CN103874701A - Pyridine compounds and uses thereof - Google Patents
Pyridine compounds and uses thereof Download PDFInfo
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- CN103874701A CN103874701A CN201280050986.2A CN201280050986A CN103874701A CN 103874701 A CN103874701 A CN 103874701A CN 201280050986 A CN201280050986 A CN 201280050986A CN 103874701 A CN103874701 A CN 103874701A
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- compound
- methyl
- phenyl
- chloro
- acid
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- 0 CC1=Nc2*[*+]**c2N2C1=*=C2* Chemical compound CC1=Nc2*[*+]**c2N2C1=*=C2* 0.000 description 2
- QCVDMTRJKPLDCH-CONRUOGLSA-N CC1(C)C=CC=C(C)C1CN/N=C(/CC=N/C1=C/C)\N(C)/C1=N/C1=CC1 Chemical compound CC1(C)C=CC=C(C)C1CN/N=C(/CC=N/C1=C/C)\N(C)/C1=N/C1=CC1 QCVDMTRJKPLDCH-CONRUOGLSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Abstract
The present invention is directed to pyridine compounds of Formula (I). Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds as therapeutic agents treating neurological and psychiatric disorders.
Description
Invention field
The present invention relates to the compound of the therapeutical agent of and mental illness neural as treatment.Independent aspects of the present invention relates to the medical composition and its use that contains described compound.
Background technology
Cyclic amp (cAMP) and cyclic guanosine monophosphate (cGMP) play the effect of second messenger in the born of the same parents that regulate a series of processes in neurone.In born of the same parents, cAMP and cGMP produce by adenylic acid (AMP) and guanylate cyclase, and by cyclic nucleotide phosphodiesterase (PDE) degraded.In the born of the same parents of cAMP and cGMP, level is by intracellular signal control, and in to the response process of GPCR activation, the stimulation/inhibition of adenylic acid (AMP) and guanylate cyclase be the mode of the reasonable sign of gate ring nucleotide concentration (Antoni,
front. Neuroendocrinol.2000,
21, 103-132).
Phosphodiesterase 2A (PDE2A) is two substrates enzymes, has higher affinity for cGMP, although it can be according to organization factors, and metabolism cAMP or cGMP.CAMP stems from adenosine triphosphate (ATP), and in many different organisms for intracellular signal transduction, conduction cAMP dependent pathway.Although PDE2A expresses around, PDE2A has high expression level in brain.Nearest immunohistochemistry research shows, in whole mammalian species, (comprises people), and the expression pattern of PDE2A in brain is the consistent (people such as Stephenson
j. Histochem. Cytochem.2009,57,933).Show, in the region relevant to cognitive function and emotion control the expression of enzyme very outstanding, comprise cortex, striatum, hippocampus, tonsilla and habenula.
Optionally PDE2A inhibitor B ay 60-7550 preferentially improves cGMP in primary neuronal culture and hippocampal slices.In rat hippocampus section, Bay 60-7550 also improves long-run gains effect (LTP) induction.Consistent with biological chemistry and the electrophysiology effect of Bay 60-7550, it is found that, it also has the activity (people such as Boess in fresh target and social identification mission
neuropharmacology2004,
47, 1081).In recent years, reported that Bay 60-7550 can reverse the defect (people such as van Donkelaar of the Target Recognition that tryptophane consumption produces
eur. J. Pharmacol.2008,
600, 98).Owing to identifying PDE2 positive cell in nucleus raphes dorsalis, these results are become interested people, and nucleus raphes dorsalis is the known region of containing the neuronic cell paste of serotonergic that the projects to forebrain (people such as Stephenson
j. Histochem. Cytochem.2009,
57, 933).The similar research of carrying out in senile rat shows, Bay 60-7550 can be reversed by neuronic nitric oxide synthase (nNOS) inhibitor the beneficial effect of Target Recognition, this explanation, the inhibition of PDE2A in central nervous system (CNS) is due to the level that has changed cGMP (Domek-Lopacinska and Strosznajder
brain Res.2008,
1216, 68).
Nearest research shows, in the treatment of anxiety state, and PDE2A suppresses also the have effect (people such as Masood
j. Pharmacol. Exp. Ther.2008,
326, 369; With people such as Masood
j. Pharmacol. Exp. Ther.2009,
331, 699).In mouse, buthionine sulfoximine (BSO) consumes the induction of maincenter glutathione level institute oxidative stress, and many anxiety disorder class behaviors are increased, and this can evaluate by spacious field time and overhead cross maze test.With Bay 60-7550 treatment, can reverse these effects.In overhead cross labyrinth, hole plate behavior and open field test (elevated plus-maze, hole-board, and open-field tests, evaluate the method used for a long time of potential anxiolytic) in, by giving PDE2 inhibitor B ay 60-7550 or ND7001 or NO donor detanonoate increases cGMP signal, can the anxiety influence of antagonism restraint stress to behavior.In overhead cross labyrinth and hole plate behavior test, these medicines are also to non-behavior generation anxiety effect that stress mouse.On the contrary, give no inhibitor (it reduces cGMP signal) and can produce the anxiety effect similar to restraint stress.
Phosphodiesterase 10 A (PDE10A) is another kind of dual specific enzyme, and it can be converted into AMP by cAMP, and cGMP is converted into the GMP (people such as Soderling
proc. Natl. Acad. Sci.1999,96,7071).PDE10A is by cAMP and cGMP hydrolysis, higher to the affinity of cAMP.In the neurone of PDE10A in striatum, nucleus accumbens septi and olfactory tubercle, express (the people such as Seeger, Brain Research, 2003,985,113-126), and in thalamus, hippocampus, volume side cortex and olfactory tubercle, express (people such as Menniti, William Harvey Research Conference, Porto, December calendar year 2001).All these brain regions participate in schizoid pathomechanism (people such as Lapiz, Neurosci Behav Physiol 2003,33,13), and therefore, the position of enzyme can show the dominating role in psychotic pathomechanism.In striatum, PDE10A is mainly present in medium-sized many sour jujubes neurone, and main associated with these neuronic postsynaptic membranes (people such as Xie,
neuroscience2006,139,597).In this position, PDE10A can input caused signal cascade for the dopaminergic in two neurotransmitter systems of medium-sized many sour jujubes neurone (it plays dominating role in psychotic pathomechanism) and Glutamatergic and have material impact.
Show, insane cGMP and cAMP level with and downstream substrate exist dysfunction (MuIy,
psychopharmacol Bull2002,36,92).In addition, in rat and patient, Haloperidol in treating respectively to cAMP and cGMP level improve relevant (people such as Leveque,
j. Neurosci.2000,20,4011).Because PDE10A is by cAMP and cGMP hydrolysis, so the restraining effect of PDE10A also can be induced and be improved cAMP and cGMP, and thus levels of cyclic nucleotides is produced with haloperidol and similarly affected.The antipsychotic potentiality of PDE 10A inhibitor have further obtained the people such as Kostowski (Pharmacol Biochem Behav 1976,5,15) support of research, this research shows, Papaverine (medium optionally PDE10A inhibitor) can alleviate the caused stereotypy of Apomorphine in psychotic rat animal model, and the catalepsy that the haloperidol of rat causes is increased, make the dopamine concentration in rat brain reduce, typical antipsychotic drug also has this activity simultaneously.Except the typical antipsychotic drug of the psychotic positive symptom of main improvement, PDE10A also has the potentiality of improving psychotic negative symptoms and cognitive symptom.
Concentrate on the dopaminergic input on medium-sized many sour jujubes neurone, PDE10A inhibitor is by raising cAMP and cGMP level, serve as D1 agonist and D2 antagonist, this be because, the activation of the Gs-albumen being connected with d1 dopamine receptor, can increase cAMP in cell, and the activation of the Gi-albumen being connected with d2 dopamine receptor, by suppressing adenylate cyclase activity, can reduce cAMP level in born of the same parents.In the born of the same parents of D1 receptor signal mediation, cAMP level raises, seem to regulate the neurone process (Sawaguchi of a series of responsible working memories in prefrontal cortex, Parkinsonism Relat. Disord. 2000,7,9), and it is reported, D1 receptor activation can make schizophrenia patient's the working memory defect (people such as Castner that improves, Science 2000,287,2020).
The people such as Rodefer (Eur. J Neurosci 2005,21,1070) provided PDE10A restraining effect other evidence to psychotic negative symptoms effect, it can show, Papaverine can reverse the sub-chronic caused attention of phencyclidine (it is nmda antagonist) that gives and set-change defect in rat.Attention deficit, comprises the attention conversion of new stimulation is weakened, and belongs to schizoid negative symptoms.In this research, give phencyclidine 7 days, be then the time of cleaning up, the power that can arouse attention defect.PDE10A inhibitor Papaverine can reverse due to the caused persistence defect of sub-chronic treatment.
These results of collecting show, the inhibition of PDE2A and/or PDE10A can be some treatment target neural and mental illness for the treatment of.Correspondingly, the medicine that the present invention relates to the pyridine that contains Triazolopyrazine, their preparation method, their medical usage and contain them.
the present invention's general introduction
The object of the invention is, the compound that can suppress PDE2A and/or PDE10A is provided.Correspondingly, the present invention relates to the compound of formula I:
Wherein X
1, X
2, X
3and X
4n or CR independently of one another
3, condition is, and an X is N, and all the other X are CR independently of one another
3;
Wherein R
1c
1-C
6alkyl, C
3-C
6cycloalkyl, THP trtrahydropyranyl, benzyl, phenyl and pyridyl, wherein benzyl, phenyl and pyridyl are optionally by one or more halogens, CN, C
1-C
4alkyl/fluoroalkyl or C
1-C
4alkoxyl group/Fluoroalkyloxy replaces;
Wherein R
2c
1-C
4alkyl or C
3-C
6cycloalkyl; With
Wherein R
3hydrogen, halogen, CN ,-CO
2h ,-CON (H or C
1-C
4alkyl)
2, CHO, C
1-C
4alkyl/fluoroalkyl, contain amino heterocycle, the C of ring
2-C
4thiazolinyl, C
2-C
4thiazolinyl or C
1-C
4alkoxyl group/Fluoroalkyloxy; Or its pharmacologically acceptable salt.
In independent aspects of the present invention, compound is selected from a kind of illustrational formula I compound.
The invention provides to contain and treat the formula I compound of significant quantity and the pharmaceutical composition of pharmaceutical carrier.
The present invention also provides treatment to suffer from the method for anxiety disorder, cognitive disorder or schizoid individuality, and the method comprises: the compound for the treatment of the formula I of significant quantity.
The present invention further provides formula I compound in the purposes of preparing in medicine, this medicine is used for the treatment of anxiety disorder, cognitive disorder or schizophrenia.
Another aspect of the present invention provides and has been used for the treatment of anxiety disorder, cognitive disorder or schizoid compound.
detailed description of the present invention
The present invention is taking discoverable type I compound as basis, and this compound can suppress PDE2A and/or PDE10A, and therefore can be used for treating some nerve and mental illness.Explain in more detail below concrete aspect of the present invention, but this specification sheets is considered to not to be to implement all variety of ways of the present invention, maybe can joins the characteristic inventory in the present invention.Thus, specification sheets below just illustrates embodiments more of the present invention, instead of illustrates exhaustively its all arrangement, combination and variation.
Those people that put into practice this area are appreciated that this compound can exist tautomeric form.In the time that the application provides a kind of concrete tautomer appellation, should be appreciated that, comprise its tautomeric form and its mixture.
The present invention relates to defined formula I compound, its pharmaceutical composition and purposes in the present invention's general introduction.
In one embodiment, R
2c
1-C
4alkyl.In one embodiment, R
2it is methyl.
In one embodiment, R
2c
3-C
6cycloalkyl.
In one embodiment, R
1c
1-C
4alkyl.
In one embodiment, R
1c
3-C
6cycloalkyl.
In one embodiment, R
1it is THP trtrahydropyranyl.
In one embodiment, R
1optionally by one or two F, Cl or C
1-C
3the benzyl that alkyl replaces.
In one embodiment, R
1optionally by one or two F, Cl or C
1-C
3the phenyl that alkyl replaces.
In one embodiment, R
1optionally by one or two F, Cl or C
1-C
3the pyridyl that alkyl replaces.
In one embodiment, R
1by one or two F, Cl or C
1-C
3the phenyl that alkyl replaces.
In one embodiment, X
1n.In one embodiment, X
2n.In one embodiment, X
3n.In one embodiment, X
4n.
In one embodiment, R
3hydrogen.In one embodiment, R
3halogen or CHO.
In one embodiment, R
3c
1-C
4alkyl or C
1-C
4alkoxyl group.
In one embodiment, R
3c
2-C
4thiazolinyl or C
2-C
4thiazolinyl.
In one embodiment, R
3to contain the amino heterocycle of ring.
In one embodiment, R
3cN ,-CO
2h or-CON (H or C
1-C
4alkyl)
2.
Can utilize known method, racemization form is split as to optically active enantiomorph, for example, with the salt of optically active its diastereomer of acid separation, and with alkaline purification, discharge optically active amine compound.For example, by fractional crystallization, can separate the salt of this diastereomer.The optically active acid that is suitable for this object can be including, but not limited to: d-or l-tartrate, amygdalic acid or camphorsulfonic acid.The another kind of method that racemic modification is split as to optically active enantiomorph is the method (in optical activity matrix) based on chromatogram.Also can split as follows compound of the present invention: for example, form non-enantiomer derivative by chiral derivatization reagent (, chirality alkylation or acylating reagent), and by its chromatographic separation, then make chiral auxiliary(reagent) fracture.Can use above-mentioned any method, split the optically active enantiomorph of the compounds of this invention itself, or split the optically active enantiomorph of synthetic intermediate, then can utilize method described herein, be converted into the finished product of optical resolution, this finished product are compounds of the present invention.
Can use other method of fractionation optically active isomer well known by persons skilled in the art.This method comprises those methods of following documents: J. Jaques, A. Collet and S. Wilen, Enantiomers, Racemates, and Resolutions, John Wiley and Sons, New York, 1981.Can also prepare activity of optically active compounds by optically active starting raw material.
Definition
Term " C used herein
1-C
6alkyl " refer to there is a straight or branched stable hydrocarbon to six carbon atom (comprising end value).Example is including, but not limited to methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl isophthalic acid-propyl group, n-pentyl and n-hexyl.Similarly, term " straight or branched C
1-C
4alkyl " refer to there is a stable hydrocarbon to four carbon atom.Example comprises methyl, ethyl and n-propyl.
Equally, term " C
1-C
4alkoxyl group " refer to there is a saturated oxygen-containing hydrocarbon group of the straight or branched to four carbon atom, on oxygen, there is open valency simultaneously.Example is including, but not limited to methoxyl group, oxyethyl group, n-butoxy and tert.-butoxy.
Term " C
1-C
6fluoroalkyl " refer to there is one to six carbon atom (comprising end value), the straight or branched stable hydrocarbon that replaced by one or more fluorine atoms.Example comprises trifluoromethyl, pentafluoroethyl group, 1-fluoro ethyl, single methyl fluoride, difluoromethyl, 1,2-bis-fluoro ethyls and 3,4-difluoro hexyl.Similarly, term " straight or branched C
1-C
4fluoroalkyloxy " refer to there is a stable hydrocarbon replacing to four carbon atom, by one or more fluorine atoms, on oxygen, there is open valency simultaneously.
Term " halogen " refers to fluorine, chlorine, bromine and iodine.
Term " C
2-C
4-thiazolinyl " refer to there are two side chain or straight-chain alkenyls to four carbon atom and two keys, comprise vinyl, propenyl and butenyl.Term " C
2-C
4-alkynyl " refer to there are two side chain or straight-chain alkynyls to four carbon atom and a triple bond, comprise ethynyl, proyl and butynyl.
For the present invention, term " contain ring amino heterocycle " refers to azetidine, tetramethyleneimine, piperidines, piperazine and morpholine." containing the amino heterocycle of ring " can be optionally by one or more straight or branched C
1-C
4alkyl replaces.
Term " CON (H or C
1-C
4alkyl)
2" refer to that the substituting group of amido part is selected from H or C independently of one another
1-C
4the amido of alkyl.Comprise-CONH of example
2,-CONHCH
3,-CON (CH
3)
2with-CON (CH
3) CH
2cH
3.
Term used herein " treatment " refers to process or the severity improving or reverse disease or obstacle, or improves or reverse one or more symptom or the side effect of this disease or obstacle." treatment " used herein also refers to suppress or blocking-up, as the process of system, symptom or the state of delay, retardation, restriction, obstruction or obstruction disease or obstacle.For purposes of the invention, " treatment " further refers to the method that obtains useful or target clinical effectiveness, wherein " useful or target clinical effectiveness " includes but not limited to: mitigation symptoms, the degree that reduces obstacle or disease, makes disease or failure condition stablize (, not worsening), postpone or slow down disease or failure condition, improve or relax disease or failure condition, and alleviating disease or obstacle, no matter be part or all of, detectable or undetectable situation.
Phrase used herein " significant quantity ", in the time being applied to compound of the present invention, represents to be enough to produce the quantity of target organism effect.
Phrase " treatment significant quantity ", in the time being applied to compound of the present invention, represents the quantity of the compound that is enough to the symptom progress of improving, relax, stablize, reverse, slow down or postpone obstacle or morbid state process or obstacle or disease.In one embodiment, method of the present invention provides the combination that gives compound.In this case, " significant quantity " is the quantity that is enough to the composition that produces target organism effect.
Pharmaceutical salts
The present invention also comprises the salt of the compounds of this invention, generally refers to pharmacologically acceptable salt.This salt comprises pharmaceutically acceptable acid additive salt.Acid salt comprises mineral acid and organic acid salt.
The representational example of suitable mineral acid comprises: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid, thionamic acid, nitric acid etc.The representational example of suitable organic acid comprises: formic acid, acetic acid, trichoroacetic acid(TCA), trifluoroacetic acid, propionic acid, phenylformic acid, styracin, citric acid, fumaric acid, glycol acid, methylene-succinic acid, lactic acid, methylsulfonic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, oxalic acid, picric acid, pyruvic, Whitfield's ointment, succsinic acid, methylsulfonic acid, ethyl sulfonic acid, tartrate, xitix, bar is acid not, dimethylene Whitfield's ointment, ethionic acid, glyconic acid, citraconic acid, aspartic acid, stearic acid, palmitinic acid, EDTA, glycol acid, para-amino benzoic acid, L-GLUTAMICACID, Phenylsulfonic acid, tosic acid, theophylline acetic acid, and 8-halo theophylline (for example, 8-bromo theophylline etc.).Pharmaceutically acceptable other example inorganic or organic acid addition salt comprises people J. Pharm. Sci. such as listing in S. M. Berge, the pharmacologically acceptable salt in 1977,66,2.
In addition, can there is not solvation form in compound of the present invention, and with acceptable solvent for example water, ethanol etc. form solvate forms.
Pharmaceutical composition
The present invention further provides to contain and treated the formula I compound of significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier.The present invention also provides to contain and has treated the disclosed a kind of particular compound of experimental section of significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier.
Compound of the present invention can give separately, or gives together with pharmaceutically acceptable carrier or vehicle in single dose or multiple doses.According to pharmaceutical composition of the present invention, can prepare together with vehicle according to conventional art and pharmaceutically acceptable carrier or thinner and any other known auxiliary agent, for example, be disclosed in those methods in following document: Remington:The Science and Practice of Pharmacy, 19
thedition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The oral pharmaceutical composition giving comprises solid dosage, for example, and capsule, tablet, lozenge, pill, lozenge, pulvis and granule.If suitable, according to method well-known in the art, can prepare said composition with for example enteric coating of coating, maybe can prepare them, provide the control of activeconstituents to discharge, for example, continue or extend to discharge.The liquid dosage form of oral administration comprises solution, emulsion, suspensoid, syrup and elixir.
The pharmaceutical composition of administered parenterally comprises aseptic water-based and non-water injection solution, dispersion agent, suspensoid or emulsion, and before using, is reassembled as the sterile powder of aseptic injectable solution agent or dispersion agent.
Conventionally give the oral dosage of one or more dosage, general every day one to three dosage.Precise dosage depend on the frequency of administration and pattern, individual sex, age, body weight and the general condition for the treatment of, sanatory character and severity and any accompanying diseases for the treatment of and the clear and definite other factors of those skilled in the art.Can also utilize method known to those skilled in the art, preparation is provided in unit dosage.For example, the unit dosage of oral administration can contain about 0.01 to about 1000 mg, about 0.05 to about 500 mg or about 0.5 to about 200 mg.
Conventionally use the compound of the present invention of dissociant or its pharmaceutical acceptable salt.An example is the acid salt with the compound of free alkali applicability.In the time that the compound of formula I contains free alkali, prepare in a usual manner this salt, process solution or the suspension of the free alkali of formula I with the pharmaceutically acceptable acid of molar equivalent.The representational example of suitable organic and mineral acid is described above.
For administered parenterally, can use the solution of formula I compound in aseptic aqueous solution, aqueous solution of propylene glycol, the vitamin-E aqueous solution or sesame or peanut oil.If necessary, should cushion suitably this aqueous solution, first use enough salt solution or glucose, make liquid diluent become the liquid of isotonicity.Aqueous solution agent is particularly suitable for intravenously, intramuscular injection, subcutaneous and intraperitoneal administration.Use standard technique well known by persons skilled in the art, the compound of formula I can easily be incorporated in known sterile aqueous media.
Suitable pharmaceutical carrier comprises: inert solid diluent or filler, aseptic aqueous solution and various organic solvent.The example of solid carrier comprises lactose, terra alba, sucrose, cyclodextrin, talcum powder, gelatin, agar, pectin, gum arabic, Magnesium Stearate, stearic acid and cellulosic lower alkyl ether.The example of liquid vehicle is including, but not limited to syrup, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, polyoxyethylene and water.Similarly, carrier or thinner can comprise any sustained-release material known in the art, for example glyceryl monostearate or distearin, and they can use separately, or mix with wax.Then, the pharmaceutical composition being combined to form by formula I compound and pharmaceutically acceptable carrier, can easily utilize the various formulation administrations that are suitable for disclosed route of administration.Utilize the method that pharmaceutical field is known, preparation can be present in unit dosage easily.
If oral administration uses solid carrier, can, by preparation compressing tablet, put into hard gelatin capsule with powder or particle form, can be maybe lozenge or lozenge form.The quantity of solid carrier can change to a great extent, but its scope is: about 25 mg of each dose unit are to about 1 g.If use liquid vehicle, preparation can be syrup, emulsion, soft gelatin capsule or aseptic injection liquor form, for example water or on-aqueous liquid suspensoid or solution form.
Therepic use
The invention provides treatment and suffer from the method for anxiety disorder, cognitive disorder or schizoid individuality, the method comprises: the compound for the treatment of the formula I of significant quantity.
The present invention further provides formula I compound in the purposes of preparing in medicine, this medicine is used for the treatment of anxiety disorder, cognitive disorder or schizophrenia.Another aspect of the present invention provides and has been used for the treatment of anxiety disorder, cognitive disorder or schizoid compound.The invention provides treatment anxiety disorder, cognitive disorder or schizoid method, the method comprises: the compound or pharmaceutically acceptable salt thereof for the treatment of the formula I of significant quantity.
The method that the invention provides treatment anxiety disorder, anxiety disorder is selected from: anxiety, panic obstacle, agoraphobia, specificity phobia, social phobia, obsessive pressure obstacle, post-traumatic stress disorder, acute nervous sexual dysfunction and generalized anxiety disorder.
The present invention further provides and treated the individual method of suffering from cognitive disorder, the method comprises: the compound that gives the formula I of individual treatment significant quantity.Can according to the example of the cognitive disorder of the present invention treatment including, but not limited to: the dementia that Alzheimer, multi-infarct dementia, alcoholic dementia or other medicines are relevant, the dementia relevant to intracranial tumors or cerebral trauma, with Heng Dingdun chorea or the relevant dementia of Parkinson's disease or the relevant dementia of AIDS and relevant cognitive ability reduction of age.
The present invention also provides treatment dyskinetic method, and the method comprises: the compound that gives the formula I of individual treatment significant quantity.Can be according to the dyskinetic example of the present invention treatment including, but not limited to: Heng Dingdun chorea with treat relevant dyskinesia to dopamine agonist.The present invention further provides and treated the dyskinetic method that is selected from Parkinson's disease and restless legs syndrome, the method comprises: the compound that gives the formula I of individual treatment significant quantity.
The invention provides the method for the following illness for the treatment of: schizophrenia, for example, the schizophrenia of paranoia's type, disorderly type, catatonic type, undifferentiated type or all the other types; Schizophreniform obstacle; Schizoaffective disorder, for example, vain hope type or depressed type; Delusional disorder; The mental disorder that material causes, for example, spills the psychosis that essence, amphetamine, hemp, Cocaine, hallucinogen, inhalation, opioid or phencyclidine cause; The personality disorder of paranoia's type; Personality disorder with schizoid type; Wherein drug habit is to spill essence, amphetamine, Cocaine or opiate habituation.
experimental section
The compound of formula I can utilize the method for listing in method and embodiment below to prepare.In method, can use variant or improved form below, itself is known for this area chemist, or is apparent to those of ordinary skill in the art.In addition,, with reference to reaction scheme and embodiment below, other method of preparing the compounds of this invention it will be apparent to those skilled in the art that.For example, these methods have been described during synthetic the compounds of this invention and have been used optionally protecting group.For concrete reaction, those skilled in the art can select suitable protecting group.The protection of this group and the method for deprotection are well known in this area, and can in following document, obtain: the people Protective Groups in Organic Synthesis such as T. Green, 1991,2
ndedition, John Wiley & Sons, New York.
the abbreviation and the chemical reagent that use
AcOH=acetic acid (for example, Sigma-Aldrich 242853).Acetonitrile (for example, Aldrich 271004).APPI=normal pressure photo-ionization.The Aq=aqueous solution.Salt solution=saturated sodium-chloride water solution (for example, Aldrich S7653).Boc
2o=tert-Butyl dicarbonate (for example, Aldrich 361941).2-chloro-benzoic acid (for example, Aldrich 135577).3-chloro-benzoic acid (for example, Fluka 23530).3-chloro-benzoyl chloride (for example, Aldrich C26801).Chloroform (for example, Sigma-Aldrich C2432).The chloro-6-methyl-phenylformic acid of 2-(for example, Lancaster X18348 or Matrix 002794).The chloro-6-methyl-Benzoyl chloride of 2-(for example, Fluorochem 38160 or Betapharm 15-47106).DBU=1,8-diazabicyclo [5.4.0] 11-7-alkene (for example, Aldrich 139009).DCM=carrene/methylene dichloride (for example, Aldrich 270997).The chloro-phenylformic acid of 2,6-bis-(for example, Aldrich D57450).2,3 diamino pyridine (for example, Aldrich 125857).3,4-diamino-pyridine (for example, Aldrich D7148).Ether (for example, Sigma-Aldrich 346136).DMAP=4-(dimethylamino) pyridine (for example, Aldrich 522805).2,6-dimethyl benzoyl chloride (for example, Fluorochem 017526 or ABCR AB173115).DMF=dimethyl formamide (for example, Sigma-Aldrich 227056).DIPEA=diisopropylethylamine (for example, Aldrich 387649).ELS=evaporat light scattering.Ethanol (for example, Sigma-Aldrich 459844).Pyruvic Acid Ethyl ester (for example, Fluka 15960).EtOAc=ethyl acetate (for example, Fluka 34972).The fluoro-3-nitro-pyridine of 2-(for example, Fluorochem 03250 or Matrix 018339).H=hour.4M HCl/1,4-diox (for example, Sigma-Aldrich 345547).Heptane (for example, Sigma-Aldrich 730491).HPLC=high performance liquid chromatography.30% aqueous hydrogen peroxide solution (for example, Sigma-Aldrich 216763).Hydrazine hydrate (for example, Sigma-Aldrich 225819).Iron powder (for example, Aldrich 12310).LC=liquid chromatography.LC/MS=liquid chromatography/mass spectrometry.4M=4 molar solution.Methyl alcohol (for example, Sigma-Aldrich 34860).MTBE=methyl tertiary butyl ether (for example, Sigma-Aldrich 306975).MW=microwave.MW condition=use Biotage Initiator instrument or CEM Explorer-48 instrument, the reaction of carrying out in sealed tube.Na
2cO
3(for example, Sigma-Aldrich S7795).NaHCO
3(for example, Sigma-Aldrich S6014).NaOH (for example, Sigma-Aldrich S5881).Na
2sO
4 (for example, Sigma-Aldrich 238597).3-nitro-pyridin-4-yl amine (for example, Aldrich 646962).10% palladium/charcoal (for example, Aldrich 75990).PDA=photodiode array.Pd (DPPF) Cl
2=[1,1'-bis-(diphenylphosphino) ferrocene] dichloro palladium (II) (for example, Aldrich 697230), Pd (DPPF) Cl
2the mixture (for example, Aldrich 379670) of-DCM mixture=[1,1'-bis-(diphenylphosphino) ferrocene] dichloro palladium (II) and methylene dichloride.Pentane (for example, Sigma-Aldrich 236705).PhPOCl
2=phenylphosphonic dichloride (for example, Aldrich 389560).POCl
3=phosphoryl chloride (for example, Aldrich 262099).PyBroP=benzotriazole-1-base-oxygen base tripyrrole alkane subbase phosphorus hexafluorophosphate (for example, Fluka 12809).The L-Ala (for example, Sigma A7502) of racemization.RT=retention time.Sat=is saturated.The T=time.Tf
2o=trifluoromethanesulfanhydride anhydride (for example, Aldrich 176176).TLC=thin-layer chromatography.Et
3n=triethylamine (for example, Sigma-Aldrich T0886).
LC/MS method 131: carry out LC/MS on the Sciex API150EX that is equipped with APPI source (operating) under positive ion mode.HPLC is made up of Shimadzu LC10-ADvp LC pump, SPD-M20A PDA detector (operating under 254 nM) and SCL-10A central controller.Automatic sampler is Gilson 215, and column oven is Jones Chromatography 7990R, and ELS detector is Sedere Sedex 85.LC condition: post is Waters Symmetry C-18,4.6 x 30 mm, 3.5 microns, operation at 60 DEG C, binary gradient is made up of water+0.05% TFA (A) and methyl alcohol+0.05% TFA, 3.0 mL/min.Gradient: 0.01 min, 17% B; 0.27 min, 28% B; 0.53 min, 39% B; 0.80 min, 50% B; 1.07 min, 59% B; 1.34 min, 68% B; 1.60 min, 78% B; 1.87 min, 86% B; 2.14 min, 93% B; 2.38 min, 100% B; 2.40 min, 17% B; 2.80 min, 7% B; Total working time: 2.8 min.
LC/MS method 132: hardware is identical with LC/MS method 131.LC condition: post is Waters Symmetry C-18,4.6 x 30 mm, 3.5 microns, operation at 60 DEG C, binary gradient is made up of water+0.05% TFA (A) and methyl alcohol+0.05% TFA, 2.5 mL/min.Gradient: 0.01 min, 5% B; 2.38 min, 100% B; 2.40 min, 5% B; 2.80 min, 5% B.Total working time: 2.8 min.
Method 550: carry out LC-MS on the Waters Aquity UPLC-MS being made up of Waters Aquity, Waters Aquity comprises post manager, binary solvent manager, sample tissue device, PDA detector (moving under 254 nM), ELS detector and be equipped with the TQ-MS in APPI source (moving) under positive ion mode.LC condition: post is Acquity UPLC BEH C18 1.7 μ m, 2.1x50mm, operation at 60 DEG C, binary gradient is made up of water+0.05% trifluoroacetic acid (A) and acetonitrile+5% water+0.05% trifluoroacetic acid, 1.2 mL/min.Gradient: 0.00 min, 10% B; 1.00 min, 100% B; 1.01 min, 10% B; 1.15 min, 10% B.Total working time: 1.15 min.
general method
Briefly, can, respectively under method 1 or the described condition of method 2, prepare Compound I of the present invention by hydrazine II.Can, under the described condition of method 3, prepare hydrazine II by compound III.In some cases, all right using method 4, is converted into I by III.Can using method 5 or method 6, obtain precursor III by lactan IV.
Method 1 comprises: for example, in suitable solvent (acetonitrile), at high temperature, with suitable acyl chlorides R
1cOCl processes hydrazine II.Sometimes, can advantageously add POCl
3or PhPOCl
2.By adding POCl
3, can prepare acyl chlorides by corresponding sour original position.Or, make hydrazine II and R
1cO
2h and PyBroP reaction, obtain corresponding hydrazides, uses subsequently PhPOCl
2process in two steps hydrazides with alkali, obtain the described compound of the present invention of example I a1.
Method 2 is alternative methods of method 1, wherein, in for example methylene dichloride of suitable solvent (DCM), makes hydrazine II and suitable aldehyde R
1cHO condensation, forms corresponding hydrazone.Subsequently, add suitable oxygenant, obtain compound of the present invention, for example, at the people such as Sadana (A.K. Sadana, Y. Mirza, K.R. Aneja, O. Prakash European Journal of Medicinal Chemistry 2003,38,533) under the condition of report, wherein oxygenant is diacetic acid iodobenzene (PhI (OAc)
2).Or, can use the people such as Mogilaiah (K. Mogilaiah, T. Kumara Swamy, K. Shiva Kumar J. Heterocyclic Chem. 2009,46,124) report method, in this method, by using chloramine-T processing, make intermediate hydrazone oxidative cyclization.
Method 3 comprises: with the X in hydrazine displacement compound III, wherein X is chlorine atom or other leavings group, for example, and the phosphorus that reaction scheme is described.This reaction usually for example, in suitable solvent (ethanol), at high temperature carry out together with hydrazine hydrate.Preparation IIc and IId are the examples of method 3.
Method 4 is: for example, in suitable solvent (acetonitrile), at high temperature, compound III and suitable acylhydrazine R1CONHNH
2reaction, is converted into Compound I of the present invention, as embodiment Id1 describes.
Method 5 is: as IId is described, in excessive phosphorus chloride, by heating substrate, lactan IV is converted into compound III, and wherein X is chlorine atom; Sometimes it is favourable, adding suitable alkali (for example triethylamine or diisopropylethylamine (DIPEA)).
Method 6 is: for example, under the existence of suitable alkali (DIPEA), with benzotriazole-1-base-oxygen base tripyrrole alkane subbase-phosphorus hexafluorophosphate (PyBroP) or similar peptide coupler processing lactan IV, compound III is provided, wherein X is phosphorus, as reaction scheme is described.For other lactan, the method is known in the literature method.(T.D. Ashton, P.J. Scammells
Australian Journal of Chemistry 2008,
61, 49)。Preparation IIa is the example of method 6.
prepare intermediate
(3-methyl-pyrido [2,3-b] pyrazine-2-yl)-hydrazine (IIa)
By fluoro-2-3-nitro-pyridine (12 g), Et
3(11.87 mixtures g) reflux and spend the night in methyl alcohol (200 mL) for the L-Ala of N (30 mL) and racemization.This mixture is cooled to envrionment temperature, and by filtrate vacuum concentration.Resistates is distributed between DCM and water.Use Na
2cO
3dry organic layer, filters, vacuum concentration, and (7.8 g) for-propionic acid to obtain 2-(3-nitro-pyridine-2-base amino).This material is dissolved in AcOH (50 mL), and (8.2 g) to add iron.This mixture is refluxed 1.5 hours.Be cooled to after envrionment temperature, filter this mixture, and by filtrate vacuum concentration.Resistates is washed with water, dry, obtain 3-methyl-3, (1.4 g) for 4-dihydro-1H-pyrido [2,3-b] pyrazine-2-ketone.This material is mixed with the 5% NaOH aqueous solution (92 mL) and water (18 mL), then add 30% aqueous hydrogen peroxide solution (9.2 mL).This mixture is stirred 10 hours at 60 DEG C.Be cooled to after envrionment temperature, pH value is adjusted to neutrality, (1.2 g) to be settled out 3-methyl isophthalic acid H-pyrido [2,3-b] pyrazine-2-ketone.This material is dissolved in DMF (10 mL), and at ambient temperature, with PyBroP, (4.6 g) and DIPEA (1.6 mL) processing 16 hours.Leach the white solid of precipitation, by washing with alcohol, dry, (benzotriazole-1-base oxygen base)-(0.4 g) for 3-methyl-pyrido [2,3-b] pyrazine to obtain 2-.By this material (0.4 g) and hydrazine hydrate (0.5 mL) in ethanol (5mL), reflux 10 minutes.Be cooled to after envrionment temperature, leach the white solid of precipitation, by washing with alcohol, dry, (0.2 g), for next step to obtain enough pure IIa.
(3-methyl-pyrido [2,3-b] pyrazine-2-yl)-hydrazine (IIc)
By 3,4-diamino-pyridine (10 g) and Pyruvic Acid Ethyl ester (53 g) mixture in chloroform (100 mL), at ambient temperature stir spend the night.Leach the solid of precipitation, with DCM washing, dry, obtain 2-methyl-4H-pyrido [3,4-b] pyrazine-3-ketone (14 g) light yellow solids.This material of 2 g is suspended in DMF (10 mL), and at ambient temperature, with PyBroP (6 g) and DIPEA (3.3 mL) process and spend the night.Leach the solid of precipitation, by washing with alcohol, dry, obtain 3-(benzotriazole-1-base oxygen base)-2-methyl-pyrido [3,4-b] pyrazine (1.7 g) white solids.This material is suspended in ethanol (50 mL), adds hydrazine hydrate, and the mixture obtaining is heated 15 minutes at 85 DEG C.Leach solid, by washing with alcohol, dry, obtain enough pure IIc (0.95g) yellow solid, for next step.
(3-methyl-pyrido [3,4-b] pyrazine-2-yl)-hydrazine (IIb)
(in 15 DCM (250 mL) suspension g), add triethylamine (30 mL), Boc to 3-nitro-pyridin-4-yl amine
2o (23.5 g) and DMAP (1.31 g).This mixture is stirred 2 days at ambient temperature.Leach solid, and by filtrate vacuum concentration.Use MTBE debris.Collect yellow crystals, (17 g) to obtain (3-nitro-pyridin-4-yl)-carboxylamine tertiary butyl ester.This material and Pyruvic Acid Ethyl ester (100 mL) are dissolved in ethanol (150 mL), and (under 3 existence g), at 50 DEG C, process two days with hydrogen (50 psi) at 10% palladium/charcoal.Leach catalyzer, and by filtrate vacuum concentration.Utilize silica gel chromatography purifying resistates (elutriant: pentane/EtOAc, 10:1 → 2:1), obtain 2-(4-t-butoxycarbonyl amino-pyridin-3-yl amino)-ethyl propionate (5 g) yellow solids.By the more volume sample (9g) of this compound of preparation in a comparable manner at 4M HCl/1, in 4-diox (40 mL), stir 5 hours at ambient temperature.Leach the solid of precipitation, with MTBE washing, and dry.Filtrate is concentrated into dry, with MTBE washing, dry, obtain second batch product.Altogether obtain 3-methyl-3,4-dihydro-1H-pyrido [3,4-b] pyrazine-2-keto hydrochloride (5 g) white solids.This material of 2.2 g is suspended in water (20 mL), and processes with 30% aqueous hydrogen peroxide solution (1.2 mL) and NaOH (pH value is adjusted to 7-8).This mixture is stirred 2 days at 75 DEG C.Add more 30% aqueous hydrogen peroxide solution (0.15 mL), and continue to stir other 2 days.Vacuum is removed volatile matter.Resistates is washed with EtOAc, obtain 3-methyl isophthalic acid H-pyrido [3,4-b] pyrazine-2-ketone (0.8 g) light yellow solid.By this material of 0.7 g and PyBroP, (2.11 g) are suspended in DMF (3 mL).Add DIPEA (1.16 mL), and this mixture is stirred and spent the night at ambient temperature.Leach the solid of precipitation, by washing with alcohol, dry, obtain 2-(benzotriazole-1-base oxygen base)-3-methyl-pyrido [3,4-b] pyrazine (0.7 g) white solid.This material of 430 mg is suspended in ethanol (13 mL), and at 85 DEG C, with hydrazine hydrate (0.5 mL) processing 20 minutes.Leach solid, by washing with alcohol, dry, obtain enough pure IId (180 mg) light yellow solid, for next step.
3-chloro-2-methyl-pyrido [2,3-b] pyrazine (IIId)
Pyruvic Acid Ethyl ester (1.22 mL) is dissolved in methyl alcohol (10 mL), and join 2,3-diamino-pyridine (in the cold soln of 1.09 g)/methyl alcohol MeOH (20 mL), stirs this mixture at ambient temperature.Leach solid, with cold methanol washing, obtain 2-methyl-4H-pyrido [2,3-b] pyrazine-3-ketone (1.1 g) gray solid.This material of 1.0 g is suspended in acetonitrile (10 mL), and adds phosphoryl chloride (1.16 mL).Under MW condition, this mixture is heated 0.5 hour at 120 DEG C.This crude mixture is distributed between water and EtOAc.With salt water washing organic layer, use Na
2sO
4dry, filter, vacuum concentration, obtains enough pure IIId (460 mg) red solid, for next step.
(2-methyl-pyrido [2,3-b] pyrazine-3-yl)-hydrazine (IId)
By IIId, (0.61 g) and the mixture of hydrazine hydrate (0.5 mL) in ethanol (5 mL), at room temperature stir 10 minutes.Leach the white solid of precipitation, by washing with alcohol, dry, (0.43 g), for next step to obtain enough pure IId.
(8-methoxyl group-2-methyl-pyrido [2,3-b] pyrazine-3-yl)-hydrazine (IIe)
At 0 DEG C, to the chloro-pyridine-2-of 4-base amine (5 96% H g)
2sO
4in (20 mL) aqueous solution, dropwise add 70% HNO
3the aqueous solution (2.5 mL) and 96% H
2sO
4the mixing solutions of the aqueous solution (10 mL).After having added, this reaction mixture is at room temperature stirred 2 hours.This solution is poured in ice/water, dropwise adds the 6M NaOH aqueous solution, pH value is adjusted to 9.Then leach solid, wash with water, dry, then, by aluminum oxide chromatogram purification (elutriant: pentane: EtOAc, 2: 1), (1.2 g) to obtain the chloro-3-nitro-pyridine-2-of 4-base amine.This material of 200 mg is dissolved in methyl alcohol (3mL), adds NaOMe (125 mg), then this mixture is stirred 16 hours at 60 DEG C.Dropwise add the 37% HCl aqueous solution, pH value is adjusted to 6.This mixture is cooled to 0 DEG C, and leaches the solid of precipitation, wash with water, dry, obtain 4-methoxyl group-3-nitro-pyridine-2-base amine (180 mg).This material is dissolved in methyl alcohol (20 mL), and under the existence of 10% palladium/charcoal, at room temperature use hydrogen (1 bar) process 2 hours.Filter this mixture, vacuum concentrated filtrate, obtains 4-methoxyl group-pyridine-2,3-diamines (50 mg).Repeat this process, obtain more material.In next step, by 4-methoxyl group-pyridine-2, (6.8 g) are dissolved in ethanol (200 mL) 3-diamines.At room temperature, in this solution, add at leisure Pyruvic Acid Methyl ester (4.9 mL), and this mixture is stirred to 3 hours at ambient temperature, and final vacuum is removed volatile matter.By silica gel chromatography purifying resistates (elutriant: pentane: EtOAc, 5: 1 to 0: 1), (6.1 g) to obtain 8-methoxyl group-2-methyl-4H-pyrido [2,3-b] pyrazine-3-ketone.To adding PyBroP in DMF (12 mL) suspension of 3 these materials of g, (7.65 g), and (3.58 g) then to add DBU.This mixture is stirred and spent the night, then leach the solid of precipitation, by washing with alcohol, dry, (3.5 g) for-8-methoxyl group-2-methyl-pyrido [2,3-b] pyrazine to obtain 3-(benzotriazole-1-base oxygen base).This material of 1.5 g is dissolved in the mixture of ethanol (10ml) and DCM (60ml).Add hydrazine monohydrate (3.6g), and this mixture is stirred and spent the night at ambient temperature, and final vacuum is removed volatile matter.Remaining solid is ground with ethanol, leach, by washing with alcohol, dry, (0.9 g) for-hydrazine IIe to obtain (8-methoxyl group-2-methyl-pyrido [2,3-b] pyrazine-3-yl).
compound of the present invention
Example I a1
1-(the chloro-phenyl of 3-)-4-methyl-2,3,5,6,9b-pentaaza-cyclopenta [a] naphthalene
Mixture by IIa (100 mg), PyBroP (277 mg), 3-chloro-benzoic acid (88.9 mg) and DIPEA (0.3 mL) in DMF (10 mL), stir 16 hours at ambient temperature.Vacuum is removed volatile matter.Resistates is stirred in DCM (5 mL), be settled out corresponding hydrazides (150 mg).This material is suspended at ambient temperature in the mixture of acetonitrile (10 mL) and DIPEA (0.4 mL) to 5 minutes.Add PhPOCl
2(0.13 mL), and this mixture is stirred at ambient temperature, make it become homogeneous phase.Continue to stir, until white solid precipitation.Leach this material, with acetonitrile washing, and dry.This material (140 mg) is dissolved in methyl alcohol (10 mL), and uses at ambient temperature Na
2cO
3(10 mg) processes 0.5 hour.Then,, in to the open flask of air, volume is reduced to about 50%.Leach the solid of precipitation, dry, obtain example I a1 (60 mg).LC/MS (method 132): RT (PDA)=1.59 minute; PDA/ELS-purity 100%/100%; Quality view measured value: 296.1.
Example I a2
1-(the chloro-6-methyl-phenyl of 2-)-4-methyl-2,3,5,6,9b-pentaaza-cyclopenta [a] naphthalene
By the mixture of IIa (90 mg), PyBroP (264 mg), the chloro-6-methyl benzoyl chloride of 2-(87 mg) and DIPEA (0.7 mL) in DMF (2 mL), stir 2 days at ambient temperature.Vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 20/1), obtains corresponding hydrazides (80 mg).More this material (100 mg) of preparation in a comparable manner is dissolved in the mixture of acetonitrile (5 mL) and DIPEA (0.42 mL), and uses at ambient temperature PhPOCl
2(0.08 mL) processes 5 minutes.Vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 20/1), obtains example I a2 (85 mg).LC/MS (method 132): RT (PDA)=1.55 minute; PDA/ELS-purity: 97.8%/100%; Quality view measured value: 310.1.
Example I a3
1-(the chloro-phenyl of 2,6-bis-)-4-methyl-2,3,5,6,9b-pentaaza-cyclopenta [a] naphthalene
By IIa (80 mg), PyBroP (221 mg), 2, the mixture of the chloro-phenylformic acid of 6-bis-(87 mg) and DIPEA (0.2 mL) at ambient temperature, in DMF, stir 2 days.Vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 20/1), obtains corresponding hydrazides (100 mg).This material is suspended in acetonitrile (3 mL), and at ambient temperature, with DIPEA (0.5 mL) and PhPOCl
2(0.08 mL) processes 5 minutes.Vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 20/1), obtains example I a3 (15 mg).LC/MS (method 131): RT (PDA)=1.07 minute; PDA/ELS-purity: 96.1%/100%; Quality view measured value: 330.1.
Example I a4
1-(2,6-dimethyl-phenyl)-4-methyl-2,3,5,6,9b-pentaaza-cyclopenta [a] naphthalene
In DMF (2 mL) mixture of IIa (100 mg), DIPEA (0.2 mL), add 2,6-dimethyl benzoyl chloride (96 mg), and this mixture is stirred 5 minutes at ambient temperature.Vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 20/1), obtains corresponding hydrazides (114 mg).This material of 45 mg is suspended in acetonitrile (2 mL), and with DIPEA (0.2 mL) processing 5 minutes, then uses PhPOCl
2(0.11 mL) processes.With preparation TLC this mixture of direct purification (elutriant: pentane/EtOAc, 1/1), obtain example I a4 (7.2 mg).LC/MS (method 132): RT (PDA)=1.54 minute; PDA/ELS-purity: 98.0%/100%; Quality view measured value: 290.0.
Example I b1
1-(the chloro-phenyl of 2-)-4-methyl-2,3,5,7,9b-pentaaza-cyclopenta [a] naphthalene
By IIb (480 mg), 2-chloro-benzoic acid (430 mg) and PyBroP, (1.33 mixtures g) are suspended in DMF (12 mL), and add DIPEA (0.97 mL).This mixture is stirred and spent the night.Vacuum is removed volatile matter.Resistates is suspended in DCM.Leach solid, with DCM washing, dry, obtain 2-chloro-benzoic acid N'-(3-methyl-pyrido [3,4-b] pyrazine-2-yl)-hydrazides (400 mg) yellow solid.At 0 DEG C, this material is suspended in acetonitrile (30 mL).Add DIPEA (1.7 mL) and PhPOCl
2(0.35 mL).This mixture is stirred 0.5 hour at 0 DEG C, be then warming up to envrionment temperature, and stir 10 minutes.Vacuum is removed most of volatile matter.Leach solid, with acetonitrile washing, dry, (0.3 g) to obtain solid.This material is dissolved in methyl alcohol (30 mL), and uses at ambient temperature Na
2cO
3(100 mg) processes 1 hour.Leach solid, and by resistates vacuum concentration.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 10:1), obtains example I b1 (180 mg) white solid.LC/MS (method 132): RT (PDA)=1.54 minute; PDA/ELS-purity: 99.0%/100%; Quality view measured value: 296.1.
Example I c1
1-(the chloro-phenyl of 2-)-4-methyl-2,3,5,8,9b-pentaaza-cyclopenta [a] naphthalene
The mixture of IIc (200 mg), 2-chloro-benzoic acid (179 mg) and PyBroP (554 mg) is suspended in DMF (7 mL).Add DIPEA (0.41 mL), and this mixture is stirred at ambient temperature.Vacuum is removed volatile matter.Resistates is suspended in DCM.Leach solid, with DCM washing, dry, obtain 2-chloro-benzoic acid N'-(2-methyl-pyrido [3,4-b] pyrazine-3-yl)-hydrazides (313 mg) yellow solid.This material of 250 mg is suspended in acetonitrile (200 mL), and at 0 DEG C with DIPEA (1.1 mL) and PhPOCl
2(0.22 mL) processes.After 10 minutes, this mixture is warming up to envrionment temperature, and stirs again 5 minutes.Vacuum is removed most of volatile matter.Leach solid, with acetonitrile washing, and dry.This material (0.32g) is dissolved in the mixture of methyl alcohol (100 mL) and acetonitrile (20 mL).Add Na
2cO
3(30 mg) and several dripping, and this mixture is stirred 0.5 hour at ambient temperature.Leach solid.Vacuum concentrated filtrate.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 10:1), obtains example I c1 (162 mg) white solid.LC/MS (method 132): RT (PDA)=1.58 minute; PDA/ELS-purity: 94.0%/100%; Quality view measured value: 296.1.
Example I d1
1-(the chloro-phenyl of 2-)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
IIId (450 mg) is dissolved in acetonitrile (10 mL), and by this solution nitrogen purging, (0.44 g) then to add 2-chlorobenzoyl hydrazine.Under MW condition, this mixture is heated 0.5 hour at 150 DEG C.Crude mixture is distributed between water and EtOAc, and use NaHCO
3alkalization.Leach solid, and by the salt water washing of the organic moiety of filtrate, use MgSO
4dry, filter vacuum concentration.Purify resistates (elutriant: 1:1 heptane/EtOAc → EtOAc) with silica gel chromatography, obtain the solid of thickness.This material is suspended in the mixture (10:1) of ether and EtOAc, leaches solid, dry, obtain example I d1 (82 mg).LC/MS (method 131): RT (PDA)=1.33 minute; PDA/ELS-purity: 97.1%/100%; Quality view measured value: 296.2.
Example I d2
1-(the chloro-phenyl of 2,6-bis-)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
As described in embodiment Id3, be prepared, use IId (100 mg) and 2,6-dichlorobenzoyl chloride (118 mg), obtain corresponding hydrazides (170 mg), make it change example I d2 (18 mg) into.LC/MS (method 132): RT (PDA)=1.77 minute; PDA/ELS-purity: 99.0%/100%; Quality view measured value: 330.1.
Example I d3
1-(2,6-dimethyl-phenyl)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
In DMF (2 mL) mixture of IId (50 mg), DIPEA (0.2 mL), add 2,6-dimethyl benzoyl chloride (48 mg), and this mixture is stirred 5 minutes at ambient temperature.Vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 20/1), obtains corresponding hydrazides (45 mg).This material is mixed with acetonitrile (2 mL) and DIPEA (0.2 mL), and use PhPOCl at ambient temperature
2(0.04 mL) processes 3 minutes.Vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 30/1), obtains example I d3 (12 mg).LC/MS (method 132): RT (PDA)=1.78 minute; PDA purity: 100%; Quality view measured value: 290.0.
Example I d4
1-(the chloro-6-methyl-phenyl of 2-)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
IId (90 mg) and DIPEA (0.4 mL) are dissolved in DMF, and add the chloro-6-methyl benzoyl chloride of 2-(106 mg).This mixture is stirred 5 minutes at ambient temperature.Vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 20:1), obtains the chloro-6-methyl-phenylformic acid of 2-N '-(2-methyl-pyrido [2,3-b] pyrazine-3-yl)-hydrazides (110 mg).This material and DIPEA (0.24 mL) are mixed in acetonitrile (2 mL), and use at ambient temperature PhPOCl
2(0.1 mL) processes 5 minutes.Vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: pentane/EtOAc, 1:3), obtains example I d4 (60 mg).LC/MS (method 132): RT (PDA)=1.79 minute; PDA/ELS-purity: 98.4%/100%; Quality view measured value: 310.3.
Example I d5
1-(the chloro-phenyl of 3-)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
As described in embodiment Id4, be prepared, use IId (200 mg) and 3-chloro-benzoyl chloride (200 mg), obtain corresponding hydrazine (130 mg).This material is suspended in acetonitrile (10 mL), and with DIPEA (0.4 mL) and PhPOCl
2(0.11 mL) processes, until this mixture becomes evenly, is settled out subsequently white solid.Leach this material, with acetonitrile washing, and dry.This dry substance (170 mg) is dissolved in methyl alcohol (20 mL), and uses at ambient temperature Na
2cO
3(10 mg) processes 2 hours.Vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: DCM/ methyl alcohol, 20:1), obtains example I d5 (31.2 mg).LC/MS (method 132): RT (PDA)=1.88 minute; PDA/ELS-purity: 99.6%/100%; Quality view measured value: 296.2.
Example I d6
1-(the chloro-4-iodo-phenyl of 2,6-bis-)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
In Isosorbide-5-Nitrae-diox (0.8 liter), under the condition refluxing, by 4-amino-2, (50 g) use Boc to the chloro-phenol of 6-bis-
2o (69g) processes 18 hours, and vacuum is removed volatile matter, and (70 g), and it need not be further purified just for next step to obtain (3,5-, bis-chloro-4-hydroxyls-phenyl)-carboxylamine tertiary butyl ester.Repeat this process, obtain more this material.By this compound of 86 g and 2,6-lutidine, (49 g) are dissolved in DCM (0.9 liter).At-78 DEG C, dropwise add Tf
2(104 g) for O.This mixture is warming up to room temperature, then stirs 2 hours.Crude mixture is distributed between water and DCM.Use Na
2sO
4dry organic layer, filters vacuum concentration.With silica gel chromatography resistates (elutriant: pentane: EtOAc 30: 1), obtain three fluoro-methylsulfonic acid 4-t-butoxycarbonyl amino-2, (73 g) for the chloro-phenylester of 6-bis-.By this material and Pd (DPPF) Cl
2(4 g), triethylamine (102 mL) mixes in the mixture of methyl alcohol (580 mL) and DMF (384 mL).This mixture is refluxed and spent the night in carbon monoxide atmosphere, then cooling, and vacuum concentration.Resistates is distributed between water and EtOAc.With salt water washing organic layer, use Na
2sO
4dry, filter vacuum concentration.With silica gel chromatography resistates (elutriant: pentane: EtOAc, 80: 1), obtain 4-t-butoxycarbonyl amino-2, (12 g) for the chloro-methyl benzoate of 6-bis-.This material of 7 g is dissolved in the 37% HCl aqueous solution (70 mL), dropwise adds the Sodium Nitrite (3.75 g) aqueous solution (100 mL) at 0 DEG C.This mixture is stirred 30 minutes at 0 DEG C, filter, and filtrate is joined in advance to (24 g) in solution at 0 DEG C of cooling potassiumiodide.This mixture is warming up to room temperature, and stirs and spend the night.Extract this mixture with EtOAc.Use saturated NaHSO
3solution washing organic layer, then uses Na
2sO
4dry, filter vacuum concentration.With silica gel chromatography resistates (elutriant: pentane: EtOAc, 50: 1), (7.9 g) to obtain the chloro-4-iodo-benzoic acid of 2,6-bis-methyl esters.This material is dissolved in the mixture of pyridine (40 mL) and water (7 mL), and with lithium iodide, (3.2 g) process 30 hours, and final vacuum is removed volatile matter at 130 DEG C.Resistates is distributed between the 2M HCl aqueous solution and EtOAc.Vacuum concentration organic layer, (3 g) to obtain the chloro-4-iodo-benzoic acid of 2,6-bis-.By this material of 0.5 g in thionyl chloride (8 mL), at 60 DEG C, stir 3 hours, and final vacuum is removed excessive thionyl chloride.Resistates is washed with ether, dry, obtain 2, the chloro-4-iodo-Benzoyl chloride of 6-bis-(0.53g), it can directly use in next step, in next step, is dissolved in the mixture of DMF (20 mL) and DIPEA (0.57 mL).In this solution, add IId (277 mg).This mixture is at room temperature stirred 1 hour.Vacuum is removed volatile matter, purify resistates (elutriant: DCM:MeOH, 100:1 to 30:1) with silica gel chromatography, obtain 2, the chloro-4-iodo-benzoic acid of 6-bis-N '-(2-methyl-pyrido [2,3-b] pyrazine-3-yl)-hydrazides (250 mg).Repeat this process, obtain more material.This compound of 380 mg is dissolved in Isosorbide-5-Nitrae-dioxs (5 mL).Add phosphoryl chloride (4 mL), and this mixture is stirred 1.5 hours at 90 DEG C.Vacuum is removed volatile matter.Resistates is distributed between DCM and water.Use saturated NaHCO
3solution washing organic layer, uses Na
2sO
4dry, filter vacuum concentration.With preparation, TLC is purified resistates (elutriant: pentane: EtOAc, 2: 1), obtains example I d6 (45.5 mg).LC/MS (method WXE-AB10): RT (PDA)=2.39 minute; PDA/ELS purity: 97.1%/98.3%; Quality view measured value: 456.0.
Example I d7
1-(2-chlorine-4-iodine generation-phenyl)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
Mixture in 2-chlorine-4-iodine phenylformic acid (470 mg) Z thionyl chloride (6 mL) is stirred 3 hours at 60 DEG C.Vacuum is removed excessive thionyl chloride.Resistates is washed with ether, and dry, (0.5 g), and it directly uses in next step, in next step, is dissolved in Isosorbide-5-Nitrae-dioxs (10 mL) to obtain 2-chlorine-4-iodine generation-Benzoyl chloride.Add phosphoryl chloride (5 mL) and IId (246 mg), and this mixture is stirred 1.5 hours at 90 DEG C.Vacuum is removed volatile matter.Resistates is distributed between water and DCM.Use saturated NaHCO
3solution washing organic layer, uses Na
2sO
4dry, filter vacuum concentration.With silica gel chromatography resistates (elutriant: pentane: EtOAc, 10: 1 to 5: 1), obtain example I d7 (250mg).LC/MS (method WXE-AB10): RT (PDA)=2.26 minute; PDA/ELS purity: 99%/99%; Quality view measured value: 422.0.
Example I d8
1-(2-methyl-phenyl)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
IId (400 mg) is dissolved in the mixture of DIPEA (0.8 mL) and DMF (8 mL).Add 2-methyl-Benzoyl chloride (368 mg), and this mixture is stirred to 0.5 hour at ambient temperature, and final vacuum is removed volatile matter.With preparation, TLC is purified resistates (elutriant: DCM:MeOH, 25:1), obtains 2-methyl-phenylformic acid N'-(2-methyl-pyrido [2,3-b] pyrazine-3-yl)-hydrazides (310 mg).This material of 100 mg is dissolved in acetonitrile (2ml), and adds DIPEA (0.24 mL) and PhP (O) Cl
2(0.07 mL).This mixture is stirred 15 minutes at ambient temperature, then purify crude mixture (elutriant: EtOAc: pentane, 3: 2) with preparation TLC, obtain example I d8 (5 mg).LC/MS (method WXE-AB01): RT (PDA)=2.05 minute; PDA/ELS purity: 95.3%/95.7%; Quality view measured value: 276.2.
Example I e1
1-(the chloro-phenyl of 2-)-6-methoxyl group-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
In DCM (80 mL) suspension of IIe (500 mg), add the chloro-phenyl aldehyde of compound 2-(377 mg).This mixture is stirred two days at 40 DEG C, and final vacuum is removed volatile matter.Purify resistates (elutriant: pentane/EtOAc with silica gel chromatography, 1:0 to 0:1), obtaining N-[1-(the chloro-phenyl of 2-)-methylene radical] (0.5 g) for-hydrazine for-N'-(8-methoxyl group-2-methyl-pyrido [2,3-b] pyrazine-3-yl).This material is dissolved in DCM (60 mL), adds (diacetoxy (bisacethoxy)) iodobenzene (540 mg), and this reaction soln is at room temperature stirred and spent the night.Vacuum is removed volatile matter, and purifies resistates (elutriant: pentane/EtOAc, 1:0 to 0:1) with silica gel chromatography, obtains example I e1 (100 mg).LC/MS (method 550): RT (PDA)=0.55 minute; PDA/ELS-purity: 90%/100%; Quality view measured value: 326.0.
Example I e2
1-(the chloro-6-methyl-phenyl of 2-)-6-methoxyl group-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
(in 0.5 DCM (80 mL) suspension g), add the chloro-6-methyl-benzaldehyde compound of 2-(377 mg) to IIe.This mixture is stirred two days at 40 DEG C, then add (diacetoxy) iodobenzene (864 mg), and continue at ambient temperature to stir to spend the night.Vacuum is removed volatile matter, and with preparation, TLC is purified resistates (elutriant: EtOAc), obtains embodiment 1e2 (185 mg).LC/MS (method WXE-AB01): RT (PDA)=1.9 minute; PDA/ELS purity: 100%/100%; Quality view measured value: 340.1.
Example I e3
1-(2,6-dimethyl-phenyl)-6-methoxyl group-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene
(in 0.5 DCM (80 mL) suspension g), add 2 to IIe, 6-dimethyl-phenyl aldehyde (377 mg), and this mixture is stirred two days at 40 DEG C, then add (diacetoxy) iodobenzene (864 mg), and this mixture is stirred and spent the night at ambient temperature.Vacuum is removed volatile matter, purifies resistates (elutriant: EtOAc) with silica gel chromatography, obtains example I e3 (175 mg).LC/MS (method WXE-AB10): RT (PDA)=1.88 minute; PDA/ELS purity: 100%/100%; Quality view measured value: 320.1.
pDE in vitro tests
In conjunction with method below, measure the inhibition activity of the compounds of this invention:
PDE10A enzyme
Prepare active PDE10A enzyme by many modes, test (Loughney, the people Gene 1999,234 such as K., 109-117 for PDE; Fujishige, the people Eur J Biochem. 1999,266 such as K., 1118-1127 and Soderling, the people Proc. Natl. Acad. Sci. 1999,96 such as S., 7071-7076).PDE10A can express with full-length proteins or truncated protein, as long as they express catalytic domain.Can in various cell types, prepare PDE10A, for example, insect cell or intestinal bacteria.An example of the method for the PDE10A of acquisition catalytic activity is as follows: utilize standard RT-PCR, by the whole RNA of the full brain of people people PDE10A (the aminoacid sequence 440-779 that increases, registration number NP 006652) catalytic domain, and be cloned into BamH1 and the Xho1 site of pET28a carrier (Novagen).According to standard scheme, in colibacillus, express.In brief, expression plasmid is transformed into BL21 (DE3) intestinal bacteria strain, inoculates 50 mL cultures with cell, allow to grow to the OD600 of 0.4-0.6, then express with 0.5mM IPTG inducible protein.After induction, by room temperature overnight incubation of cell, then centrifugal collecting cell.The cell of expressing PDE10A is resuspended in to 12 mL (50 mM TRIS-HCl-pH8.0,1 mM MgCl
2and proteinase inhibitor) in.By supersound process, make cytolysis, all cells according to Novagen scheme, adds TritonX100 after dissolving.By PDE10A partial purification on Q agarose, and most active fraction is merged.
PDE10A inhibition test
Typical PDE10A test is carried out as follows: contain fixed amount PDE2A enzyme (being enough to transform the cyclic nucleotide substrate of 20-25%), damping fluid (50mM HEPES, pH7.6 with 60 μ L; 10 mM MgCl
2; 0.02% Tween20), 10 nM carry out this test with the cAMP of tritium spike and the sample of different quantities inhibitor.By adding cyclic nucleotide substrate to carry out initiation reaction, reaction is at room temperature carried out 1 hour, then, by mixing with 20 μ L (0.2 mg) yttrium silicate SPA particulates (Amersham), make reaction terminating.Make in the dark sedimentation of particulate 1 hour, then in Wallac 1450 Microbeta counters, plate is counted.Change the signal of mensuration into activity (with respect to untamed contrast (100%)), and use XlFit (model 205, IDBS), calculate IC
50value.
PDE2A enzyme
Equally, prepare active people PDE2A enzyme (ATCC68585) by many modes, for PDE test, method is well known to those skilled in the art.
PDE2A inhibition test
Typical PDE2A test is carried out as follows: contain fixed amount PDE2A enzyme (being enough to transform the cyclic nucleotide substrate of 20-25%), damping fluid (50mM HEPES, pH7.6 with 60 μ L; 10 mM MgCl
2; 0.02% Tween20), 0.1 mg/ml BSA, 15 nM carry out this test with the cAMP of tritium spike and the sample of different quantities inhibitor.By adding cyclic nucleotide substrate to carry out initiation reaction, reaction is at room temperature carried out 1 hour, then, by mixing with 20 μ L (0.2 mg) yttrium silicate SPA particulates (Amersham), make reaction terminating.Make in the dark sedimentation of particulate 1 hour, then in Wallac 1450 Microbeta counters, plate is counted.Change the signal of mensuration into activity (with respect to untamed contrast (100%)), and use XlFit (model 205, IDBS), calculate IC
50value.
The data that the embodiment selecting is obtained are listed in the following table.
Claims (26)
1. the compound of formula I:
Wherein X
1, X
2, X
3and X
4n or CR independently of one another
3, condition is, and an X is N, and all the other X are CR independently of one another
3;
Wherein R
1c
1-C
6alkyl, C
3-C
6cycloalkyl, THP trtrahydropyranyl, benzyl, phenyl and pyridyl, wherein benzyl, phenyl and pyridyl are optionally by one or more halogens, CN, C
1-C
4alkyl/fluoroalkyl or C
1-C
4alkoxyl group/Fluoroalkyloxy replaces;
Wherein R
2c
1-C
4alkyl or C
3-c
6cycloalkyl;
Wherein R
3hydrogen, halogen, CN ,-CO
2h ,-CON (H or C
1-c
4alkyl)
2, CHO, C
1-C
4alkyl/fluoroalkyl, contain amino heterocycle, the C of ring
2-C
4thiazolinyl, C
2-C
4thiazolinyl or C
1-C
4alkoxyl group/Fluoroalkyloxy; Or its pharmacologically acceptable salt.
2. the compound of claim 1, wherein R
2c
1-C
4alkyl.
3. the compound of claim 1 or 2, wherein R
2it is methyl.
4. the compound of claim 1, wherein R
2c
3-C
6cycloalkyl.
5. the compound of any one of claim 1-4, wherein R
1c
1-C
4alkyl.
6. the compound of any one of claim 1-4, wherein R
1c
3-C
6cycloalkyl.
7. the compound of any one of claim 1-4, wherein R
1it is THP trtrahydropyranyl.
8. the compound of any one of claim 1-4, wherein R
1optionally by one or two F, Cl or C
1-C
3the benzyl that alkyl replaces.
9. the compound of any one of claim 1-4, wherein R
1optionally by one or two F, Cl or C
1-C
3the phenyl that alkyl replaces.
10. the compound of any one of claim 1-4, wherein R
1optionally by one or two F, Cl or C
1-C
3the pyridyl that alkyl replaces.
The compound of any one of 11. claim 1-4, wherein R
1by one or two F, Cl or C
1-C
3the phenyl that alkyl replaces.
The compound of any one of 12. claim 1-11, wherein X
1n.
The compound of any one of 13. claim 1-11, wherein X
2n.
The compound of any one of 14. claim 1-11, wherein X
3n.
The compound of any one of 15. claim 1-11, wherein X
4n.
The compound of any one of 16. claim 1-15, wherein R
3hydrogen.
The compound of any one of 17. claim 1-15, wherein R
3halogen or CHO.
The compound of any one of 18. claim 1-15, wherein R
3c
1-C
4alkyl or C
1-C
4alkoxyl group.
The compound of any one of 19. claim 1-15, wherein R
3c
2-C
4thiazolinyl or C
2-C
4thiazolinyl.
The compound of any one of 20. claim 1-15, wherein R
3to contain the amino heterocycle of ring.
The compound of 21. claims 1, wherein this compound is selected from: 1-(the chloro-phenyl of 3-)-4-methyl-2,3,5,6,9b-pentaaza-cyclopenta [a] naphthalene; 1-(the chloro-6-methyl-phenyl of 2-)-4-methyl-2,3,5,6,9b-pentaaza-cyclopenta [a] naphthalene; 1-(the chloro-phenyl of 2,6-bis-)-4-methyl-2,3,5,6,9b-pentaaza-cyclopenta [a] naphthalene; 1-(2,6-dimethyl-phenyl)-4-methyl-2,3,5,6,9b-pentaaza-cyclopenta [a] naphthalene; 1-(the chloro-phenyl of 2-)-4-methyl-2,3,5,7,9b-pentaaza-cyclopenta [a] naphthalene; 1-(the chloro-phenyl of 2-)-4-methyl-2,3,5,8,9b-pentaaza-cyclopenta [a] naphthalene; 1-(the chloro-phenyl of 2-)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene; 1-(the chloro-phenyl of 2,6-bis-)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene; 1-(2,6-dimethyl-phenyl)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene; 1-(the chloro-6-methyl-phenyl of 2-)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene; And 1-(the chloro-phenyl of 3-)-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta [a] naphthalene.
The pharmaceutical composition of 22. compound or pharmaceutically acceptable salt thereofs that contain claim 1 and pharmaceutically acceptable carrier.
The method of 23. treatment anxiety disorders, the method comprises: the compound for the treatment of any one of the claim 1-21 of significant quantity.
The method of 24. treatment cognitive disorders, the method comprises: the compound for the treatment of any one of the claim 1-21 of significant quantity.
The schizoid method of 25. treatment, the method comprises: the compound for the treatment of any one of the claim 1-21 of significant quantity.
The compound of any one of 26. claim 1-21 is used for the treatment of.
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