300MHz，CDCl
3)：
(ppm)3.88(s，3H)，4.25(s，2H)，4.76(s，2H)，7.02(s，1H)，7.17(d，2H)，7.28(s，1H)，7.37(d，2H)。
Embodiment 21:5,7-dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone
Under nitrogen atmosphere, to the 4-bromo-5 in benzene, 7-dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone (0.200g, 0.45mmol) add 2, two (the 2-methyl propionitrile) AIBN (5.0mg) of 2 '-azo, then add tributyltin hydride (0.238mL, 0.9mmol).The mixture that obtains was refluxed in oil bath 2 hours.Disappear until starting raw material by the GC-MS monitoring reaction.Make reaction mixture be cooled to room temperature, stirred 45 minutes with Potassium monofluoride (200mg).Cross filter solid and concentrated filtrate.With column chromatography (the common 40% ethyl acetate/hexane) material that purifying obtains, obtain 5,7-dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone (0.106g, 64%).
1H?NMR(300MHz，CDCl
3)：
(ppm)3.82(s，3H)，3.95(s，3H)，4.17(s，2H)，4.72(s，2H)，6.43(d，2H)，7.16(d，2H)，7.32(d，2H).GC-MS：m/z?367(M)
+，349(M-18)
+。
Embodiment 22:5,7-dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindole-1-ketone
Under nitrogen atmosphere, to the 4-bromo-5 in benzene, 7-dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindole-1-ketone (0.100g, 0.25mmol) middle adding 2, two (the 2-methyl propionitrile) AIBN (5.0mg) of 2 '-azo, then add tributyltin hydride (0.132mL, 0.5mmol).The mixture that obtains was refluxed in oil bath 2 hours.Disappear until starting raw material by the GC-MS monitoring reaction.Make reaction mixture be cooled to room temperature, stirred 45 minutes with Potassium monofluoride (200mg).Cross filter solid and concentrated filtrate.With column chromatography (the common 40% ethyl acetate/hexane) material that purifying obtains, obtain 5,7-dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindole-1-ketone (0.035g, 44%).
1H?NMR(300MHz，CDCl
3)：
(ppm)3.82(s，3H)，3.95(s，3H)，4.15(s，2H)，4.69(s，2H)，6.43(d，2H)，7.25(m，4H).GC-MS：m/z?317(M)
+，299(M-18)
+。
Embodiment 23:5,7-dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindole-1-ketone
Under nitrogen atmosphere, to the 4-bromo-5 in benzene, 7-dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindole-1-ketone (0.112g, 0.27mmol) middle adding 2, two (the 2-methyl propionitrile) AIBN (5.0mg) of 2 '-azo, then add tributyltin hydride (0.145mL, 0.55mmol).The mixture that obtains was refluxed in oil bath 2 hours.Disappear until starting raw material by the GC-MS monitoring reaction.Make reaction mixture be cooled to room temperature, stirred 45 minutes with Potassium monofluoride (200mg).Cross filter solid and concentrated filtrate.With column chromatography (the common 40% ethyl acetate/hexane) material that purifying obtains, obtain 5,7-dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindole-1-ketone (0.056g, 63%).
1H?NMR(300MHz，CDCl
3)：
(ppm)1.43(d，3H)，3.63(s，3H)，3.68(d，1H)，3.74(s，3H)，3.99(d，1H)，5.53(q，1H)，6.23(dd，2H)，7.15(m，4H).GC-MS：m/z?331(M)
+，316(M-15)
+。
Claims (10)
1. compound or its pharmacy acceptable salt, hydrate, solvate, optical isomer or its combination according to a formula I:
Wherein:
R
1Be to contain the first ring of the one or more heteroatomic 3-7 that independently is selected from N, O and S, wherein said ring can be replaced by one or more A;
R
2And R
3Independently be selected from H, C
1-6-alkyl, C
2-6-alkenyl, C
2-6-alkynyl, aryl, heteroaryl, Heterocyclylalkyl, C
3-8-cycloalkyl, C
1-6-alkyl-aryl, C
1-6-alkyl-heteroaryl, C
1-6-alkyl-Heterocyclylalkyl and C
1-6-alkyl-C
3-8-cycloalkyl, wherein R
2And R
3Can be replaced by one or more A;
R
4And R
6Independently be selected from H, hydroxyl, F, Cl, Br, I, nitro, cyano group, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, aryl, C
1-6-alkylaryl, OC
0-6-alkylaryl, (CO) R
10, O (CO) R
10, O (CO) OR
10, C (O) OR
10, O (CNR
10) OR
11, C
1-6-alkyl OR
10, OC
2-6-alkyl OR
10, C
1-6-alkyl (CO) R
10, OC
1-6-alkyl (CO) R
10, C
0-6-alkyl CO
2R
10, OC
1-6-alkyl CO
2R
10, C
1-6-alkyl cyano group, OC
2-6-alkyl cyano group, C
0-6-alkyl NR
10R
11, OC
2-6-alkyl NR
10R
11, C
1-6-alkyl (CO) NR
10R
11, OC
1-6-alkyl (CO) NR
10R
11, C
0-6-alkyl NR
10(CO) R
11, OC
2-6-alkyl NR
10(CO) R
11, C
0-6-alkyl NR
10(CO) NR
10R
11, C
0-6-alkyl SR
10, OC
2-6-alkyl SR
10, C
0-6-alkyl (SO) R
10, OC
2-6-alkyl (SO) R
10, C
0-6-alkyl SO
2R
10, OC
2-6-alkyl SO
2R
10, C
0-6-alkyl (SO
2) NR
10R
11, OC
2-6-alkyl (SO
2) NR
10R
11, C
0-6-alkyl NR
10(SO
2) R
11, OC
2-6-alkyl NR
10(SO
2) R
11, C
0-6-alkyl NR
10(SO
2) NR
10R
11, OC
2-6-alkyl NR
10(SO
2) NR
10R
11, (CO) NR
10R
11, O (CO) NR
10R
11, NR
10OR
11, C
0-6-alkyl NR
10(CO) OR
11, OC
2-6-alkyl NR
10(CO) OR
11, SO
3R
10With can contain the one or more heteroatomic 5-7 unit ring that independently is selected from N, O and S, wherein R
4And R
6Can be replaced by one or more A and wherein any cycloalkyl or aryl optional with can contain the one or more heteroatomic 5-7 unit that independently is selected from C, N, O and S and encircle and condense;
R
5Be selected from CN, OC
0-6-alkyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, C
0-6-alkylaryl, OC
0-6-alkylaryl, C
0-6-miscellaneous alkyl aryl, OC
0-6-miscellaneous alkyl aryl, Heterocyclylalkyl, C
1-6-alkyl heterocycle alkyl, OC
0-6-alkyl heterocycle alkyl and (CO) R
10, wherein any loop section can be replaced by one or more B;
R
7Be selected from H, F, Cl, Br, I, nitro, cyano group, OC
1-4-alkyl, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl and C
3-8-cycloalkyl;
R
8And R
9Independently be selected from H, F, Cl, Br, I, nitro, cyano group, C
1-6-alkyl, halo C
1-6-alkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl and OC
2-6-alkynyl,
Perhaps, n wherein is greater than 1, the two or more R on the adjacent carbons
8And/or R
9May not exist, form alkenyl or alkynyl part;
R
10And R
11Independently be selected from H, hydroxyl, oxo, F, Cl, Br, I, nitro, cyano group, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, aryl, C
1-6-alkylaryl, OC
0-6-alkylaryl, C
0-6-alkyl-Heterocyclylalkyl, OC
1-6-alkyl-Heterocyclylalkyl, heteroaryl, C
1-6Miscellaneous alkyl aryl, Heterocyclylalkyl-C
1-6-alkylaryl and Heterocyclylalkyl-C
1-6-miscellaneous alkyl aryl, wherein any loop section is optional to condense with containing the first ring of the one or more heteroatomic 5-7 that independently is selected from C, N, O and S, and the optional substituting group that is selected from alkyl, halogeno-group, hydroxyl, O alkyl, haloalkyl and O haloalkyl of any loop section replaces;
A is selected from H, hydroxyl, F, Cl, Br, I, nitro, cyano group, oxo, C
1-6-alkyl, C
1-6-haloalkyl, OC
1-6Alkyl, OC
1-6-haloalkyl, C
2-6-alkenyl, OC
2-6-alkenyl, C
2-6-alkynyl, OC
2-6-alkynyl, C
3-8-cycloalkyl, C
1-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, aryl, C
1-6-alkylaryl, OC
0-6-alkylaryl, C
1-6-alkyl-heterocyclic radical, C
1-6-alkyl-Heterocyclylalkyl, OC
0-6-alkyl-Heterocyclylalkyl, (CO) R
10, O (CO) R
10, O (CO) OR
10, O (CNR
10) OR
11, C
1-6-alkyl OR
10, OC
2-6-alkyl OR
10, C
1-6-alkyl (CO) R
10, OC
1-6-alkyl (CO) R
10, C
0-6-alkyl CO
2R
10, OC
1-6-alkyl CO
2R
10, C
1-6-alkyl cyano group, OC
2-6-alkyl cyano group, C
0-6-alkyl NR
10R
11, OC
2-6-alkyl NR
10R
11, C
0-6-alkyl (CO) NR
10R
11, OC
1-6-alkyl (CO) NR
10R
11, C
0-6-alkyl NR
10(CO) R
11, OC
2-6-alkyl NR
10(CO) R
11, C
0-6-alkyl NR
10(CO) NR
10R
11, C
0-6-alkyl SR
10, OC
2-6-alkyl SR
10, C
0-6-alkyl (SO) R
10, OC
2-6-alkyl (SO) R
10, C
1-6-alkyl SO
2R
10, OC
2-6-alkyl SO
2R
10, C
0-6-alkyl (SO
2) NR
10R
11, OC
2-6-alkyl (SO
2) NR
10R
11, C
0-6-alkyl NR
10(SO
2) R
11, OC
2-6-alkyl NR
10(SO
2) R
11, C
0-6-alkyl NR
10(SO
2) NR
10R
11, OC
2-6-alkyl NR
10(SO
2) NR
10R
11, (CO) NR
10R
11, O (CO) NR
10R
11, NR
10OR
11, C
0-6-alkyl NR
10(CO) OR
11, OC
2-6-alkyl NR
10(CO) OR
11, SO
3R
10With can contain the one or more heteroatomic 5-7 unit ring that independently is selected from N, O and S, wherein said 5-7 unit ring is optional by one or more R
10And R
11Replace;
B is selected from C
0-6-alkyl-C
3-8-cycloalkyl, OC
0-6-alkyl-C
3-8-cycloalkyl, C
0-6-alkylaryl, OC
0-6-alkylaryl, C
1-6-alkyl-Heterocyclylalkyl, OC
0-6-alkyl-Heterocyclylalkyl, C
1-6-miscellaneous alkyl aryl and OC
1-6-miscellaneous alkyl aryl, wherein any loop section is selected from halogeno-group, alkyl, haloalkyl, alkoxyl group, oxo, COR, CO
2R, SO
2At least one substituting group of R and CN replaces;
R is selected from H and alkyl;
With
N is selected from 1,2,3,4,5,6,7 and 8;
Prerequisite is that described compound is not following compound:
5-(4-benzyl-piperazine-1-carbonyl)-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
7-methyl-5-(4-pyridin-4-yl methyl-piperazine-1-carbonyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
7-methyl-5-[4-(2-pyridin-4-yl-ethyl) piperazine-1-carbonyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
4-{4-[7-methyl isophthalic acid-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-ylmethyl]-piperidines-1-ylmethyl }-benzonitrile,
2-benzyl-1-oxo-2,3-dihydro-1H-isoindole-5-nitrile,
7-chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-nitrile,
7-methyl isophthalic acid-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-nitrile,
7-methyl isophthalic acid-oxo-2-(4-chloro-benzyl)-2,3-dihydro-1H-isoindole-5-nitrile,
1-oxo-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-1H-isoindole-5-nitrile,
3-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-4, the 6-dintrile,
7-iodo-5-methoxyl group-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
2-benzyl-5-methoxyl group-2,3-dihydro-isoindole-1-ketone and
7-chloro-5-methoxyl group-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone.
2. one kind is selected from following compound or its pharmacy acceptable salt, hydrate, solvate, optical isomer or its combination:
1) 7-chloro-2-[(4,4-difluoro cyclohexyl) methyl]-1-oxoisoindoline diindyl-5-nitrile,
2) 7-chloro-5-[5-(4-hydroxy-piperdine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
3) 7-chloro-5-[5-(4-oxo-piperidines-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
4) 7-chloro-5-[5-(4-fluoro-piperidine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
5) 7-chloro-2-(4,4-two fluoro-cyclohexyl-methyl)-5-[5-(4-fluoro-piperidine-1-ylmethyl)-[1,2,4] oxadiazole-3-yl]-2,3-dihydro-isoindole-1-ketone,
6) 4-{5-[7-methyl isophthalic acid-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-yl]-[1,2,4] oxadiazole-3-ylmethyls }-piperazine-1-formaldehyde,
7) 2-cyclopropyl methyl-5-[1-(2-fluoro benzyl)-piperidin-4-yl methyl]-7-methyl-2,3-dihydro-isoindole-1-ketone,
8) 7-methyl-5-[3-(4-methyl-piperazine-1-ylmethyl)-[1,2,4] oxadiazole-5-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
9) 4-{5-[7-methyl isophthalic acid-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-yl]-[1,2,4] oxadiazole-3-ylmethyls }-piperazine-1-carboxylic acid tertiary butyl ester,
10) 2-cyclopropyl methyl-5-[1-(3-fluoro-benzyl)-piperidin-4-yl methyl]-7-methyl-2,3-dihydro-isoindole-1-ketone,
11) 2-cyclopropyl methyl-5-[1-(2-methoxyl group-benzyl)-piperidin-4-yl methyl]-7-methyl-2,3-dihydro-isoindole-1-ketone,
12) 2-cyclopropyl methyl-5-[1-(3-methoxyl group-benzyl)-piperidin-4-yl methyl]-7-methyl-2,3-dihydro-isoindole-1-ketone,
13) 2-cyclopropyl methyl-5-[1-(4-methoxyl group-benzyl)-piperidin-4-yl methyl]-7-methyl-2,3-dihydro-isoindole-1-ketone,
14) 2-cyclopropyl methyl-5-[1-(4-fluoro-benzyl)-piperidin-4-yl methyl]-7-methyl-2,3-dihydro-isoindole-1-ketone,
15) 2-cyclohexyl methyl-5-[1-(3-fluoro-benzyl)-piperidin-4-yl methyl]-7-methyl-2,3-dihydro-isoindole-1-ketone,
16) 2-cyclohexyl methyl-5-[1-(4-fluoro-benzyl)-piperidin-4-yl methyl]-7-methyl-2,3-dihydro-isoindole-1-ketone,
17) 2-cyclopropyl methyl-5-[1-(3-fluoro-benzyl)-piperidin-4-yl methoxyl group]-7-methyl-2,3-dihydro-isoindole-1-ketone,
18) 2-cyclopropyl methyl-5-[1-(4-methoxy-benzyl)-piperidin-4-yl methoxyl group]-7-methyl-2,3-dihydro-isoindole-1-ketone,
19) 5-(1-benzyl-tetramethyleneimine-3-base is amino)-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
20) 7-methyl-5-[5-(4-methyl-piperazine-1-ylmethyl)-pyridin-3-yl] 2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
21) 7-methyl-5-[6-(4-methyl-piperazine-1-ylmethyl)-pyridin-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
22) 4-{4-[7-chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-ylmethyl]-piperidines-1-ylmethyl }-benzonitrile,
23) 4-[4-(7-chloro-2-cyclopropyl methyl isophthalic acid-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl)-piperidines-1-ylmethyl]-benzonitrile,
24) 4-{4-[7-chloro-2-(4-chloro-benzyl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-piperidines-1-ylmethyl }-benzonitrile,
25) 4-{4-[7-chloro-2-(4-difluoro-methoxy-benzyl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-piperidines-1-ylmethyl }-benzonitrile,
26) 4-{4-[7-chloro-2-(4-ethyl-benzyl)-1-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl]-piperidines-1-ylmethyl }-benzonitrile,
27) 4-{4-[7-chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-ylmethyl]-piperazine-1-methyl }-the cigarette nitrile,
28) 3-{3-[1-(7-chloro-2-cyclopropyl methyl isophthalic acid-oxo-2,3-dihydro-1H-isoindole-5-ylmethyl)-piperidin-4-yl]-propyl group }-benzonitrile,
29) 7-chloro-2-cyclopropyl methyl isophthalic acid-oxo-2,3-dihydro-1H-isoindole-5-nitrile,
30) 5-fluoro-2-(4-ethyl-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindole-1-ketone,
31) 5,7-dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindole-1-ketone,
32) 5,7-dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindole-1-ketone and
33) 5,7-dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindole-1-ketone.
3. medicinal compositions, it comprises compound and the pharmaceutically acceptable carrier or the vehicle of claim 1 or 2.
4. claim 1 or 2 compound, it is as medicine.
Claim 1 or 2 compound preparation be used for the treatment of L-glutamic acid dysfunction related neural sick learn and the medicine of psychiatric disorders in purposes.
6. the purposes of claim 5, wherein said neurological and psychiatric disorders be selected from the heart bypass operation and transplant after the brain that causes damaged, apoplexy, cerebral ischemia, spinal cord injuries receptor, wound, perinatal hypoxia, heart stopping collecting, hypoglycemic neuronal damage, dull-witted, the dementia that AIDS brings out, presenile dementia, huntington's chorea, amyotrophic lateral sclerosis, ocular injury, retinopathy, cognitive disorder, spontaneous and drug-induced Parkinson's disease, muscle spasm and comprise with the muscle spasm diseases associated is trembled, epilepsy, faint from fear, the brain of epileptic state that is secondary to prolongation is damaged, migraine, the migraine headache, the urinary incontinence, the material tolerance, disease is given up in substance abuse, psychosis, schizophrenia, anxiety disorder, generalized anxiety disorder, paranoid fears, social phobia, obsession and post-traumatic stress disorder (PTSD), mood disorder, dysthymia disorders, mania, two-way affective disorder, the circadian rhythm obstacle, jet lag, shift work syndrome, trigeminal neuralgia, hearing disability, tinnitus, the eyes macular degeneration, vomiting, cerebral edema, pain, acute pain, chronic pain, have an intense pain, refractory pain, neuropathic pain, pain after inflammatory pain and the wound, tardive dyskinesia, somnopathy, hypnolepsy, attention disappearance/hyperfunction obstacle and behavior disorder.
7. treatment or prevention need that the L-glutamic acid dysfunction related neural of the animal of treatment like this is sick to be learned and the method for psychiatric disorders, and this method comprises the step according to the compound of claim 1 or 2 that gives described treatment of animals significant quantity.
8. treatment or prevention need that the L-glutamic acid dysfunction related neural of the animal of treatment like this is sick to be learned and the method for psychiatric disorders, and this method comprises the step according to the medicinal compositions of claim 3 that gives described treatment of animals significant quantity.
9. according to the method for claim 7 or 8, it is damaged that wherein said neurological and psychiatric disorders are selected from the brain that causes after heart bypass operation and the transplanting, apoplexy, cerebral ischemia, spinal cord injuries receptor, wound, perinatal hypoxia, heart stopping collecting, hypoglycemic neuronal damage, dull-witted, the dementia that AIDS brings out, presenile dementia, huntington's chorea, amyotrophic lateral sclerosis, ocular injury, retinopathy, cognitive disorder, spontaneous and drug-induced Parkinson's disease, muscle spasm and comprise with the muscle spasm diseases associated is trembled, epilepsy, faint from fear, the brain of epileptic state that is secondary to prolongation is damaged, migraine, the migraine headache, the urinary incontinence, the material tolerance, disease is given up in substance abuse, psychosis, schizophrenia, anxiety disorder, generalized anxiety disorder, paranoid fears, social phobia, obsession and post-traumatic stress disorder (PTSD), mood disorder, dysthymia disorders, mania, two-way affective disorder, the circadian rhythm obstacle, jet lag, shift work syndrome, trigeminal neuralgia, hearing disability, tinnitus, the eyes macular degeneration, vomiting, cerebral edema, pain, acute pain, chronic pain, have an intense pain, refractory pain, neuropathic pain, pain after inflammatory pain and the wound, tardive dyskinesia, somnopathy, hypnolepsy, attention disappearance/hyperfunction obstacle and behavior disorder.
10. the brain of epileptic state that the method for claim 9, wherein said neurological and psychiatric disorders be selected from presenile dementia, be secondary to prolongation is damaged, disease, psychosis, schizophrenia, anxiety disorder, generalized anxiety disorder, paranoid fears, social phobia, obsession and post-traumatic stress disorder (PTSD), mood disorder, dysthymia disorders, mania and two-way affective disorder are given up in material tolerance, substance abuse.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2005/028760 WO2006020879A1 (en) | 2004-08-13 | 2005-08-12 | Isoindolone compounds and their use as metabotropic glutamate receptor potentiators |
| USPCT/US2005/028760 | 2005-08-12 |
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| CN101309905A true CN101309905A (en) | 2008-11-19 |
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| CNA2006800363117A Pending CN101277934A (en) | 2005-08-12 | 2006-02-15 | Metabotropic glutamate-receptor-potentiating isoindolones |
| CNA2006800353774A Pending CN101309905A (en) | 2005-08-12 | 2006-02-15 | Substituted isoindolones and their use as metabotropic glutamate receptor potentiators |
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| CNA2006800363117A Pending CN101277934A (en) | 2005-08-12 | 2006-02-15 | Metabotropic glutamate-receptor-potentiating isoindolones |
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| Country | Link |
|---|---|
| EP (2) | EP1912940A1 (en) |
| JP (2) | JP5031745B2 (en) |
| CN (2) | CN101277934A (en) |
| WO (2) | WO2007021309A1 (en) |
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- 2006-02-15 JP JP2008525976A patent/JP5031745B2/en not_active Expired - Fee Related
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- 2006-02-15 WO PCT/US2006/005246 patent/WO2007021308A1/en active Application Filing
- 2006-02-15 EP EP06720759A patent/EP1912940A1/en not_active Withdrawn
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102791706A (en) * | 2010-01-07 | 2012-11-21 | 阿斯利康(瑞典)有限公司 | Process for making a metabotropic glutamate receptor positive allosteric modulator-874 |
| CN105837557A (en) * | 2016-05-05 | 2016-08-10 | 青岛辰达生物科技有限公司 | Preparation method of alogliptin for treating type-II diabetes |
| CN106279182A (en) * | 2016-07-29 | 2017-01-04 | 中国药科大学 | A kind of pyrrolo-[2,1 a] iso-indole ketone compounds and synthetic method thereof |
| CN111148744A (en) * | 2017-09-26 | 2020-05-12 | 布拉格玛治疗公司 | Novel heterocyclic compounds as MGLUR7 modulators |
| CN110498759A (en) * | 2019-09-12 | 2019-11-26 | 天津瑞岭化工有限公司 | The synthetic method of isoindoline ketone compound |
Also Published As
| Publication number | Publication date |
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| JP2009509920A (en) | 2009-03-12 |
| WO2007021308A1 (en) | 2007-02-22 |
| WO2007021309A1 (en) | 2007-02-22 |
| CN101277934A (en) | 2008-10-01 |
| JP2009509921A (en) | 2009-03-12 |
| JP5031745B2 (en) | 2012-09-26 |
| EP1912939A1 (en) | 2008-04-23 |
| EP1912940A1 (en) | 2008-04-23 |
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