CN101743239A - cyanoisoquinoline - Google Patents

cyanoisoquinoline Download PDF

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Publication number
CN101743239A
CN101743239A CN200880021250A CN200880021250A CN101743239A CN 101743239 A CN101743239 A CN 101743239A CN 200880021250 A CN200880021250 A CN 200880021250A CN 200880021250 A CN200880021250 A CN 200880021250A CN 101743239 A CN101743239 A CN 101743239A
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Prior art keywords
dimethoxy
isoquinoline
nitrile
piperazine
phenyl
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J·克勒
J·尼尔森
M·兰加尔德
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H Lundbeck AS
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H Lundbeck AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

This invention is directed to compounds, which are PDE10A enzyme inhibitors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The present invention also provides a process for the preparation of the compounds of formula (I). The present invention further provides a method of treating a subject suffering from a neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a compound of formula (I). The present invention further provides a method of treating a subject suffering from a psychiatric disorder comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

Description

Cyanoisoquinoline
Invention field
The invention provides the compound that also therefore can be used for treating relevant nervus retrogression (neurodegenerative) obstacle and mental disorder as the PDE10A enzyme inhibitors.The present invention especially provides the compound of comparing with PDE3 preferentially at PDE10.The present invention also provides pharmaceutical composition and uses the method for the described obstacle of compounds for treating of the present invention.
Background of invention
The application in the whole text in, various open source literatures are incorporated by reference in this text to be examined.The disclosure of these open source literatures through this quote incorporate into the application with more abundant description the present invention under the existing situation in field.
Cyclic nucleotide, cyclic amp (cAMP) and cyclic guanosine monophosphate (cGMP) serve as second messenger in the cell of regulating a series of processes in the neurone.Intracellular cAMP and cGMP are generated by adenylate cyclase and guanylate cyclase, and are degraded by cyclic nucleotide phosphodiesterase (PDE).Transmit level in the cell of controlling cAMP and cGMP by signal in the cell, and the stimulation of response GPCR activatory adenylate cyclase and guanylate cyclase/check is the mode (Antoni of the gate ring nucleotide concentration that fully characterizes, F.A.Front.Neuroendocrinol.2000,21 (2), 103-132).In neurone, this comprises the activation of cAMP and cGMP dependent kinases and the proteinic phosphorylation subsequently that participates in the acute adjusting of cynapse transmission and participate in neurone differentiation and survival.
21 kinds of phosphodiesterase genes are arranged, and they can be divided into 11 gene families.10 adenylate cyclase enzyme families are arranged, 2 guanylate cyclase families and 11 phosphodiester enzyme families.PDE regulates a class intracellular enzyme of cAMP and cGMP level via the monophosphic acid nucleotide separately that cyclic nucleotide is hydrolyzed into them.Some PDE degraded cAMP, some cGMP that degrade, some degrade both.Most PDE have and express relatively widely and play a role in many tissues, and some are in limited space more.
Phosphodiesterase 10 A (PDE 10A) can change into cAMP dual specificity phosphodiesterase (Loughney, people Gene1999 such as K., 234, the 109-117 that AMP can change into cGMP GMP again; Fujishige, people Eur.J.Biochem.1999 such as K., 266,1118-1127 and Soderling, people Proc.Natl.Acad.Sci.1999 such as S., 96,7071-7076).PDE10A mainly be expressed in the neurone in striatum, nucleus accumbens septi and the olfactory tubercle (Kotera, people Biochem.Biophys.Res.Comm.1999 such as J., 261,551-557 and Seeger, people Brain Research such as T.F., 2003,985,113-126).
Mouse PDE10A is first member (Fujishige, people J.Biol.Chem.1999 such as K., 274 of the PDE10 family of phosphodiesterase, 18438-18445 and Loughney, people Gene 1999,234 such as K., 109-117), terminal variant (Kotera, people Biochem.Biophys.Res.Comm.1999 such as J., 261 of engaging of N-of rat and people's gene have been identified, 551-557 and Fujishige, K. wait people Eur.J.Biochem.1999,266,1118-1127).What have height strides the species homology.With respect to other PDE family, PDE10A only is confined in the Mammals.The mRNA of PDE10 expresses (Fujishige, people Eur J Biochem.1999 such as K., 266,1118-1127 at testis and brain camber; Soderling, people Proc.Natl.Acad.Sci.1999 such as S., 96,7071-7076 and Loughney, people Gene 1999,234 such as K., 109-117).These studies show that in brain, it is the highest that PDE10 is expressed in striatum (tail and nucleocapsid), nucleus accumbens septi and the olfactory tubercle.More nearest, by analysis PDE10AmRNA (Seeger, T.F. wait people Abst.Soc.Neurosci.2000,26,345.10) and PDE10A protein (Menniti, people William Harvey Research Conference ' Phosphodiesterase in Health and Disease ' such as F.S., Porto, Portugal, 5-7 day December calendar year 2001) expression map in the rodent brain.
Medium-sized many sour jujubes neurone of tail nuclear, nucleus accumbens septi (medium spiny neuron, MSN) and the corresponding neurone high level expression PDE10A of olfactory tubercle.This constitutes the core of basal ganglion system.This MSN plays a role in the loop at cortex-basal ganglion-thalamus cortex, and the cortex of integrated convergence/thalamus is imported and sent this integrated information back to cortex.In addition, MSN expresses the neurone of two function types: express D 1The D of Dopamine Receptors 1Class and expression D 2The D of Dopamine Receptors 2Class.D 1The neurone of class is the part of " directly " striatum outgoing route, and it is widely used in the promotion behavior reaction.D 2The class neurone is the part of " indirectly " striatum outgoing route, its be used for suppressing with " directly " path the behavior reaction of promoted those competitions.These contended path show as brake and accelerator in the automobile.Consider that the most simply the poverty of movement in the parkinsonism is from the overactivity in " indirectly " path, and represent the overactivity of direct-path as the overexercise in the deficiency disorder of Huntington chorea and so on.In these neuronic dendroid compartments, transmit the cAMP of signal and/or the PDE10A adjusting of cGMP and may participate in filtering cortex/thalamus input NSN.In addition, PDE10A may participate in the adjusting that the GABA in black substance and the pallidum discharges (Seeger, people Brain Research such as T.F., 2003,985,113-126).
Dopamine D 2Receptor antagonist is very certain in schizoid treatment.From generation nineteen fifty, dopamine D 2Receptor antagonist is exactly the main dependence in the psychiatric treatment, and all effective antipsychotic drugs antagonism D all 2Acceptor.D 2Effect may mainly pass through neurone mediation in striatum, nucleus accumbens septi and the olfactory tubercle because these zones are accepted the most intensive dopaminergic projection and are had the strongest D 2Expression of receptor (Konradi, C. and Heckers, S.Society ofBiological Psychiatry, 2001,50,729-742).Dopamine D 2Receptor agonism causes the reduction of cAMP level in the cell (suppressing to express by adenylate cyclase this its), and this is D 2The component that signal transmits (Stoof, J.C. and Kebabian J.W.Nature 1981,294,366-368 and Neve, people Journal of Receptors and Signal Transduction2004 such as K.A., 24 (3), 165-205).On the contrary, D 2Receptor antagonist effectively improves the cAMP level, and can simulate this effect by the inhibition of cAMP of degraded phosphodiesterase.
Great majority in 21 kinds of phosphodiesterase genes are wide expression all; Therefore suppress to have side effect.Because PDE10A has required expression pattern in this case---have high and expression relative specificity in the neurone in striatum, nucleus accumbens septi and olfactory tubercle, thereby PDE10A suppresses may have and D 2Receptor antagonist similarly acts on, and therefore has antipsycholic action.
Although PDE10A suppresses to estimate partial simulation D 2Receptor antagonist, but it may estimate to have different patterns.D 2Acceptor has signal other except that cAMP and transmits component (Neve, K.A. wait people Journal of Receptors and Signal Transduction 2004,24 (3), 165-205), therefore, suppress to interfere cAMP to bear to regulate by PDE10A but not pass through D 2The direct antagonism Dopamine HCL of acceptor signal transmits.This may reduce the strong D of use 2Observed outer cone danger of side effects during antagonism.On the contrary, PDE10A suppresses to have use D 2More unobserved effects during receptor antagonist.Expressing D 1Also express in the striatal neuron of acceptor PDE10A (Seeger, people Brain Research such as T.F., 2003,985,113-126).Because D 1Receptor agonism causes the stimulation of adenylate cyclase and the raising of cAMP level thereupon, and PDE10A suppresses also to have analog D 1The effect of receptor agonism.At last, PDE10A suppresses not only to improve the cAMP in the cell, also may estimate to improve the cGMP level, because PDE10A is the dual specificity phosphodiesterase.Many target proteins in the cGMP activating cells as cAMP, and also interact with the cAMP signal path.In a word, PDE10A suppresses partial simulation D similarly 2Therefore receptor antagonist also has antipsycholic action, but this pattern may be different from the typical D of use 2The observed pattern of receptor antagonist.
PDE10A inhibitor Papaverine shows as activity in several antipsychotic models.Papaverine is strengthened D 2The stiff effect of receptor antagonist haloperidol in rat, but itself does not cause stiff (WO 03/093499).Papaverine reduces the rat superfunction that PCP brings out, and the ergogenic reduction that amphetamine brings out not significantly (WO 03/093499).These models show that PDE10A suppresses to have the typical antipsychotic potentiality of being considered expectation by theory.WO03/093499 further discloses selective PDE 10 inhibitors and has been used for the treatment of the relevant nerve and the purposes of mental disorder.In addition, PDE10A suppress to reverse rat attention set that inferior chronic PCP brings out shift defective (people Eur.J.Neurosci.2005 such as Rodefer, 4,1070-1076).This model shows that PDE10A suppresses to alleviate the cognitive defect relevant with schizophrenia.
Correspondingly, can bring out the signal enhancing that realizes via cAMP and cGMP raising by using the PDE10A inhibitor, thus relevant nerve and the mental disorder of treatment.PDE10A inhibitor of the present invention is estimated to serve as the therapeutical agent that is used for the treatment of related neural and mental disorder, and may have not the benefit of the undesired side effect relevant with present therapy on the market.
In addition, nearest open source literature (WO 2005/120514, people such as WO 2005012485, Cantin, Bioorganic ﹠amp; Medicinal Chemistry Letters 17 (2007) 2869-2873) propose, the PDE10A inhibitor may can be used for treatment of obesity and non insulin dependent diabetes.
About the inhibitor of PDE10A, EP 1250923 discloses and has used generally speaking selective PDE 10 inhibitors and Papaverine particularly to treat some nerve and mental disorder.
WO 05/113517 discloses benzodiazepine
Figure G2008800212506D00041
(benzodiazepine) the Stereoselective compound is as phosphodiesterase, the inhibitor of 2 and 4 type phosphodiesterases especially, and the prevention and the treatment that relate to the pathology of maincenter and/or periphery obstacle.WO 02/88096 discloses benzodiazepine
Figure G2008800212506D00042
Derivative and they in the treatment field as phosphodiesterase, the purposes of the inhibitor of 4 type phosphodiesterases especially.WO 04/41258 disclose benzodiazepinone derivative and they in the treatment field as phosphodiesterase, the purposes of the inhibitor of 2 type phosphodiesterases especially.
Pyrrolo-dihydro-isoquinoline and variant thereof the inhibitor as PDE10 is disclosed in WO 05/03129 and WO 05/02579.The quinazoline and the isoquinoline 99.9 of the piperidyl replacement of serving as PDE 10 inhibitor are disclosed in WO 05/82883.WO 06/11040 discloses substituted quinazoline and the isoquinoline compound that serves as the PDE10 inhibitor.US20050182079 discloses the quinazoline that serves as effective phosphodiesterase (PDE) inhibitor and the substituted tetrahydroisoquinolicompounds radical derivative of isoquinoline 99.9.Especially, US20050182079 relates to described compound, and it is the selective depressant of PDE-10.Similarly, US20060019975 discloses the quinazoline that serves as effective phosphodiesterase (PDE) inhibitor and the piperidine derivative of isoquinoline 99.9.US20060019975 also relates to the compound as the selective depressant of PDE10.
WO 06/028957 discloses cinnoline derivatives as the 10 type phosphodiesterase inhibitors that are used for the treatment of spirit and nervous syndrome.
But these open source literatures do not relate to and comprise the compound that is connected to the Cyanoisoquinoline on 2-aryl piperazines, 2-aryl thiomorpholine or the 2-aryl morpholine via the N-C key; Nowadays described compound is found it is the PDE10A enzyme inhibitors of high activity by the contriver.This compounds can provide alternatives for the present market therapy (they are not all effective in all patients) of nervus retrogression obstacle and/or mental disorder.Therefore, still need the alternative treatment method.
Phosphodiesterase 3 (PDE3) family is made of two kinds of gene PDE3A and PDE3B.Their codings can be hydrolyzed into cAMP and cGMP respectively the enzyme of AMP and GMP.Be expressed in thrombocyte, vascular smooth muscle, myocardial cell and the parent cell to the PDE3A relative height.PDE3B is the main PDE in fatty tissue, liver, pancreas and the cardiovascular organization.The PDE3 inhibitor has been approved for the treatment congestive heart failure.But, although they in acute treatment effectively, use the chronic treatment of PDE3 inhibitor cause death the significantly improving of rate (MatthewA.Movsesian, Journal of Cardiac Failure Vol.9No.6,2003,475-480).
Described before and contained 6, several PDE10 inhibitor of 7-dimethoxy-quinazoline motif (people: Discovery of a Series of 6 such as Chappie, 7-Dimethoxy-4-pyrrolidylquinazoline PDE10A Inhibitors, American Chemical Society, Published on Web 12/22/2006).That wherein describes contains 6, and the compound of 7-dimethoxy-quinazoline shows all that significant PDE3 activity-all these has the PDE3AIC50 less than 800nM.Therefore, realize the selectivity of PDE3 is looked like the total problem of the PDE10 inhibitor with this motif, consider that pde3 suppresses to cause the tendency of cardiac side effects, this causes serious problems to their potential application in chronic treatment.
Summary of the invention
The purpose of this invention is to provide at the compound that does not influence under the situation that PDE3 suppresses as the PDE10A enzyme inhibitors.
Another object of the present invention provides and compares this type of the active compound that has with improved solubleness, metabolic stability and/or bioavailability with the compound of prior art.
Another object of the present invention provides effective treatment, particularly long-term treatment of human patients, and the side effect that does not cause existing therapy general and neural and mental disorder to link together.
Other purpose of the present invention is conspicuous behind this specification sheets of reading.
Correspondingly, in one aspect in, the present invention relates to the compound or pharmaceutically acceptable salt thereof of formula I:
Figure G2008800212506D00061
Wherein
● Q is selected from NH, O or S
● R 1And R 2Be C independently 1-C 4Alkyl
● R 3, R 4, R 5, R 6And R 7Be independently selected from:
Zero H, (C 1-C 6) alkyl, (C 1-C 6) alkoxyl group, halogen, halo (C 1-C 6) alkyl, (C 1-C 6) hydroxyalkyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl, (C 1-C 6) hydroxyl cycloalkyl, (C 3-C 8) cycloalkyloxy, (C 1-C 6) alkoxyl group (C 3-C 8) cycloalkyl, Heterocyclylalkyl, hydroxyl Heterocyclylalkyl and (C 1-C 6) alkoxyl group-Heterocyclylalkyl, wherein each (C 3-C 8) cycloalkyl or Heterocyclylalkyl part can be independently by 1 to 3 (C 1-C 6) the alkyl replacement;
Zero-NR 8R 9Group, wherein R 8And R 9Be independently selected from hydrogen, C 1-C 6Alkyl, halo (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl, Heterocyclylalkyl;
The aliphatic heterocycle of zero 6-7-unit:
Figure G2008800212506D00062
Wherein n be 1 or 2 and Z be oxygen or NR 10, R wherein 10Be hydrogen or (C 1-C 6) alkyl, or
Zero ketone, sulfone, ester, acid amides, sulphonate or sulphonamide are selected from
Wherein Y is hydrogen or (C 1-C 6) alkyl and X be selected from:
● (the C that does not replace or replaced by one or more halogens 1-C 6) alkyl,
● do not replace or by one or more halogens replace-O-(C 1-C 6) alkyl,
●-NR 11R 12Group, wherein R 11And R 12Be independently selected from hydrogen, C 1-C 6Alkyl, halo (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl, Heterocyclylalkyl, or
● the aliphatic heterocycle of 6-7-unit:
Figure G2008800212506D00072
Wherein n is 1 or 2; And W is oxygen or NR 13, R wherein 13Be hydrogen or (C 1-C 6) alkyl, or
● two adjacent substituting groups that are selected from R3, R4, R5, R6 and R7 can form 5-7 unit, saturated or undersaturated ring with the aromatic ring that links to each other with them, and this ring contains carbon and one or two heteroatoms and optional quilt (C1-C6) alkoxyl group that is selected from N, O or S replaces.Its excess-three substituting group that is selected from R3, R4, R5, R6 and R7 that does not constitute the part of this ring is selected independently as mentioned above.
In a specific embodiments, the present invention relates to the compound of the formula I of single enantiomer, single diastereomer, enantiomeric mixture, non-enantiomer mixture or polymorphic form form.
In independently embodiment of the present invention, this compound is selected from one of disclosed particular compound in the experimental section.
The invention provides compound or its pharmaceutically useful acid salt as the formula I of medicine.
On the other hand, the invention provides the compound that comprises the formula I that treats significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier or thinner.
The present invention further provides the purposes that the compound of formula I or its pharmaceutically useful acid salt are used to prepare the medicine of neurological sexual dysfunction or mental disorder.
In addition,, the invention provides the method that treatment suffers from the patient of neurological sexual dysfunction, comprise compound the formula I of this patient's administering therapeutic significant quantity more on the one hand.In aspect another, the invention provides the patient's who suffers from the treatment mental disorder method, comprise compound the formula I of this patient's administering therapeutic significant quantity.In another embodiment, the invention provides treatment and suffer from drug habit, as the patient's of alcohol, amphetamine, Cocaine or opiate habituation method.
Detailed Description Of The Invention
Substituent definition
Term " halo " and " halogen " used among the present invention are used interchangeably and are meant fluorine, chlorine, bromine or iodine.
In addition, term " C 1-C 6Alkyl " be meant the straight or branched stable hydrocarbon of (the comprising 1 and 6) carbon atom that has 1 to 6.This class examples of groups includes, but not limited to methyl, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl group, 2-methyl-1-butene base and n-hexyl.Similarly, term " C 1-C 4Alkyl " be meant the straight or branched stable hydrocarbon of (the comprising 1 and 4) carbon atom that has 1 to 4.Term " C 1-C 6Hydroxyalkyl " be meant by the as above specified C of a hydroxyl replacement 1-C 6Alkyl.Term " halo (C 1-C 6) alkyl " be meant by the as above specified C of maximum 3 halogen atoms replacements 1-C 6Alkyl.
Term " C 1-C 6Alkoxyl group " be meant the saturated alkoxyl group of the straight or branched of (the comprising 1 and 6) carbon atom that has 1 to 6 on oxygen, to have open valency (open valency).This class examples of groups includes, but not limited to methoxyl group, oxyethyl group, n-butoxy, 2-methyl-pentyloxy and positive hexyloxy.Term " halo (C 1-C 6) alkoxyl group " be meant by the as above specified C of maximum 3 halogen atoms replacements 1-C 6Alkoxyl group.Term " C 1-C 6Alkoxyl group (C 1-C 6) alkyl " be meant by as above specified C 1-C 6The as above specified C that alkoxyl group replaces 1-C 6Alkyl.
Term " C 3-C 8Cycloalkyl " typically refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.Term " C 3-C 8The hydroxyl cycloalkyl " be meant by the as above specified C of a hydroxyl replacement 3-C 8Cycloalkyl.Term " C 1-C 6Alkoxyl group (C 3-C 8) cycloalkyl " be meant by straight or branched C 1-C 6The as above specified C that alkoxyl group replaces 3-C 8Cycloalkyl.Term " C 3-C 8Cycloalkyloxy " normally finger ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base and ring octyloxy, wherein open valency is on Sauerstoffatom.
Term " Heterocyclylalkyl " is meant 4 to 8 yuan of rings of carbon atoms and maximum 3 N, O or S atom, and condition is that these 4 to 8 yuan of rings do not contain adjacent O or adjacent S atom.Open valency is on heteroatoms or carbon atom.This class examples of groups includes, but not limited to azetidinyl, oxetanyl, piperazinyl, morpholinyl, thio-morpholinyl and [1,4] Diazesuberane base (diazepanyl).Term " hydroxyl Heterocyclylalkyl " is meant the as above specified Heterocyclylalkyl that is replaced by a hydroxyl.Term " C 1-C 6Alkoxyl group-Heterocyclylalkyl " be meant by C 1-C 6The as above specified Heterocyclylalkyl that alkoxyl group replaces.
In addition, the present invention further provides following certain embodiments of the present invention.
Formula I is by ring variable Q and pass through substituent R 1, R 2, R 3, R 4, R 5, R 6And R 7Specify compound of the present invention.
In a preferred embodiment of the invention, Q=NH.
In one embodiment, R 1And R 2Be C independently 1-C 2Alkyl is as methyl.R1 and R 2Usually all be methyl.
In one embodiment, R 3Be selected from hydrogen, (C 1-C 6) alkoxy or halogen, as hydrogen, methoxyl group, chlorine and bromine; Or be selected from the carboxylic acid amides or the sulphonamide of following formula:
Figure G2008800212506D00091
R 3Hydrogen normally.
In another embodiment of the present invention, R 4Be selected from hydrogen, (C 1-C 6) alkoxyl group, halogen or nitro, as hydrogen, methoxyl group, chlorine, bromine and nitro, or be selected from the carboxylic acid amides or the sulphonamide of following formula:
Figure G2008800212506D00092
R 4Normally hydrogen or methoxyl group.
In an embodiment again, R 5Be selected from:
Zero H, (C 1-C 6) alkyl, (C 1-C 6) alkoxyl group, halogen, halo (C 1-C 6) alkyl, nitro or
Zero amino-NR 8R 9, R wherein 8And R 9Be independently selected from hydrogen, C 1-C 6Alkyl, halo (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl, Heterocyclylalkyl, or
The aliphatic heterocycle of zero 6-7-unit:
Figure G2008800212506D00101
Wherein n be 1 or 2 and Z be oxygen or NR 10, R wherein 10Be hydrogen or (C 1-C 6) alkyl, or be selected from the carboxylic acid amides or the sulphonamide of following formula:
Figure G2008800212506D00102
For example hydrogen, methyl, ethyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, nitro, dimethylamino, morpholinyl.R 5Normally hydrogen, methyl, dimethylamino, methoxyl group fluorine, chlorine or trifluoromethyl.
In another embodiment, R 6Be selected from hydrogen, (C 1-C 6) alkoxyl group, halogen or nitro, as hydrogen, methoxyl group, chlorine, bromine and nitro, or be selected from the carboxylic acid amides or the sulphonamide of following formula:
Figure G2008800212506D00103
R 6Normally hydrogen or methoxyl group.
In one embodiment, R 7Be selected from hydrogen, (C 1-C 6) alkoxy or halogen, as hydrogen, methoxyl group, chlorine and bromine; Or be selected from the carboxylic acid amides or the sulphonamide of following formula:
Figure G2008800212506D00104
R 7Hydrogen normally.
In another embodiment, be selected from R 3, R 4, R 5, R 6And R 7Two adjacent substituting groups can form 5-7 unit, saturated or undersaturated ring with the aromatic ring that links to each other with them, optional contain the heteroatoms that one or two is selected from N, O or S, for example contain 5 yuan of rings of 2 Sauerstoffatoms or 6 yuan of rings of carbon atoms only.
In an embodiment again, R 3, R 4, R 5, R 6And R 7In 2 to 5 be H.Usually, R 3, R 4, R 5, R 6And R 7In 3 to 4 be H.
In a preferred embodiment, R 4, R 5Or R 6In 1 to 3 be to electron substituent group, (C for example 1-C 6) alkoxyl group, (C 1-C 6) alkyl or-NR 8R 9, R wherein 8And R 9Be independently selected from hydrogen, C 1-C 6Alkyl, halo (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl, Heterocyclylalkyl, for example methoxyl group, methyl, ethyl, dimethylamino and morpholinyl.
In another embodiment, be selected from R 3, R 4, R 5, R 6And R 7Two adjacent substituting groups can form 5 yuan of saturated rings that contain 2 Sauerstoffatoms with the aromatic ring that links to each other with them:
Figure G2008800212506D00111
In an embodiment again, be selected from R 3, R 4, R 5, R 6And R 7Two adjacent substituting groups can form 6 yuan of aromatic rings with the aromatic ring that links to each other with them:
Figure G2008800212506D00112
Or its pharmacologically acceptable salt.
Another aspect of the present invention is the method for the compound of preparation formula I, comprises the compound that makes formula II:
Wherein L is selected from Cl, Br, I, OSO 2CF 3Leaving group, and R 1And R 2As above definition;
Under the solvent-free situation or in inert solvent or solvent mixture,, choose in the presence of alkali compound reaction wantonly with the formula III of free alkali or its additive salt form 0 to about 200 ℃ temperature:
Figure G2008800212506D00121
Wherein Q, R 3, R 4, R 5, R 6And R 7As above definition; Aftertreatment and go out the product of formula I with its free alkali or its acid salt isolated in form then.
In one embodiment of the invention, the solvent that is used for the compound of preparation formula I is toluene or toluene and protonic solvent, as the mixture of 2-propyl alcohol, is preferably 1: 1 mixture of toluene and 2-propyl alcohol.
In another embodiment of the present invention, the alkali that is used for the compound of preparation formula I is salt of wormwood.
In an embodiment more of the present invention, the preferable reaction temperature that is used for the compound of preparation formula I is 180 ℃.
In further embodiment, the method that is used for the compound of preparation formula I comprises the compound of the compound that makes formula II and formula III in alkoxide base, as sodium tert-butoxide with pass through with palladium (II) source, as Pd (OAc) 2Or Pd 2(dba) 3With biphosphine ligand, as BINAP (promptly 2,2 '-two (diphenylphosphino)-1,1 '-binaphthylyl) mix and palladium catalyst that original position is made exists down, at reaction solvent easily, as reacting in the toluene, heated this reaction mixture 3-12 hour down at 50-150 ℃ then, following 7 hours at 100 ℃ usually.
Pharmacologically acceptable salt
The present invention also comprises the salt of this compound, usually pharmacologically acceptable salt.This class salt comprises pharmaceutically useful acid salt.Acid salt comprises mineral acid and organic acid salt.
The representative example of suitable mineral acid comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, sulfuric acid, thionamic acid, nitric acid and analogue.The representative example of appropriate organic comprises formic acid, acetate, trichoroacetic acid(TCA), trifluoroacetic acid, propionic acid, phenylformic acid, styracin, citric acid, fumaric acid, oxyacetic acid, methylene-succinic acid, lactic acid, methylsulfonic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, oxalic acid, picric acid, pyruvic acid, Whitfield's ointment, succsinic acid, methylsulfonic acid, ethyl sulfonic acid, tartrate, xitix, pamoic acid, the dimethylene Whitfield's ointment, ethionic acid, glyconic acid, citraconic acid, aspartic acid, stearic acid, palmitinic acid, EDTA, oxyacetic acid, para-amino benzoic acid, L-glutamic acid, Phenylsulfonic acid, tosic acid, theophylline acetate, and 8-halo theophylline, for example 8-bromine theophylline and analogue.Pharmaceutically useful further example inorganic or organic acid addition salt comprises Berge, people such as S.M., and J.Pharm.Sci.1977, the pharmacologically acceptable salt of enumerating in 66,2, its content is incorporated herein by this reference.
In addition, compound of the present invention can be with solvation form not and using acceptable solvent, exists as the solvation form of water, ethanol and analogue.Generally for the purpose of the present invention, the solvation form is considered to be equal to not solvation form.
Racemic form can split into optically active enantiomorph by currently known methods, for example with optically-active acid its non-mapping salt of separation and by discharge the optically active amine compound with alkaline purification.The separation of the non-mapping salt of this class can for example realize by fractional crystallization.The optically-active acid that is applicable to this purpose can include but not limited to, d-or l-tartrate, amygdalic acid or camphorsulfonic acid.The other method that racemate resolution is become optically active enantiomorph is based on the chromatography on optically-active matrix.Compound of the present invention also can be by non-mapping derivative formation and with chirality derivation agent, separate (for example chromatographic separation) as chirality alkylating agent or acylation agent, the cracking chiral auxiliary(reagent) splits then.
Can use other method of fractionation optical isomer well known by persons skilled in the art.These class methods comprise J.Jaques, and A.Collet and S.Wilen be at Enantiomers, Racemates, and Resolutions, John Wiley and Sons, those that discuss among the New York 1981.Also by optically-active raw material preparing optically-active compound.
Pharmaceutical composition
The present invention further provides the compound that comprises the formula I that treats significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier or thinner.The present invention also provides and comprises one of the disclosed particular compound in experimental section for the treatment of significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier or thinner.
Compound of the present invention can be in single or multiple dosage, separately or with pharmaceutically acceptable carrier, thinner or vehicle Combined Preparation.Pharmaceutical composition of the present invention can be with pharmaceutically acceptable carrier or thinner and any other known adjuvant and vehicle according to routine techniques, as Remington:The Science and Practice of Pharmacy, the 19th edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, those disclosed technology preparation in 1995.
This pharmaceutical composition can be mixed with specially by any suitable way administration, as oral, rectum, intranasal, lung, part (comprising oral cavity and hypogloeeis), in skin, brain pond, intraperitoneal, vagina and non-enteron aisle (comprise in subcutaneous, intramuscular, the sheath, intravenously and intracutaneous) approach.Recognize the character and the activeconstituents of the symptom that route of administration depends on the general situation of the object that will treat and age, will treat.
Orally administered pharmaceutical composition comprises solid dosage, as capsule, tablet, dragee, pill, lozenge, pulvis and granule.If suitably, said composition can use dressing, prepare as enteric coating, or they can be mixed with the controlled release that activeconstituents is provided according to method well known in the art, as slowly-releasing or long-acting release.Liquid dosage form for oral use comprises solution, emulsion, suspension agent, syrup and elixir.
The pharmaceutical composition that parenterai administration is used comprises sterile aqueous and non-water injection, dispersion, suspension agent or emulsion and the sterile powder of reconstruct in aseptic parenteral solution or dispersion before use.Other suitable form of medication includes, but not limited to suppository, sprays, ointment, creme, gel, inhalation, skin patch and implant.
Typical case's oral dosage is that every day about 0.001 is to about 100 milligrams/kg body weight.Typical case's oral dosage also is that every day about 0.01 is to about 50 milligrams/kg body weight.Typical case's oral dosage further is that every day about 0.05 is to about 10 milligrams/kg body weight.Oral dosage divides potion or multi-agent common every day, potion to three dose administration every day usually.Character and seriousness and any subsidiary disease that will treat and the conspicuous other factors of those skilled in the art of the patient's that precise dosage depends on administration frequency and pattern, will treat sex, age, body weight and overall state, the symptom that will treat.
This preparaton also can be rendered as unit dosage by method known to those skilled in the art.For illustrating, typical flat formulation for oral use can contain about 0.01 to about 1000 milligrams, and about 0.05 to about 500 milligrams, or about 0.5 milligram to about 200 milligrams.
To parenteral route, as in intravenously, the sheath, intramuscular and similar route of administration, typical doses is the only about half of of dosage for oral use.
The present invention also provides the method for making pharmaceutical composition, comprises compound and at least a pharmaceutically acceptable carrier or mixing diluents with the formula I of treatment significant quantity.In one embodiment of the invention, used compound is one of disclosed particular compound in the experimental section in the aforesaid method.
Compound of the present invention uses with the form of dissociant or its pharmacologically acceptable salt usually.An example is the acid salt with compound of free alkali effectiveness.When the compound of formula I contained free alkali, this class salt prepared by solution or the suspension of handling the free alkali of formula I with the pharmaceutically acceptable acid of molar equivalent in a usual manner.The representative example of suitable organic and mineral acid has above been described.
For parenterai administration, can use the solution of compound in aseptic aqueous solution, aqueous solution of propylene glycol, the vitamin-E aqueous solution or sesame oil or peanut oil of formula I.If necessary, this class aqueous solution should cushion suitably, and at first with capacity salt solution or glucose liquid diluent etc. is oozed.This aqueous solution is specially adapted to intravenously, intramuscular, subcutaneous and intraperitoneal administration.The compound of formula I can use standard technique well known by persons skilled in the art easily to mix in the known aseptic aqueous medium.
Suitable pharmaceutical carrier comprises inert solid diluent or filler, aseptic aqueous solution and various organic solvent.The example of solid carrier comprises lactose, carclazyte, sucrose, cyclodextrin, talcum, gelatin, agar, pectin, Sudan Gum-arabic, Magnesium Stearate, stearic acid and cellulosic low-carbon alkyl ether.The example of liquid vehicle includes but not limited to, syrup, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, polyoxyethylene and water.Similarly, this carrier or thinner can comprise any slow-release material known in the art, as separately or with wax blended glyceryl monostearate or distearin.The pharmaceutical composition that compound and pharmaceutically acceptable carrier by combination type I forms is subsequently easily to be fit to the various formulation administrations of disclosed route of administration.This preparaton can be rendered as unit dosage by the known method of pharmacy field easily.
The preparaton of the present invention that is fit to oral administration can be discrete unit, as capsule or tablet, contains the activeconstituents and the optional suitable vehicle of predetermined amount separately.In addition, can be powder or particle, the solution in water-based or on-aqueous liquid or suspension or oil-in-water or water-in-oil emulsion form for oral preparaton.
If solid carrier is used for oral administration, said preparation can compressing tablet, place hard gelatin capsule or its with powder or pill form can be lozenge or lozenge form.The amount of solid carrier extensively changes, but is about 25 milligrams of extremely about 1 grams of every dose unit.If use liquid vehicle, said preparation can be syrup, milk sap, soft gelatin capsule or aseptic parenteral solution, as water-based or on-aqueous liquid suspension or solution form.
Pharmaceutical composition of the present invention can be by the preparation of the ordinary method in this area.For example, can by with activeconstituents and common adjuvant and/or mixing diluents and subsequently in conventional tabletting machine this mixture of compacting prepare tablet.The example of adjuvant or thinner comprises: W-Gum, yam starch, talcum, Magnesium Stearate, gelatin, lactose, natural gum and analogue.Can use be usually used in this classification any other adjuvant or additive, as tinting material, spices, sanitas etc., condition is that they and activeconstituents are compatible.
Treatment of conditions
As mentioned above, the compound of formula I is the PDE10A enzyme inhibitors, therefore can be used for treating relevant nerve and mental disorder.The invention provides treatment and suffer from the patient's who is selected from cognitive disorder or dyskinetic neurological sexual dysfunction method, it comprises the compound to the formula I of this patient's administering therapeutic significant quantity.
The present invention also provides treatment to suffer from the patient's of mental disorder method, and it comprises the compound to the formula I of this patient's administering therapeutic significant quantity.The example of the mental disorder that can treat according to the present invention includes but not limited to, schizophrenia, for example intolerance style, disintegrate the schizophrenia of type, catatonic type, undifferentiated type or residual type; Class schizophrenia; Schizoaffective disorder, for example delusional type or depressive type; Paranoea; The mental disorder that material brings out, for example psychosis of bringing out by alcohol, amphetamine, hemp, Cocaine, halluoinogen, inhalation, opioid or phencyclidine; The paranoid personality disorder; With the schizoid personality obstacle; And anxiety disorder, be selected from Phobias; Agoraphobia; Specific phobias; Social phobia; Obsession; Posttraumatic stress disorder; Acute stress disorder; And generalized anxiety disorder.
The invention provides treatment cognitive disorder patient's method, it comprises the compound to the formula I of this patient's administering therapeutic significant quantity.The example of the cognitive disorder that can treat according to the present invention includes but not limited to that Alzheimer's disease, multiple cerebral infarction dementia, alcoholic dementia or other medicines dependency dementia, the dementia relevant with intracranial tumors or cerebral trauma, the dementia of being correlated with Huntington chorea or parkinsonism or AIDS-are relevant dull-witted; Delirium; Amnesia; Posttraumatic stress disorder; Mental retardation; Learning disorder, for example Dyslexia, mathematics disorder or write the expression obstacle; Attention-deficient/hyperkinetic syndrome; And the cognitive decline relevant with the age.
The present invention also provides treatment dyskinetic method, and it comprises the compound to the formula I of patient's administering therapeutic significant quantity.The dyskinetic example that can treat according to the present invention includes but not limited to, Huntington chorea and the dyskinesia that is associated with the dopamine agonist treatment.The present invention further provides the dyskinetic method that treatment is selected from parkinsonism and restless leg syndrome, it comprises the compound to the formula I of patient's administering therapeutic significant quantity.
The present invention also provides the method for treatment mood disorder (mood disorder), and it comprises the compound to the formula I of patient's administering therapeutic significant quantity.The example of the mood disorder that can treat according to the present invention includes but not limited to, light-duty, medium-sized or heavy severe depression outbreak, manic or mixed feeling outbreak (mood episode), hypomania's affective attack; Paralepsy with characteristic feature; Paralepsy with depressed feature; Paralepsy with nervous feature; Post-natal depression; Apoplexy retarded depression disease; The severe depression obstacle; Dysthymic disorder; Minor depressive disorder; Through preceding irritated disease; Schizoid postpsychotic depression; Be superimposed upon mental disorder, as the major depressive disorder on paranoea or the schizophrenia; Two-phase obstacle, for example two-phase I type obstacle, two-phase II type obstacle and cycle penalty.Mood disorder is understood that it is mental disorder.
The purposes that the present invention also provides the compound of formula I or its pharmaceutically useful acid salt to be used to prepare the medicine of neurological sexual dysfunction or mental disorder, wherein this neurological sexual dysfunction is selected from Alzheimer's disease, multiple cerebral infarction dementia, alcoholic dementia or other medicines dependency dementia, the dementia relevant with intracranial tumors or cerebral trauma, dementia or the AIDS-relevant with Huntington chorea or parkinsonism is relevant dull-witted; Delirium; Amnesia; Posttraumatic stress disorder; Mental retardation; Learning disorder, for example Dyslexia, mathematics disorder or write the expression obstacle; Attention-deficient/hyperkinetic syndrome; And the cognitive decline relevant with the age, and wherein this mental disorder is selected from schizophrenia, for example intolerance style, disintegrate type, catatonic type, undifferentiated type or residual schizophrenia; Class schizophrenia; Schizoaffective disorder, for example delusional type or depressive type; Paranoea; The mental disorder that material brings out, for example psychosis of bringing out by alcohol, amphetamine, hemp, Cocaine, halluoinogen, inhalation, opioid or phencyclidine; The paranoid personality disorder; With the schizoid personality obstacle.
The present invention further provides the treatment Mammals, comprise human drug habit, the method of alcohol, amphetamine, Cocaine or opiate habituation for example, this method comprise the effective compound of the formula I of the amount of the described drug habit of treatment of described administration.
The present invention also provides the treatment Mammals, comprises human drug habit, and the method for alcohol, amphetamine, Cocaine or opiate habituation for example, this method comprise the compound of formula I that described administration is effectively suppressed the amount of PDE10.
" drug habit " used herein is meant the abnormal demand to medicine, and is feature with the motivation disorder usually, as obtains the outbreak that forces impulsion and strong medicine to thirst for of required medicine.
The present invention also provides and has been used for the treatment of Mammals, comprise human neurological sexual dysfunction, mental disorder and drug habit formula I compound or its pharmaceutically useful acid salt and contain the pharmaceutical composition of this compounds, wherein this neurological sexual dysfunction be selected from Alzheimer's disease, multiple cerebral infarction dementia, alcoholic dementia or other medicines dependency dementia, the dementia relevant with intracranial tumors or cerebral trauma, relevant dementia or the AIDS-dementia of being correlated with Huntington chorea or parkinsonism; Delirium; Amnesia; Posttraumatic stress disorder; Mental retardation; Learning disorder, for example Dyslexia, mathematics disorder or write the expression obstacle; Attention-deficient/hyperkinetic syndrome; And the cognitive decline relevant with the age, and wherein mental disorder is selected from schizophrenia, for example intolerance style, disintegrate type, catatonic type, undifferentiated type or residual schizophrenia; Class schizophrenia; Schizoaffective disorder, for example delusional type or depressive type; Paranoea; The mental disorder that material brings out, for example psychosis of bringing out by alcohol, amphetamine, hemp, Cocaine, halluoinogen, inhalation, opioid or phencyclidine; The paranoid personality disorder; With the schizoid personality obstacle, and wherein this drug habit is alcohol, amphetamine, Cocaine or opiate habituation.
In another embodiment, the invention provides treatment target to reduce the method for body fat or body weight or treatment non insulin dependent diabetes (NIDDM), metabolism syndrome or glucose intolerance, comprise compound the formula I of object administering therapeutic significant quantity that needs are arranged.In a preferred embodiment, this to as if human, this object is overweight or fat, and this antagonist of oral administration.In another preferred embodiment, this method further comprises uses second therapeutical agent to this object, be preferably antiobesity agent, for example Rimonabant, orlistat, sibutramine, bromocriptine, ephedrine, leptin (leptin), pseudoephedrine or peptide YY3-36 or its analogue.
Term used herein " metabolism syndrome " is to instigate the people to be in a series of illnesss under the excessive risk of coronary artery disease.These illnesss comprise diabetes B, obesity, hypertension and have the poor blood fat situation of the triglyceride level of LDL (" the bad ") cholesterol of rising, low HDL (" good ") cholesterol and rising.All these illnesss are all relevant with high blood insulin levels.Basic defective in the metabolism syndrome is the insulin resistant in fatty tissue and the muscle.
Understand the present invention better from following experimental section.But, it will be readily appreciated by those skilled in the art that concrete grammar as herein described and result only illustrate the present invention of more abundant description in claim after this.
Experimental section
General method
On the PESciex API 150EX instrument of being furnished with normal atmosphere photo-ionisation and Shimadzu LC-8A/SLC-10A LC system, obtain to analyze the LC-MS data.Post: 30X4.6mm WatersSymmetry C18 post, 3.5 micron granularities; Solvent system: A=water/trifluoroacetic acid (100: 0.05) and B=water/acetonitrile/trifluoroacetic acid (5: 95: 0.03); Method: with 90%A to 100%B flow velocity linear gradient elution with 2 ml/min in 4 minutes.By the integration of UV (254nm) and ELSD trace, measure purity.The residence time (t R) with a minute expression.
Be prepared LC-MS-on the same instruments of atmospheric pressure chemical ionization and purify having.Post: 50X20mm YMC ODS-A, 5 micron granularities; Method: with 80%A to 100%B flow velocity linear gradient elution with 22.7 ml/min in 7 minutes.Carrying out fraction by shunting MS detection method collects.
The preparation of compound of the present invention
Figure G2008800212506D00191
The compound that can described in following reaction scheme, prepare general formula I of the present invention.Unless indicate separately, in reaction scheme and following argumentation, R 1-R 7, Q and L as above define.Graphic 1 has described the linked reaction between 2-aryl piperazines, 2-aryl thiomorpholine or the 2-aryl morpholine derivative of the compound of formula II and formula III, the compound that replaces with the dialkoxy of production I.
Graphic 1
Figure G2008800212506D00192
This reaction for example in the toluene, is chosen wantonly in the presence of carbonate bases usually at solvent, carries out to about 200 ℃ temperature at about 0 ℃.Other suitable solvent comprises benzene, chloroform, dioxane, ethyl acetate, 2-propyl alcohol and dimethylbenzene.Perhaps, can use solvent mixture, as toluene/2-propyl alcohol.Preferably under refluxing, in the solvent mixture of toluene and 2-propyl alcohol, heated this reactant about 2 hours to about 24 hours, the optional microwave oven that uses.
Reaction shown in graphic 1 also can be carried out in the catalytic mode of palladium easily.Usually, at solvent easily, in toluene, at biphosphine ligand (as 2,2 '-two (diphenylphosphino)-1,1 '-binaphthylyl " BINAP ") and alkoxide base (as sodium tert-butoxide) have the compound of underfeed furnace II, the compound and palladium (II) source of formula III, as Pd (OAc) 2Or Pd 2(dba) 3Mixture.This reaction mixture was stirred 7 hours down at 100 ℃, then by preparing the HPLC purified product to obtain required product.
The compound of making all shows gratifying water-soluble.But (formula I Q=NH) seems and has than similar morpholine-or obvious better solubility of thiomorpholine derivatives (formula I, Q difference=O or S) bridged piperazine derivatives usually.
The starting material of formula II can be as in the document, and for example Canadian Journal of Chemistry prepares described in 461160 (1968).
The starting material of formula III can be buied or can be as document, Wolters for example, people such as R.J.; J.Pharm.Sci.; 63; 1974; 1379-1382, Busch, people such as N.; Eur.J.Med.Chem.Chim.Ther.; 11; 1976; 201-207, Ruano, people J.Org.Chem. such as J.L.; 57; 15; 1992; 4215-4224, J.Med.Chem.1983,26,254 pages; Ref.Patent; Hokuriku Pharm.; DE 2718451; 1977; Chem.Abstr.; EN; 88; 89714; People Bioorg.Med.Chem.Lett.2002 such as Blythin, preparation described in 12,3161.
The raw-material general synthesis program of moiety formula III
With 0.03 equivalent Pd (OAc) 2 and 0.04 equivalent 1, the two stirred mixture of (diphenylphosphino) ferrocene (dppf) in dimethyl formamide of 1-heated 0.25 hour down at 50 ℃.After cooling, add 1 normal 2-chloro-pyrazine, 1.1 equivalent areneboronic acids and 1.4 equivalent Et3N, and this mixture was stirred 12 hours down at 90 ℃.After cooling, this black mixture is concentrated into dried on vaporizer, and product is placed in 50 milliliters of chloroforms, with 25 milliliters of rare NH4OH solution washings, and be concentrated into dried.Residue is purified on the flash chromatography post to produce the pure products of formula III.
By the present invention disclosed herein of the further illustration of following non-limiting examples.
Embodiment 1
(1.1-[3-4-fluoro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
With 2-(4-fluorophenyl)-piperazine (1.12 grams; 6.2 mmole), 1-chloro-6,7-dimethoxy-isoquinoline 99.9-4-nitrile (1.4 grams; 6.2 mmole) and triethylamine (2.59 milliliters) add in 1: 1 mixture of toluene (8 milliliters) and 2-propyl alcohol (8 milliliters), be equivalent to the ultimate density of about 0.39M.This reaction mixture was heated 15 minutes down at 180 ℃ in microwave oven.Remove under vacuum and desolvate and use ethyl acetate on silica gel: methyl alcohol: the mixture of triethylamine (95: 5: 1) imposes preparative chromatography as eluent to the gained solid.Collection contains the fraction of product, compiles and evaporates in a vacuum to produce product.
Prepare following compounds similarly:
2.6,7-dimethoxy-1-[3-(3-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
3.6,7-dimethoxy-1-[3-(3-methoxyl group-phenyl)-piperazine-1-yl]-3-methyl-isoquinoline 99.9-4-nitrile
4.6,7-dimethoxy-1-(3-naphthalene-1-base-piperazine-1-yl)-isoquinoline 99.9-4-nitrile
5.6,7-dimethoxy-1-[3-(4-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
6.6,7-dimethoxy-1-[3-(2-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
(7.1-[3-4-dimethylamino-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(8.1-3-benzo [1,3] dioxole-5-base (dioxol-5-yl)-piperazine-1-yl)-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
9.6,7-dimethoxy-1-[3-(3-nitro-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
10.6,7-dimethoxy-1-(3-naphthalene-2-base-piperazine-1-yl)-isoquinoline 99.9-4-nitrile
(11.1-[3-3,5-dimethoxy-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(12.1-[3-2,5-dimethoxy-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
13.6,7-dimethoxy-1-[3-(4-trifluoromethyl-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
(14.1-[3-2,5-two chloro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(15.1-[3-2,4-two chloro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
16.6,7-dimethoxy-1-[3-(4-morpholine-4-base-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
(17.1-[3-2,4-two chloro-5-fluoro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
18.6,7-dimethoxy-1-[2-(4-methoxyl group-phenyl)-morpholine-4-yl]-isoquinoline 99.9-4-nitrile
19.6,7-dimethoxy-1-(2-p-methylphenyl-morpholine-4-yl)-isoquinoline 99.9-4-nitrile
(20.1-[2-4-chloro-phenyl)-morpholine-4-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(21.1-[2-2-chloro-phenyl)-morpholine-4-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
22.6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-morpholine-4-yl]-isoquinoline 99.9-4-nitrile
(23.+)-6,7-dimethoxy-1-[3-(3-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
(24.-)-6,7-dimethoxy-1-[3-(3-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
25.6,7-dimethoxy-1-(3-p-methylphenyl-piperazine-1-yl)-isoquinoline 99.9-4-nitrile
(26.1-[3-3-chloro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(27.1-[3-4-bromo-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
28.6,7-dimethoxy-1-[3-(6-methoxyl group-naphthalene-2-yl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
29.6,7-dimethoxy-1-(2-phenyl-thiomorpholine-4-yl)-isoquinoline 99.9-4-nitrile
(30.1-[3-4-chloro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
31.6,7-dimethoxy-3-methyl isophthalic acid-(3-p-methylphenyl-piperazine-1-yl)-isoquinoline 99.9-4-nitrile
32.6,7-dimethoxy-1-[3-(4-methoxyl group-phenyl)-piperazine-1-yl]-3-methyl-isoquinoline 99.9-4-nitrile
33.6,7-dimethoxy-3-methyl isophthalic acid-(3-naphthalene-2-base-piperazine-1-yl)-isoquinoline 99.9-4-nitrile
34.6,7-dimethoxy-3-methyl isophthalic acid-(3-naphthalene-1-base-piperazine-1-yl)-isoquinoline 99.9-4-nitrile
(35.1-[3-3,5-dimethoxy-phenyl)-piperazine-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile
(36.1-[3-2,5-dimethoxy-phenyl)-piperazine-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile
(37.1-[3-4-bromo-phenyl)-piperazine-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile
38.6,7-dimethoxy-1-[3-(6-methoxyl group-naphthalene-2-yl)-piperazine-1-yl]-3-methyl-isoquinoline 99.9-4-nitrile
39.6,7-dimethoxy-1-[2-(4-methoxyl group-phenyl)-morpholine-4-yl]-3-methyl-isoquinoline 99.9-4-nitrile
40.6,7-dimethoxy-3-methyl isophthalic acid-((R)-3-phenyl-Piperazine-1-yl)-isoquinoline 99.9-4-nitrile
(41.1-[3-4-fluoro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile
42.6,7-dimethoxy-1-[3-(2-methoxyl group-phenyl)-piperazine-1-yl]-3-methyl-isoquinoline 99.9-4-nitrile
(43.1-3-benzo [1,3] dioxole-5-base-piperazine-1-yl)-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile
44.6,7-dimethoxy-1-((S)-3-phenyl-Piperazine-1-yl)-isoquinoline 99.9-4-nitrile
45.6,7-dimethoxy-1-(4-methyl-3-p-methylphenyl-piperazine-1-yl)-isoquinoline 99.9-4-nitrile
(46.1-[3-4-ethyl-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(47.1-[3-4-dimethylamino-phenyl)-piperazine-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile
48.6,7-dimethoxy-3-methyl isophthalic acid-[3-(3,4,5-trimethoxy-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
49.6,7-dimethoxy-3-methyl isophthalic acid-((S)-3-phenyl-Piperazine-1-yl)-isoquinoline 99.9-4-nitrile
50.6,7-dimethoxy-3-methyl isophthalic acid-[3-(3-nitro-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
51.6,7-dimethoxy-3-methyl isophthalic acid-[3-(4-morpholine-4-base-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
52.6,7-dimethoxy-1-(
Figure G2008800212506D00231
-3-phenyl-Piperazine-1-yl)-isoquinoline 99.9-4-nitrile
53.6,7-dimethoxy-1-[3-(4-methoxyl group-2-methyl-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
(54.1-[3-3-fluoro-4-methoxyl group-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(55.1-[3-4-oxyethyl group-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(56.1-[3-3-chloro-4-methoxyl group-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(57.1-[3-4-isopropoxy-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(58.1-[3-2,4-dimethoxy-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(59.1-[3-4-oxyethyl group-3-methyl-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
60.6,7-dimethoxy-1-[3-(4-trifluoromethoxy-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
61.6, the 7-dimethoxy-1-[(R)-3-(4-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
62.6, the 7-dimethoxy-1-[(S)-3-(4-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
(63.1-[3-4-isopropoxy-3-methyl-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
64.6,7-dimethoxy-1-[3-(4-methoxyl group-2,6-dimethyl-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
65.6,7-dimethoxy-1-[3-(4-methoxyl group-3,5-dimethyl-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
(66.1-[3-2,3-dihydro-benzo [1,4] dioxin-6-base (dioxin-6-yl))-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(67.1-[3-4-isobutoxy-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
68.6,7-dimethoxy-1-[3-(4-methoxyl group-3-trifluoromethyl-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile
(69.1-[3-4-oxyethyl group-2-methyl-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile
(70.N-{5-[4-4-cyano group-6,7-dimethoxy-isoquinolyl-1)-piperazine-2-yl]-2-methoxyl group-phenyl }-ethanamide
(71.-)-N-{5-[4-(4-cyano group-6,7-dimethoxy-isoquinolyl-1)-piperazine-2-yl]-2-methoxyl group-phenyl }-ethanamide
(72.+)-N-{5-[4-(4-cyano group-6,7-dimethoxy-isoquinolyl-1)-piperazine-2-yl]-2-methoxyl group-phenyl }-ethanamide
Following table has been summarized the analytical data of exemplary compounds
Figure G2008800212506D00241
Figure G2008800212506D00261
The pharmacology test
The PDE10A enzyme
Prepare active PDE10A enzyme in many ways to be used for PDE check (Loughney, people Gene 1999,234 such as K., 109-117; Fujishige, people Eur J Biochem.1999 such as K., 266,1118-1127 and Soderling, people Proc.Natl.Acad.Sci.1999 such as S., 96,7071-7076).PDE10A can be used as full length protein or expresses as truncated protein matter, as long as they express catalytic domain.PDE10A can for example prepare in insect cell or the dust Xi Shi intestinal bacteria at different cell types.The example of method of PDE 10A that obtains catalytic activity is as follows: strengthen the catalytic domain (is the amino acid 440-779 of the sequence of NP 006652 from registration number) of people PDE10A and be cloned into the BamH1 and the Xho1 position of pET28a carrier (Novagen) from the total RNA of total human brain by standard RT-PCR.Carry out expression in intestinal bacteria according to standard schedule.In brief, expression plasmid is converted into BL21 (DE3) dust Xi Shi e. coli strains, and before expressing, makes inoculation have 50 milliliters of cultures of these cells to grow to the OD600 of 0.4-0.6 with 0.5mM IPTG induced protein.After inducing, with these cells at room temperature overnight incubation, after this centrifugal collecting cell.The cell of expressing PDE10A is resuspended in 12 milliliters of (50mM TRIS-HCl-pH8.0,1mM MgCl 2And proteinase inhibitor) in.Make cytolysis by sonication, and after all cells dissolving, add TritonX100 according to the Novagen rules.At Q agarose top purification PDE10A and compile the most active fraction.
PDE10A and Pde3A suppress check
PDE10A checks and can for example followingly carry out with Pde3A: containing the relevant PDE enzyme of fixed amount (being enough to transform the cyclic nucleotide substrate of 20-25%), buffer reagent (50mMHEPES7.6; 10mM MgCl 20.02%Tween20), 0.1 mg/ml BSA, 225pCi 3Carry out PDE10A and Pde3A check in the 60 microlitre samples of the inhibitor of the cyclic nucleotide substrate of H-mark, tritium-labeled cAMP (to the ultimate density of 5nM) and various amounts.By adding cyclic nucleotide substrate, initiation reaction, and reaction was at room temperature carried out 1 hour, stop by mixing then with 15 microlitres, 8 mg/ml yttrium silicate SPA pearls (Amersham).Make these pearls sedimentation in the dark 1 hour, then tally in Wallac 1450 Microbeta counters.Can the signal that record be changed into activity with respect to the contrast (100%) that does not suppress, and can use Xlfit extension to EXCEL to calculate IC 50Value.
Experimental result shows that test-compound of the present invention is to be lower than the IC of 700nM 50Value suppresses the PDE10A enzyme.
Figure G2008800212506D00271
Figure G2008800212506D00281
Figure G2008800212506D00291
Figure G2008800212506D00301
Figure G2008800212506D00311
Figure G2008800212506D00321
Figure G2008800212506D00331
Figure G2008800212506D00351

Claims (23)

1. the compound or pharmaceutically acceptable salt thereof that has structure I
Figure F2008800212506C00011
Wherein
● Q is selected from NH, O or S
● R 1And R 2Be C independently 1-C 4Alkyl
● R 3, R 4, R 5, R 6And R 7Be independently selected from:
Zero H, (C 1-C 6) alkyl, (C 1-C 6) alkoxyl group, halogen, halo (C 1-C 6) alkyl, (C 1-C 6) hydroxyalkyl, (C 1-C 6) alkoxyl group (C 1-C 6) alkyl, (C 1-C 6) hydroxyl cycloalkyl, (C 3-C 8) cycloalkyloxy, (C 1-C 6) alkoxyl group (C 3-C 8) cycloalkyl, Heterocyclylalkyl, hydroxyl Heterocyclylalkyl and (C 1-C 6) alkoxyl group-Heterocyclylalkyl, wherein each (C 3-C 8) cycloalkyl or Heterocyclylalkyl part can be independently by 1 to 3 (C 1-C 6) the alkyl replacement;
Zero-NR 8R 9Group, wherein R 8And R 9Be independently selected from hydrogen, C 1-C 6Alkyl, halo (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl, Heterocyclylalkyl;
The aliphatic heterocycle of zero 6-7-unit:
Figure F2008800212506C00012
Wherein n be 1 or 2 and Z be oxygen or NR 10, R wherein 10Be hydrogen or (C 1-C 6) alkyl, or
Zero ketone, sulfone, ester, acid amides, sulphonate or sulphonamide are selected from
Wherein Y is hydrogen or (C 1-C 6) alkyl and X be selected from:
● (the C that does not replace or replaced by one or more halogens 1-C 6) alkyl,
● do not replace or by one or more halogens replace-O-(C 1-C 6) alkyl,
●-NR 11R 12Group, wherein R 11And R 12Be independently selected from hydrogen, C 1-C 6Alkyl, halo (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl, Heterocyclylalkyl, or
● the aliphatic heterocycle of 6-7-unit:
Wherein n is 1 or 2; And W is oxygen or NR 13, R wherein 13Be hydrogen or (C 1-C 6) alkyl, or
● two adjacent substituting groups that are selected from R3, R4, R5, R6 and R7 can form 5-7 unit, saturated or undersaturated ring with the aromatic ring that links to each other with them, and this ring contains carbon and one or two heteroatoms and optional quilt (C1-C6) alkoxyl group that is selected from N, O or S replaces; Its excess-three substituting group that is selected from R3, R4, R5, R6 and R7 that does not constitute the part of this ring is selected independently as mentioned above.
2. according to each compound of aforementioned claim, wherein R 1And R 2Be C independently 1-C 2Alkyl.
3. according to each compound of aforementioned claim, wherein R 3Be selected from H, (C 1-C 6) alkoxy or halogen.
4. according to each compound of aforementioned claim, wherein R 4Be selected from H, (C 1-C 6) alkoxyl group, halogen or nitro.
5. according to each compound of aforementioned claim, wherein R 5Be selected from
Zero hydrogen, (C 1-C 6) alkyl, (C 1-C 6) alkoxyl group, halogen, halo (C 1-C 6) alkyl, nitro or
Zero-NR 8R 9Group, wherein R 8And R 9Be independently selected from hydrogen, C 1-C 6Alkyl, halo (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl, Heterocyclylalkyl, or
The aliphatic heterocycle of zero 6-7-unit:
Figure F2008800212506C00022
Wherein n be 1 or 2 and Z be oxygen or NR 10, R wherein 10Be hydrogen or (C 1-C 6) alkyl.
6. according to each compound of aforementioned claim, wherein R 6Be selected from H, (C 1-C 6) alkoxyl group, halogen or nitro.
7. according to each compound of aforementioned claim, wherein R 7Be selected from H, (C 1-C 6) alkoxy or halogen.
8. according to each compound of aforementioned claim, wherein be selected from R 3, R 4, R 5, R 6And R 7Two adjacent substituting groups form 5-7 unit, saturated or undersaturated ring with the aromatic ring that links to each other with them, optional contain the heteroatoms that one or two is selected from N, O or S.
9. according to each compound of aforementioned claim, wherein Q=NH.
10. according to each compound of claim 1-8, wherein Q=O.
11. according to each compound of claim 1-8, wherein Q=S.
12. the compound of claim 1, wherein this compound is selected from 1-[3-(4-fluoro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(3-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(3-methoxyl group-phenyl)-piperazine-1-yl]-3-methyl-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-(3-naphthalene-1-base-piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(4-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(2-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 1-[3-(4-dimethylamino-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-(3-benzo [1,3] dioxole-5-base-piperazine-1-yl)-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(3-nitro-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-(3-naphthalene-2-base-piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 1-[3-(3,5-dimethoxy-phenyl)-and piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[3-(2,5-dimethoxy-phenyl)-and piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(4-trifluoromethyl-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 1-[3-(2,5-two chloro-phenyl)-and piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[3-(2,4-two chloro-phenyl)-and piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(4-morpholine-4-base-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 1-[3-(2,4-two chloro-5-fluoro-phenyl)-and piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[2-(4-methoxyl group-phenyl)-morpholine-4-yl]-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-(2-p-methylphenyl-morpholine-4-yl)-isoquinoline 99.9-4-nitrile, 1-[2-(4-chloro-phenyl)-morpholine-4-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[2-(2-chloro-phenyl)-morpholine-4-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-morpholine-4-yl]-isoquinoline 99.9-4-nitrile, (+)-6,7-dimethoxy-1-[3-(3-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, (-)-6,7-dimethoxy-1-[3-(3-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-(3-p-methylphenyl-piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 1-[3-(3-chloro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[3-(4-bromo-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(6-methoxyl group-naphthalene-2-yl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-(2-phenyl-thiomorpholine-4-yl)-isoquinoline 99.9-4-nitrile, 1-[3-(4-chloro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-3-methyl isophthalic acid-(3-p-methylphenyl-piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(4-methoxyl group-phenyl)-piperazine-1-yl]-3-methyl-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-3-methyl isophthalic acid-(3-naphthalene-2-base-piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-3-methyl isophthalic acid-(3-naphthalene-1-base-piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 1-[3-(3,5-dimethoxy-phenyl)-piperazine-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile, 1-[3-(2,5-dimethoxy-phenyl)-and piperazine-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile, 1-[3-(4-bromo-phenyl)-piperazine-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(6-methoxyl group-naphthalene-2-yl)-piperazine-1-yl]-3-methyl-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[2-(4-methoxyl group-phenyl)-morpholine-4-yl]-3-methyl-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-3-methyl isophthalic acid-((R)-3-phenyl-Piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 1-[3-(4-fluoro-phenyl)-piperazine-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(2-methoxyl group-phenyl)-piperazine-1-yl]-3-methyl-isoquinoline 99.9-4-nitrile, 1-(3-benzo [1,3] dioxole-5-base-piperazine-1-yl)-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-((S)-3-phenyl-Piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-(4-methyl-3-p-methylphenyl-piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 1-[3-(4-ethyl-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[3-(4-dimethylamino-phenyl)-piperazine-1-yl]-6,7-dimethoxy-3-methyl-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-3-methyl isophthalic acid-[3-(3,4,5-trimethoxy-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-3-methyl isophthalic acid-((S)-3-phenyl-Piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-3-methyl isophthalic acid-[3-(3-nitro-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-3-methyl isophthalic acid-[3-(4-morpholine-4-base-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-(
Figure F2008800212506C00041
-3-phenyl-Piperazine-1-yl)-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(4-methoxyl group-2-methyl-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 1-[3-(3-fluoro-4-methoxyl group-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[3-(4-oxyethyl group-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[3-(3-chloro-4-methoxyl group-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[3-(4-isopropoxy-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[3-(2,4-dimethoxy-phenyl)-and piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[3-(4-oxyethyl group-3-methyl-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(4-trifluoromethoxy-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6, the 7-dimethoxy-1-[(R)-3-(4-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6, the 7-dimethoxy-1-[(S)-3-(4-methoxyl group-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 1-[3-(4-isopropoxy-3-methyl-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(4-methoxyl group-2,6-dimethyl-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(4-methoxyl group-3,5-dimethyl-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 1-[3-(2,3-dihydro-benzo [1,4] dioxin-6-yl)-and piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 1-[3-(4-isobutoxy-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, 6,7-dimethoxy-1-[3-(4-methoxyl group-3-trifluoromethyl-phenyl)-piperazine-1-yl]-isoquinoline 99.9-4-nitrile, 1-[3-(4-oxyethyl group-2-methyl-phenyl)-piperazine-1-yl]-6,7-dimethoxy-isoquinoline 99.9-4-nitrile, N-{5-[4-(4-cyano group-6,7-dimethoxy-isoquinolyl-1)-piperazine-2-yl]-2-methoxyl group-phenyl }-ethanamide, (-)-N-{5-[4-(4-cyano group-6,7-dimethoxy-isoquinolyl-1)-piperazine-2-yl]-2-methoxyl group-phenyl }-ethanamide, (+)-N-{5-[4-(4-cyano group-6,7-dimethoxy-isoquinolyl-1)-piperazine-2-yl]-2-methoxyl group-phenyl }-ethanamide; Or its pharmacologically acceptable salt.
13. be used for the method for the compound of preparation formula I, comprise the compound that makes formula II:
Figure F2008800212506C00051
Wherein L is selected from Cl, Br, I, OSO 2CF 3Leaving group, and R 1And R 2As defined in claim 1;
Under the solvent-free situation or in inert solvent or solvent mixture, 0 to about 200 ℃ temperature, choose wantonly in the presence of alkali, choose in the presence of palladium catalyst compound reaction wantonly with the formula III of free alkali or its additive salt form:
Figure F2008800212506C00061
Wherein Q, R 3, R 4, R 5, R 6And R 7As defined in claim 1; Aftertreatment and go out the product of formula I with its free alkali or its acid salt isolated in form then.
14. the method for claim 13 is wherein passed through with palladium (II) source, as Pd (OAc) in reaction solvent 2Or Pd 2(dba) 3With biphosphine ligand, as BINAP (2,2 '-two (diphenylphosphino)-1,1 '-binaphthylyl) mix and original position forms palladium catalyst.
15. comprise the compound of the claim 1 for the treatment of significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier or thinner.
16. claim 1 to 12 each compound or the purposes of its pharmaceutically useful acid salt medicine of being used to prepare neurological sexual dysfunction or mental disorder, wherein this neurological sexual dysfunction is selected from Alzheimer's disease, multiple cerebral infarction dementia, alcoholic dementia or other medicines dependency dementia, the dementia relevant with intracranial tumors or cerebral trauma, dementia or the AIDS-relevant with Huntington chorea or parkinsonism is relevant dull-witted; Delirium; Amnesia; Posttraumatic stress disorder; Mental retardation; Learning disorder, for example Dyslexia, mathematics disorder or write the expression obstacle; Attention-deficient/hyperkinetic syndrome; And the cognitive decline relevant with the age, and described mental disorder is selected from schizophrenia, for example intolerance style, disintegrate the schizophrenia of type, catatonic type, undifferentiated type or residual type; Class schizophrenia; Schizoaffective disorder, for example delusional type or depressive type; Paranoea; The mental disorder that material brings out, for example psychosis of bringing out by alcohol, amphetamine, hemp, Cocaine, halluoinogen, inhalation, opioid or phencyclidine; The paranoid personality disorder; With the schizoid personality obstacle.
17. each compound or its pharmaceutically useful acid salt of claim 1 to 12, be used for the treatment of neurological sexual dysfunction or mental disorder, wherein this neurological sexual dysfunction is selected from Alzheimer's disease, multiple cerebral infarction dementia, alcoholic dementia or other medicines dependency dementia, the dementia relevant with intracranial tumors or cerebral trauma, the dementia of being correlated with Huntington chorea or parkinsonism or the relevant dementia of AIDS-; Delirium; Amnesia; Posttraumatic stress disorder; Mental retardation; Learning disorder, for example Dyslexia, mathematics disorder or write the expression obstacle; Attention-deficient/hyperkinetic syndrome; And the cognitive decline relevant with the age, and described mental disorder is selected from schizophrenia, for example intolerance style, disintegrate the schizophrenia of type, catatonic type, undifferentiated type or residual type; Class schizophrenia; Schizoaffective disorder, for example delusional type or depressive type; Paranoea; The mental disorder that material brings out, for example psychosis of bringing out by alcohol, amphetamine, hemp, Cocaine, halluoinogen, inhalation, opioid or phencyclidine; The paranoid personality disorder; With the schizoid personality obstacle.
18. each compound of claim 1 to 12 is used for the treatment of Mammals, comprises human drug habit, as alcohol, amphetamine, Cocaine or opiate habituation.
19. each compound of claim 1 to 12 is used to prepare Mammals, comprises human drug habit, as the purposes of the medicine of alcohol, amphetamine, Cocaine or opiate habituation.
20. each compound or its pharmaceutically useful acid salt of claim 1-12 is as medicine.
21. treatment suffers from the patient's of neurological sexual dysfunction or mental disorder method, comprise the compound to the claim 1-12 of this patient's administering therapeutic significant quantity, wherein this neurological sexual dysfunction is selected from Alzheimer's disease, multiple cerebral infarction dementia, alcoholic dementia or other medicines dependency dementia, the dementia relevant with intracranial tumors or cerebral trauma, the dementia of being correlated with Huntington chorea or parkinsonism or the relevant dementia of AIDS-; Delirium; Amnesia; Posttraumatic stress disorder; Mental retardation; Learning disorder, for example Dyslexia, mathematics disorder or write the expression obstacle; Attention-deficient/hyperkinetic syndrome; And the cognitive decline relevant with the age, and described mental disorder is selected from schizophrenia, for example intolerance style, disintegrate type, catatonic type, undifferentiated type or residual schizophrenia; Class schizophrenia; Schizoaffective disorder, for example delusional type or depressive type; Paranoea; The mental disorder that material brings out, for example psychosis of bringing out by alcohol, amphetamine, hemp, Cocaine, halluoinogen, inhalation, opioid or phencyclidine; The paranoid personality disorder; With the schizoid personality obstacle.
22. treatment suffers from drug habit in comprising human Mammals, the method for the object of alcohol, amphetamine, Cocaine or opiate habituation for example, this method comprise the compound of formula I of described object being used the amount of effective medicine habituation.
23. treatment suffers from drug habit in comprising human Mammals, the method for the object of alcohol, amphetamine, Cocaine or opiate habituation for example, this method comprise the compound of formula I of described object being used the amount of effective inhibition PDE10A.
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