CN1777582A - Substituted indoline and indole derivatives - Google Patents

Substituted indoline and indole derivatives Download PDF

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CN1777582A
CN1777582A CNA2004800110190A CN200480011019A CN1777582A CN 1777582 A CN1777582 A CN 1777582A CN A2004800110190 A CNA2004800110190 A CN A2004800110190A CN 200480011019 A CN200480011019 A CN 200480011019A CN 1777582 A CN1777582 A CN 1777582A
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alkene
base
alkane
alkynes
cycloalkanes
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N·汉津
M·罗特莱恩德
W·P·沃特森
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H Lundbeck AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms

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  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to aniline derivatives of the general formula I or pharmaceutically acceptable salts thereof, [Formula (I)], and their use.

Description

The indoline and the indole derivatives that replace
The present invention relates to indoles and indolin derivatives as the new substituted of KCNQ family potassium-channel opener.These compounds are used for the obstacle open relevant with KCNQ family potassium-channel and prevention, treatment and the inhibition of disease, and epilepsy is a kind of this class disease.
Background of invention
Ionic channel comprises that for regulating ion flow potassium, calcium, chlorine and sodium flow to and flow out the cell protein of cell.This passage is present in all animal and human's class cells, and influences various processes, comprises nerve conduction, Muscle contraction and emiocytosis.
The mankind have more than 70 kind of coding potassium channel hypotype (Jentsch NatureReviews Neuroscience 2000,1, gene 21-30) that 26S Proteasome Structure and Function is different.Mainly the acting as of finding at brain of neurone potassium channel keeps the resting membrane electric potential of bearing and passes through action potential controlling diaphragm repolarization.
A hypotype of potassium channel gene is a KCNQ family.Found that 4/5ths KCNQ transgenation causes disease, comprise arrhythmia, deafness and epilepsy (Jentsch NatureReviews Neuroscience 2000,1,21-30).
Think the relevant molecule of potassium channel in the I type hair cell of the external hair cell of KCNQ4 genes encoding and cochlea and vestibular, its sudden change causes hereditary hearing impairment.
The product of KCNE1 (minimum K (+)-channel protein) gene in KCNQ1 (KvLQT1) and the heart forms heart delayed rectification K (+) electric current jointly.Sudden change in this passage can cause the long QT syndromes of a kind of heredity I type (LQT1), and relevant with a kind of deafness (RobbinsPharmacol Ther 2001,90,1-19).
Gene KCNQ2 and KCNQ3 are found in 1988, and think and in a kind of heredity epilepsy that is known as the benign familial neonatal convulsion, morph (Rogawski Trends inNeurosciences 2000,23,393-398).Concentrate on by the albumen of KCNQ2 and KCNQ3 genes encoding in the cone neurone of the cortex in people's brain zone and hippocampus, this zone and epileptic seizures and propagate relevant (people such as Cooper, Proceedings National Academy ofScience USA 2000,97,4914-4919).
When in vitro expressing, KCNQ2 and KCNQ3 are the potassium channel hypotype of two kinds of formation " M-electric current ".The M-electric current is the nonactive potassium current that is present in multiple neuronal cell type.In various cell types, by as the irritability of unique sustained current major control film in action potential initiation scope (Marrion Annual Review Physiology1997,59,483-504).The adjusting of M-electric current has very big influence for neuronic irritability, and for example the activation of electric current will reduce neuronic irritability.The promoting agent of the opener of these KCNQ passages or M-electric current will reduce the over-drastic neuronal activity, therefore can be used for treating, preventing or suppress with the over-drastic neuronal activity is epileptic seizures and the other diseases and the obstacle of feature, comprises convulsions, epilepsy and neuropathy sex change pain as the neurone hyperexcitability.
EP 554543 discloses retigabine (D-23129; N-(2-amino-4-(4-luorobenzyl amino)-phenyl) urethanum) and analogue.The anticonvulsion compound that is wide spectrum and has effective anticonvulsion characteristic with external retigabine in vivo.After rat and mouse oral administration and intraperitoneal administration, it is a series of anticonvulsion tests and hereditary animal model (DBA/2 mouse, people such as Rostock, Epilepsy Research 1996,23, be that effectively these anticonvulsion tests comprise: electric inductive epilepsy in 211-223); The epilepsy of pentetrazole, Picrotoxin and N-methyl-D-aspartate salt (NMDA) chemical induction.In addition, effectively, this shows that also this compound can be used for anticonvulsion treatment to retigabine in amygdala epilepsy (amygdala kindling) model of the incomplete epilepsy of complexity.In clinical trial, shown recently retigabine can effectively reduce the chance of epileptic patient outbreak (people such as Bialer, Epilepsy Research2002,51,31-71).
Shown K (+) electric current in the retigabine activation neuronal cell, this faradic pharmacology shows consistent with the pharmacology of disclosed M-passage, and it is relevant with KCNQ2/3K (+) passage heteromultimers (heteromultimer) that the M-passage is found recently.This shows that the activation of KCNQ2/3 passage may cause some anti-convulsant activity (people such as Wickenden of this reagent, Molecular Pharmacology 2000,58,591-600), and other reagent by identical mechanism effect may have identical purposes.
Reported that KCNQ2 and 3 passages are used for regulating (upregulate) neurodynia model (people such as Wickenden, Society for Neuroscience Abstracts 2002,454.7), and suppose that potassium channel modulating agents all has activity (people such as Schroder for neurodynia and epilepsy, Neuropharmacology 2001,40,888-898).
Shown that also retigabine is for neuralgic animal model effective (Blackburn-Munro and Jensen European Journal of Pharmacology 2003,460,109-116), the opener of therefore advising the KCNQ passage is used for the treatment of and comprises neuralgic pain disease.
It is reported that KCNQ passage mRNA concentrates on brain and other central nervous systems relevant with pain (Goldstein etc., Society for Neuroscience Abstracts 2003,53.8).
Except the effect in neuralgia, expression at the mRNA of trigeminal nerve and dorsal root ganglion and the KCNQ2-5 in tail side nuclei quintus shows that the opener of these passages also can influence migrainous sense process (people such as Goldstein, Society for NeuroscienceAbstracts 2003,53.8).
Recently report proof KCNQ3 and 5 and the mRNA of KCNQ2 be expressed in spider cell and the neurogliocyte.Therefore KCNQ2,3 and 5 passages can help regulate the synaptic activity in the central nervous system, and help neutral provide protection people such as (, Society for Neuroscience Abstracts 2003,53.9) Noda of KCNQ channel opener.
Therefore retigabine and other KCNQ conditioning agents can be protected the neurodegeneration of avoiding epilepsy; because shown the marker expression (people such as Ebert of apoptosis after the epilepsy that retigabine prevents that kainic acid brings out in edge neurodegeneration and the rat body; Epilepsia 2002; 43 augment 5,86-95).This can prevent patient's induced seizures, i.e. anti-epileptic.In another model of epilepsy research, shown retigabine postpone the intravital hippocampus induced seizures of rat (people such as Tober, European Journal of Pharmacology 1996,303,163-169).
Therefore these character that show retigabine and other KCNQ conditioning agents can prevent to activate the nerve injury of bringing out by excessive nerve, and can be used for treating the disease of DPN, and are disease mitigation (modifying) (or anti-epileptic) agent of epileptic.
Be used for clinical treatment at known anticonvulsion compound (for example benzodiazepine and 5-chloromethyl thiazole (chlorme-thiazole)) and give up ethanol syndromes and other anticonvulsion compounds (for example gabapentin) (people such as Watson, Neuropharmacology 1997,36,1369-1375) in the animal model of this syndromes under the very effective condition, we expect that other anticonvulsion compounds (as the KCNQ opener) also can be used for this disease effectively.
The mRNA of KCNQ2 and 3 hypotypes is found in and anxiety and mood behavior (bipolarity disease for example, as hippocampus and amygdala) relevant brain area (people such as Saganich, Journal ofNeuroscience 2001,21,4609-4624), it is reported that retigabine has activity (people such as Hartz in some animal model of anxiety class behavior, Journal of Psychopharmacology 2003,17 augment 3, A28, B16), and the anticonvulsion compound of other clinical uses be used for the treatment of the bipolarity disease.
WO 200196540 discloses the purposes of the modulators for treatment insomnia of the M-electric current that KCNQ2 and KCNQ3 genetic expression forms, and WO 2001092526 discloses the conditioning agent of KCNQ5 and can be used for treating somnopathy.
WO01/022953 has described retigabine and has been used for prevention and treatment neurodynia, as allodynia, hyperpathia pain, phantom pain, the neurodynia relevant with diabetic neuropathy and the neurodynia of being correlated with migraine.
WO02/049628 has described the purposes that retigabine is used to prevent, treat, suppress and alleviate anxiety disorders, for example stress disease after anxiety, generalized anxiety disorder, panic anxiety disorder, obsessional idea and behavior disease, social phobia, behavior anxiety, the wound, gross stress reaction, adjustment disorder, hypochondriasis, separation anxiety disorder, agoraphobia and specific phobia disease.
WO97/15300 has described the purposes that retigabine is used for the treatment of neurodegenerative disease, for example Alzheimer, Huntington Chorea, sclerosis such as multiple sclerosis and amyotrophic lateral sclerosis; Encephalopathic that Creutzfeldt-Jakob disease, Parkinson's disease, AIDS-bring out and the encephalopathic that causes by rubella virus, simplexvirus, Borrelia and unknown pathogenic infection, neurodegeneration that wound causes and in medicine withdrawal or because the degenerative disease (as polyneuropathy and polyneuritis (polyneuritides)) of the drunk neuronal excitation transient state that causes, peripheral nervous system.
Therefore, the novel cpd as the effective opener of KCNQ family potassium channel there is very big demand.
Also need to compare, have the novel cpd of improved performance with known compound (for example retigabine) as KCNQ family potassium channel openers.Need to improve one or more following parameters: transformation period, clearance rate, selectivity, with interaction, bioavailability, usefulness, adjustable property, chemical stability, metabolic stability, membrane permeability, solubleness and the therapeutic index of other drug.The improvement of these parameters causes following improvement:
● improve dosage regimen by reducing every day required administration number of times,
● be convenient to administration by multiple dose regimen to patient,
● reduce side effect,
● increase therapeutic index,
● improve tolerance, or
● improve conformability (compliance).
Summary of the invention
One object of the present invention is for providing novel cpd, and described compound is the effective opener of KCNQ family potassium-channel.
Compound of the present invention is indoline and indole derivatives or its salt of the replacement of general formula I:
Figure A20048001101900251
Wherein dotted line, q, s, U, Y, X, Z, R 1, R 1 ', R 2And R 3As give a definition.The invention still further relates to the medical composition and its use that comprises formula I compound.
Invention is described
Therefore, the present invention relates to indoles and indolin derivatives or its salt of the replacement of general formula I,
Figure A20048001101900261
Wherein
Dotted line is represented the key chosen wantonly;
R 1And R 1 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Or
R 1And R 1 'Connected carbon atom forms 3 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1 or 2 heteroatoms;
S is 0 or 1;
U is O, NR 11, S, SO 2, SO 2NR 11, CO-O or CO-NR 11R wherein 11Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Or R 2And R 11Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
R 2Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-NO 2, NR 10R 10 '-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 3-8-cycloalkanes (alkene) base and NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
Wherein
R 10And R 10 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 10And R 10 'Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
Condition is to work as R 2Be NO 2, when halogen or cyano group, s is 0; With
Condition is to work as R 2For hydrogen atom or acyl group and s are 1 o'clock, U is NR 11, O or S;
Group-(U) wherein s-R 2Be connected indoles or indoline 4 or 6;
Q is 0 or 1;
Z is O or S;
X is CO or SO 2Condition be when X be SO 2The time, q is 0;
R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-heterocycle alkane (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 3-8-cycloalkanes (alkene) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes)-heterocycle alkane (alkene) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-carbonyl of-cycloalkanes (alkene)-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-heterocycle alkane (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-aryl, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-cycloalkanes (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base and-NR 12R 12 ', the optional NR that replaces 12R 12 '-C 1-6-alkane (alkene/alkynes) base, the optional NR that replaces 12R 12 '-C 3-8-cycloalkanes (alkene) base, the optional NR that replaces 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 12And R 12 'Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
Condition is to work as R 3Be NR 12R 12 'The time, q is 0;
With
The group of Y expression II, III, IV, V, VI, XXX and XXXI:
Figure A20048001101900291
Or
Figure A20048001101900292
Wherein
Straight line is represented key that the group shown in the Y is connected with carbon atom;
W is O or S;
T is N, NH or O;
L is N, C or CH;
A is 0,1,2 or 3;
B is 0,1,2,3 or 4;
C is 0 or 1;
D is 0,1,2 or 3;
E is 0,1 or 2;
F is 0,1,2,3,4 or 5;
G is 0,1,2,3 or 4;
H is 0,1,2 or 3;
J is 0,1,2 or 3; Condition is when T is nitrogen-atoms, and j is 0,1,2 or 3; With when T is NH or Sauerstoffatom, j is 0,1 or 2;
K is 0,1,2,3 or 4; And
R 5Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-sulfenyl, aryl-oxygen base, acyl group, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8The basic oxygen base of-cycloalkanes (alkene), C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes), halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-CO-NR 6R 6 ', cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-NR 7R 7 ',-S-R 8With-SO 2R 8, or two adjacent R 5Connected aryl forms optional one or two heteroatomic 4 to 8 yuan of rings that comprise together;
R 6And R 6 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and aryl;
R 7And R 7 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl and acyl group;
With
R 8Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl and-NR 9R 9 'R wherein 9And R 9 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Condition is to work as R 8For-NR 9R 9 'The time, R 5Be not-S-R 8
A special embodiment of the present invention relates to indoles and the indolin derivatives and the salt thereof of the replacement of general formula I,
Figure A20048001101900311
Wherein
Dotted line is represented the key chosen wantonly;
R 1And R 1 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Or
R 1And R 1 'Form 3 to 8 yuan of saturated or unsaturated rings, described ring is chosen wantonly and is comprised 1 or 2 other heteroatoms;
S is 0 or 1;
U is O, NR 11, S, SO 2, SO 2NR 11, CO-O or CO-NR 11R wherein 11Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Or
R 2And R 11Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
R 2Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-NO 2, NR 10R 10 '-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 3-8-cycloalkanes (alkene) base and NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
Wherein
R 10And R 10 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 10And R 10 'Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
Condition is to work as R 2Be NO 2, when halogen or cyano group, s is 0; With
Condition is to work as R 2For hydrogen atom or acyl group and s are 1 o'clock, U is NR 11, O or S;
Group-(U) wherein s-R 2Be connected indoles or indoline 4 or 6;
Q is 0 or 1;
Z is O or S;
X is CO or SO 2Condition be when X be SO 2The time, q is 0;
R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-heterocycle alkane (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 3-8-cycloalkanes (alkene) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes)-heterocycle alkane (alkene) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-carbonyl of-cycloalkanes (alkene)-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halogenated heterocyclic alkane (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-aryl, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-cycloalkanes (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base and-NR 12R 12 'Wherein
R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 12And R 12 'Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
Condition is to work as R 3Be NR 12R 12 'The time, q is 0;
With
The group of Y expression II, III, IV, V and VI:
Or
Figure A20048001101900342
Wherein
Straight line is represented key that group shown in the Y is connected with carbon atom;
W is O or S;
A is 0,1,2 or 3;
B is 0,1,2,3 or 4;
C is 0 or 1;
D is 0,1,2 or 3;
E is 0,1 or 2;
F is 0,1,2,3,4 or 5;
G is 0,1,2,3 or 4;
H is 0,1,2 or 3; With
R 5Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, acyl group, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8The basic oxygen base of-cycloalkanes (alkene), C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes), halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-CO-NR 6R 6 ', cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-NR 7R 7 ',-S-R 8With-SO 2R 8, or
Two adjacent R 5Connected aryl forms optional one or two heteroatomic 4 to 8 yuan of rings that comprise together;
R 6And R 6 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and aryl;
R 7And R 7 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl and acyl group;
With
R 8Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl and-NR 9R 9 'Wherein
R 9And R 9 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
Condition is to work as R 8For-NR 9R 9 'The time, R 5Be not-S-R 8
One embodiment of the invention relate to formula I compound, and wherein dotted line is represented key.
Another embodiment of the invention relates to formula I compound, and wherein dotted line is not represented key.
Another embodiment of the present invention relates to formula I compound, wherein R 1And R 1 'Be independently selected from hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
Another embodiment of the invention relates to formula I compound, wherein R 1And R 1 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
Another embodiment of the present invention relates to formula I compound, wherein R 1And R 1 'Form 3 to 8 yuan of saturated or unsaturated rings, described ring is chosen wantonly and is comprised 1 or 2 heteroatoms.At 3 to 8 yuan of saturated or unsaturated rings described in another embodiment is saturated carbon ring, is generally cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Another embodiment of the present invention relates to formula I compound, wherein R 1And R 1 'Be independently selected from hydrogen atom and C 1-6-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein R 1And R 1 'In at least one is C 1-6-alkane (alkene/alkynes) base is generally C 1-3-alkane (alkene/alkynes) base.
In a preferred embodiment, the present invention relates to formula I compound, wherein R 1Or R 1 'Be hydrogen atom.
In a preferred embodiment, the present invention relates to formula I compound, wherein R 1And R 1 'In at least one is a hydrogen atom.
In a more preferred, the present invention relates to formula I compound, wherein R 1And R 1 'It all is hydrogen atom.
In a preferred embodiment, the present invention relates to formula I compound, wherein s is 0.
In a further preferred embodiment, the present invention relates to formula I compound, wherein s is 1.
In one embodiment, the present invention relates to formula I compound, wherein s be 1 and U be O.
In another embodiment, the present invention relates to formula I compound, wherein s be 1 and U be S.
In a further embodiment, the present invention relates to formula I compound, wherein s be 1 and U be SO 2
In a further embodiment, the present invention relates to formula I compound, wherein s be 1 and U be SO 2NR 11
In a further embodiment, the present invention relates to formula I compound, wherein s be 1 and U be CO-O.
In a further embodiment, the present invention relates to formula I compound, wherein s be 1 and U be CO-NR 11
In a preferred embodiment, the present invention relates to formula I compound, wherein s be 1 and U be NR 11
In a further embodiment, the present invention relates to formula I compound, wherein s is 1, and U is SO 2NR 11, CO-NR 11Or NR 11And R 11Be hydrogen atom.
In a preferred embodiment, the present invention relates to formula I compound, wherein s is 1, and U is NR 11And R 11Be hydrogen atom.
One embodiment of the invention relate to formula I compound, wherein R 2Be selected from acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 3-8-cycloalkanes (alkene) base and NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
Condition is to work as R 2For acyl group and s are 1 o'clock, U is NR 11, O or S.
Another embodiment of the invention relates to formula I compound, wherein R 2Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
Another embodiment of the present invention relates to formula I compound, wherein R 2Be selected from aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base and aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
Another embodiment of the present invention relates to formula I compound, wherein R 2Be selected from halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and cyano group;
Condition is to work as R 2During for halogen or cyano group, s is 0.
In a preferred embodiment, the present invention relates to formula I compound, wherein R 2Be NO 2Or hydrogen atom;
Condition is to work as R 2Be NO 2The time, s is 0; With
Condition is to work as R 2For hydrogen atom and s are 1 o'clock, U is NR 11, O or S.
In one embodiment, the present invention relates to formula I compound, wherein R 2Be NO 2, hydrogen atom or halogen atom;
Condition is to work as R 2Be NO 2Or during halogen atom, s is 0; With
Condition is to work as R 2For hydrogen atom and s are 1 o'clock, U is NR 11, O or S.
In another embodiment, the present invention relates to formula I compound, wherein s is 0 and R 2Be NO 2Or halogen atom.
In one embodiment, the present invention relates to formula I compound, wherein R 2Be hydrogen atom.
In one embodiment, the present invention relates to formula I compound, wherein s is 0 and R 2Be selected from NO 2, halogen and cyano group.
In another embodiment, the present invention relates to formula I compound, wherein s is 0 and R 2Be hydrogen atom.
In a further embodiment, the present invention relates to formula I compound, wherein R 2Be C 1-6-alkane (alkene/alkynes) base is generally C 1-3-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein R 2Be C 3-8-cycloalkanes (alkene) base is generally C 3-6-cycloalkanes (alkene) base.
In a further embodiment, the present invention relates to formula I compound, wherein R 2Be aryl.
In a further embodiment, the present invention relates to formula I compound, wherein R 2Be aryl-C 1-6-alkane (alkene/alkynes) base is generally aryl-C 1-3-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein R 2Be halo-C 1-6-alkane (alkene/alkynes) base is generally halo-C 1-3-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein s is 0 and R 2Be halogen atom.
In a further embodiment, the present invention relates to formula I compound, wherein s is 0 and R 2Be cyano group.
In a further preferred embodiment, the present invention relates to formula I compound, wherein s is 0 and R 2Be NO 2
In a preferred embodiment, the present invention relates to formula I compound, wherein R 2Be hydrogen atom; Condition is when s is 1, and U is NR 11, O or S.
In one embodiment, the present invention relates to formula I compound, wherein R 2Be hydrogen atom; Condition is when s is 1, and U is NR 11
In another embodiment, the present invention relates to formula I compound, wherein R 2Be hydrogen atom, s is 1, and U is NR 11And R 11Be hydrogen atom.
In one embodiment, the present invention relates to formula I compound, wherein group-(U) sR 2Be connected indoles or indoline 6.
In a preferred embodiment, the present invention relates to formula I compound, wherein group-(U) sR 2Be connected indoles or indoline 4.
In a preferred embodiment, the present invention relates to formula I compound, wherein X is CO.
In a preferred embodiment, the present invention relates to formula I compound, wherein X is SO 2
In a preferred embodiment, the present invention relates to formula I compound, wherein q is 0.
In a preferred embodiment, the present invention relates to formula I compound, wherein q is 1.
In one embodiment, the present invention relates to formula I compound, wherein q be 1 and Z be sulphur atom.
In a preferred embodiment, the present invention relates to formula I compound, wherein q be 1 and Z be Sauerstoffatom.
In one embodiment, the present invention relates to formula I compound, wherein X is SO 2And q is 0.
In one embodiment, the present invention relates to formula I compound, wherein X is that CO and q are 0.
In one embodiment, the present invention relates to formula I compound, wherein X is CO, q be 1 and Z be Sauerstoffatom.
In one embodiment, the present invention relates to formula I compound, wherein R 3Be selected from C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, aryl-heterocycle alkane (alkene) base, aryl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes)-heterocycle alkane (alkene) base, C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-carbonyl of-cycloalkanes (alkene)-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-cycloalkanes (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base and acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base.
In another embodiment, the present invention relates to formula I compound, wherein R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 3-8-cycloalkanes (alkene) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-C 1-6Alkane (alkene/alkynes) base-aryl, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-aryl and-NR 12R 12 'Condition is to work as R 3Be NR 12R 12 'The time, q is 0.
In a further embodiment, the present invention relates to formula I compound, wherein R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6Alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base and-NR 12R 12 'Condition is to work as R 3Be NR 12R 12 'The time, q is 0.
In a further embodiment, the present invention relates to formula I compound, wherein R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base and-NR 12R 12 'Condition is to work as R 3Be NR 12R 12 'The time, q is 0.
In a preferred embodiment, the present invention relates to formula I compound, wherein R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base and-NR 12R 12 'Condition is to work as R 3Be NR 12 'R 12 'The time, q is 0.
In a further preferred embodiment, the present invention relates to formula I compound, wherein R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base and-NR 12R 12 'Condition is to work as R 3Be NR 12R 12 'The time, q is 0.
In a further preferred embodiment, the present invention relates to formula I compound, wherein R 3Be C 1-6-alkane (alkene/alkynes) base is generally C 1-3-alkane (alkene/alkynes) base.
In another preferred embodiment, the present invention relates to formula I compound, wherein R 3Be C 3-8-cycloalkanes (alkene) base.
In another preferred embodiment, the present invention relates to formula I compound, wherein R 3Be C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
In another preferred embodiment, the present invention relates to formula I compound, wherein R 3Be heterocycle alkane (alkene) base.
In another preferred embodiment, the present invention relates to formula I compound, wherein R 3Be aryl.
In another preferred embodiment, the present invention relates to formula I compound, wherein R 3Be aryl-C 1-6-alkane (alkene/alkynes) base.
In another preferred embodiment, the present invention relates to formula I compound, wherein R 3Be C 1-6-alkane (alkene/alkynes) base-oxygen base-C 1-6-alkane (alkene/alkynes) base.
In another preferred embodiment, the present invention relates to formula I compound, wherein R 3Be aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base.
In another preferred embodiment, the present invention relates to formula I compound, wherein R 3Be aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein R 3Be C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein R 3Be halo-C 1-6-alkane (alkene/alkynes) base is as halo-C 1-3-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein R 3Be halo-C 1-6-alkane (alkene/alkynes) base-aryl is as halo-C 1-3-alkane (alkene/alkynes) base-aryl.
In another preferred embodiment, the present invention relates to formula I compound, wherein R 3For-NR 12R 12 'And q is 0.
In one embodiment, the present invention relates to formula I compound, wherein X is CO, and q is 1, and Z is a Sauerstoffatom, R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to formula I compound, wherein X is CO, and q is 1, and Z is a Sauerstoffatom, R 3Be selected from C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base and halo-C 1-6-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to formula I compound, wherein X is CO, and q is 0, R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base and-NR 12R 12 '
In a further embodiment, the present invention relates to formula I compound, wherein X is CO, and q is 0, R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base and-NR 12R 12 '
In a further embodiment, the present invention relates to formula I compound, wherein X is SO 2, q is 0, R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base.
In a further embodiment, the present invention relates to formula I compound, wherein X is SO 2, q is 0, R 3Be C 1-6-alkane (alkene/alkynes) base or aryl-C 1-6-alkane (alkene/alkynes) base.
In one embodiment, the present invention relates to formula I compound, wherein R 3Be NR 12R 12 'And q is 0, wherein R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base and aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to formula I compound, wherein R 3Be NR 12R 12 'And q is 0, wherein R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, aryl and aryl-C 1-6-alkane (alkene/alkynes) base or R wherein 12And R 12 'Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms.
In a preferred embodiment, the present invention relates to formula I compound, wherein R 3Be NR 12R 12 'And q is 0, wherein R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, aryl and aryl-C 1-6-alkane (alkene/alkynes) base.
In a further preferred embodiment, the present invention relates to formula I compound, wherein R 3Be NR 12R 12 'And q is 0, wherein R 12And R 12Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms.
In one embodiment, the present invention relates to formula I compound, wherein R 3Be NR 12R 12 'And q is 0, wherein R 12And R 12 'In at least one is a hydrogen atom.
In another embodiment, the present invention relates to formula I compound, wherein R 3Be NR 12R 12 'And q is 0, wherein R 12And R 12 'In at least one is C 1-6-alkane (alkene/alkynes) base is generally C 1-3-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein R 3Be NR 12R 12 'And q is 0, wherein R 12And R 12 'In one be aryl.
In a further embodiment, the present invention relates to formula I compound, wherein R 3Be NR 12R 12 'And q is 0, R 12And R 12 'In one be aryl-C 1-6-alkane (alkene/alkynes) base is generally aryl-C 1-3-alkane (alkene/alkynes) base.
In a preferred embodiment, the present invention relates to formula I compound, wherein Y is formula II, III, V, XXX or XXXI.
In one embodiment, the present invention relates to formula I compound, wherein Y is formula III or IV.
In a preferred embodiment, the present invention relates to formula I compound, wherein Y is formula II or V.
In a preferred embodiment, the present invention relates to formula I compound, wherein Y is formula V or XXXI.
In a preferred embodiment, the present invention relates to formula I compound, wherein Y is that formula II or III and W are sulphur atom.
In a preferred embodiment, the present invention relates to formula I compound, wherein Y is that formula II or III and W are Sauerstoffatom.
In a preferred embodiment, the present invention relates to formula I compound, wherein Y is formula V.
In a preferred embodiment, the present invention relates to formula I compound, wherein Y is that formula XXX and T are NH.
In a preferred embodiment, the present invention relates to formula I compound, wherein Y is that formula XXX and T are nitrogen-atoms or Sauerstoffatom.
In a preferred embodiment, the present invention relates to formula I compound, wherein Y is that formula XXXI and L are nitrogen-atoms.
In a preferred embodiment, the present invention relates to formula I compound, wherein Y is that formula XXXI and L are C or CH.
In one embodiment, the present invention relates to formula I compound, wherein R 5Be selected from aryl-C independently of one another 1-6-alkane (alkene/alkynes) base, acyl group ,-CO-NR 6NR 6 ', cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to formula I compound, wherein R 5Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8The basic oxygen base of-cycloalkanes (alkene), C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes), halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-NR 7R 7 ',-S-R 8With-SO 2R 8Or two adjacent R 5Connected aryl forms optional one or two heteroatomic 4 to 8 yuan of rings that comprise together.
In a further embodiment, the present invention relates to formula I compound, wherein R 5Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8The basic oxygen base of-cycloalkanes (alkene), C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes) ,-NR 7R 7 ',-S-R 8With-SO 2R 8Or two adjacent R 5Connected aryl forms optional one or two heteroatomic 4 to 8 yuan of rings that comprise together.
In a further embodiment, the present invention relates to formula I compound, wherein R 5Be selected from halogen, halo-C independently of one another 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base and halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein R 5Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-sulfenyl, aryl-oxygen base, halogen atom, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base or two adjacent R 5Connected aryl forms optional one or two heteroatomic 4 to 8 yuan of rings that comprise together.
In a preferred embodiment, the present invention relates to formula I compound, wherein R 5Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, aryl, aryl-sulfenyl, aryl-oxygen base, halogen, halo-C 1-6-alkane (alkene/alkynes) base or two adjacent R 5Connected aryl forms optional one or two heteroatomic 4 to 8 yuan of rings that comprise together.
In a further preferred embodiment, the present invention relates to formula I compound, wherein R 5Be selected from halogen and halo-C independently of one another 1-6-alkane (alkene/alkynes) base.
In one embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5Be halogen atom.
In another embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5Be halo-C 1-6-alkane (alkene/alkynes) base is generally halo-C 1-3-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5Be C 1-6-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5Be aryl.
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5Be aryl-sulfenyl.
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5Be aryl-oxygen base.
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5Be C 1-6The basic oxygen base of-alkane (alkene/alkynes).
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5For-NR 7R 7 '
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5For-S-R 8
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5For-SO 2R 8
In a further embodiment, the present invention relates to formula I compound, wherein two adjacent R 5Connected aryl forms optional one or two heteroatomic 4 to 8 yuan of rings that comprise together.
In a preferred embodiment, the present invention relates to formula I compound, wherein two adjacent R 5Formation-(CH together 2) N '-CH 2-,-CH=CH-(CH 2) M '-,-CH 2-CH=CH-(CH 2) P '-,-CH=CH-CH=CH-,-(CH 2) N '-O-,-O-(CH 2) M '-O-,-CH 2-O-(CH 2) P '-O-,-CH 2-O-CH 2-O-CH 2-,-(CH 2) N '-S-,-S-(CH 2) M '-S-,-CH 2-S-(CH 2) P '-S-,-CH 2-S-CH 2-S-CH 2-,-(CH 2) N '-NH-,-NH-(CH 2) M '-NH-,-CH 2-NH-(CH 2) P '-NH-,-CH=CH-NH-,-O-(CH 2) M '-NH-,-CH 2-O-(CH 2) P '-NH-or-O-(CH 2) P '-NH-CH 2-,-S-(CH 2) M '-NH-,-N=CH-NH-,-N=CH-O-or-N=CH-S-, wherein m ' is 1,2 or 3, n ' be 2,3 or 4 and p ' be 1 or 2.
In a further embodiment, the present invention relates to formula I compound, wherein two adjacent R 5Formation-CH together 2-O-CH 2-.
In a further embodiment, the present invention relates to formula I compound, wherein two adjacent R 5Formation-CH=CH-CH=CH-together.
In a further embodiment, the present invention relates to formula I compound, wherein two adjacent R 5Formation-O-CH together 2-O-.
In a further embodiment, the present invention relates to formula I compound, wherein two adjacent R 5Formation-O-CH together 2-O-CH 2-.
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5For-NR 7R 7 'And R wherein 7And R 7 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5For-NR 7R 7 'And R wherein 7And R 7 'Be independently selected from hydrogen and C 1-6-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5For-NR 7R 7 'And R wherein 7And R 7 'Be C 1-6-alkane (alkene/alkynes) base is generally C 1-3-alkane (alkene/alkynes) base.
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5For-S-R 8Or-SO 2R 8And R wherein 8Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and aryl.
In a further embodiment, the present invention relates to formula I compound, wherein at least one substituent R 5For-S-R 8Or-SO 2R 8And R wherein 8Be selected from C 1-6-alkane (alkene/alkynes) base and aryl.
One embodiment of the invention relate to formula I compound, wherein s be 0 and q be 0.
Another embodiment of the invention relates to formula I compound, wherein R 2For hydrogen atom and X are CO.
Another embodiment of the present invention relates to formula I compound, wherein s be 0 and X be CO.
Another embodiment of the present invention relates to formula I compound, wherein R 2For hydrogen atom and q are 0.
Another embodiment of the present invention relates to formula I compound, wherein q be 0 and X be CO.
One embodiment of the invention relate to formula I compound, wherein in substituent R 2, R 3And R 5Middle aryl sum equals 0,1,2 or 3, is generally 0 or 1.
Another embodiment of the invention relates to formula I compound, wherein R 2, R 3Or R 5Do not comprise aryl.
Another embodiment of the present invention relates to formula I compound, wherein in substituent R 2, R 3And R 5Middle aryl sum equals 1.
Another embodiment of the present invention relates to formula I compound, wherein in substituent R 2, R 3And R 5Middle aryl sum equals 2.
One embodiment of the invention relate to formula I compound, and wherein working as X is SO 2And q is 0 o'clock, R 3Be not CH 3
Another embodiment of the invention relates to formula I compound, wherein when Y is formula V, and X-(Z) q-R 3All be not SO 2-CH 3
Another embodiment of the present invention relates to formula I compound, wherein R 3Be NR 12R 12 'And R 12And R 12 'It is not aryl.
Another embodiment of the present invention relates to formula I compound, wherein R 3Be NR 12R 12 'And R 12And R 12 'In one be aryl, condition is that described aryl is for quinoline or phenyl.
Another embodiment of the invention relates to formula I compound, wherein when X be CO, q is 0 and R 3Be NR 12R 12 ', and R 12And R 12 'In one be aryl, when described aryl was generally quinoline or phenyl, Y was not formula V.
In another embodiment, formula I compound is not:
N-[1-(phenyl methyl)-1H indoles-5-yl]-Toluidrin;
The N-[1-[(4-fluorophenyl) methyl]-1H indoles-5-yl]-Toluidrin;
N-[2,3-dihydro-1-(phenyl methyl)-1H-indoles-5-yl]-Toluidrin;
N-[1-(phenyl methyl)-1H-indoles-5-yl]-N '-4-quinolyl-urea;
N-[1-(phenyl methyl)-1H indoles-5-yl]-N '-4-quinolyl-urea; Or
1-(1-benzyl-5-indolinyl)-3-phenyl-urea.
An aspect of of the present present invention relates to compound and the salt thereof of general formula VII:
Figure A20048001101900491
Wherein dotted line, f, q, s, U, X, Z, R 1, R 1 ', R 2, R 3And R 5Define suc as formula I.Any embodiment that relates to formula I also is the embodiment of formula VII.
In one embodiment, the present invention relates to the compound of general formula VII, wherein f is 0.
In another embodiment, the present invention relates to the compound of general formula VII, described compound is by a substituent R 5Replace (as adjacent, or contraposition).
In a preferred embodiment, the present invention relates to contraposition by a substituent R 5The compound of the general formula VII that replaces.
In one embodiment, the present invention relates to the compound of general formula VII, described compound is by two independent R that select 5Substituting group replace (as neighbour and contraposition, and a contraposition and an adjacent and position).
In another embodiment, the present invention relates to by three independent R that select 5The compound of the general formula VII that substituting group replaces.
Another aspect of the present invention relates to the compound or its salt of general formula VIII:
Figure A20048001101900501
Wherein dotted line, g, h, q, s, U, X, Z, R 1, R 1 ', R 2, R 3And R 5Define suc as formula I.Any embodiment that relates to formula I also is the embodiment of formula VIII.
In one embodiment, the present invention relates to the compound of general formula VIII, wherein nitrogen-atoms is connected 1 of naphthyl by methylene radical.
In another embodiment, the present invention relates to the compound of general formula VIII, wherein nitrogen-atoms is connected 2 of naphthyl by methylene radical.
In a further embodiment, the present invention relates to the compound of general formula VIII, wherein g is 0,1,2 or 3, is generally 0,1 or 2.
In a further embodiment, the present invention relates to the compound of general formula VIII, wherein h is 0,1 or 2, is generally 0 or 1.
In a further embodiment, the present invention relates to the compound of general formula VIII, wherein g+h equals 0,1,2 or 3.
In a further embodiment, the present invention relates to the VIII compound of general formula, wherein g and h are 0.
In a further embodiment, the present invention relates to by a R 5The compound of the general formula VIII that substituting group replaces.
In a further embodiment, the present invention relates to by two independent R that select 5The compound of the general formula VIII that substituting group replaces.
In a further embodiment, the present invention relates to by three independent R that select 5The compound of the general formula VIII that substituting group replaces.
Another aspect of the present invention relates to the compound or its salt of general formula I X:
Figure A20048001101900511
Wherein dotted line, a, q, s, U, X, Z, R 1, R 1 ', R 2, R 3And R 5Define suc as formula I.Any embodiment that relates to formula I also is the embodiment of formula IX.
In one embodiment, the present invention relates to the compound of general formula I X, wherein nitrogen-atoms is connected 2 of heteroaryl by methylene radical.
In another embodiment, the present invention relates to the compound of general formula I X, wherein nitrogen-atoms is connected 3 of heteroaryl by methylene radical.
In a further embodiment, the present invention relates to the compound of general formula I X, wherein W is a Sauerstoffatom.
In preferred embodiments, the present invention relates to the compound of general formula I X, wherein W is a sulphur atom.
In another embodiment, the present invention relates to the compound of general formula I X, wherein a is 0,1 or 2.
In a further embodiment, the present invention relates to the compound of general formula I X, wherein a is 0.
In a further embodiment, the present invention relates to by a substituent R 5The compound that replaces the general formula I X of (as at 5).
In a further embodiment, the present invention relates to by two independent R that select 5Substituting group replaces the compound of general formula I X.
In one embodiment, the present invention relates to the compound of general formula I X, wherein nitrogen-atoms is connected 2 of heteroaryl, wherein substituent R by methylene radical 5Be connected 5 of heteroaryl.
Another aspect of the present invention relates to the compound or its salt of general formula X:
Wherein dotted line, b, c, q, s, U, X, Z, R 1, R 1 ', R 2, R 3And R 5Define suc as formula I.Any embodiment that relates to formula I also is the embodiment of formula X.
In one embodiment, the present invention relates to the compound of general formula X, wherein nitrogen-atoms is connected in 2 of heteroaryl by methylene radical.
In another embodiment, the present invention relates to the compound of general formula X, wherein nitrogen-atoms is connected in 3 of heteroaryl by methylene radical.
In a further embodiment, the present invention relates to the compound of general formula X, wherein W is a Sauerstoffatom.
In a further embodiment, the present invention relates to the compound of general formula X, wherein W is a sulphur atom.
In a further embodiment, the present invention relates to the compound of general formula X, wherein b is 0,1,2 or 3, is generally 0,1 or 2.
In a further embodiment, the present invention relates to the compound of general formula X, wherein c is 0 or 1, is generally 0.
In a further embodiment, the present invention relates to the compound of general formula X, wherein b+c equals 0,1,2,3 or 4.
In a further embodiment, the present invention relates to the compound of general formula X, wherein b and c are 0.
In a further embodiment, the present invention relates to the compound of general formula X, wherein b+c equals 1.A kind of situation is that b is 1 and c is 0, and another kind of situation is that b is 0 and c is 1.
In a further embodiment, the present invention relates to by a substituent R 5The compound of the general formula X that replaces.
In a further embodiment, the present invention relates to by two independent R that select 5The compound of the general formula X that substituting group replaces.
In a further embodiment, the present invention relates to by three independent R that select 5The compound of the general formula X that substituting group replaces.
Another aspect of the present invention relates to the compound or its salt of general formula X I:
Figure A20048001101900541
Wherein dotted line, d, e, q, s, U, X, Z, R 1, R 1 ', R 2, R 3And R 5Define suc as formula I.Any embodiment that relates to formula I also is the embodiment of formula XI.
In one embodiment, the present invention relates to the compound of general formula X I, wherein nitrogen-atoms is connected in 4 of heteroaryl by methylene radical.
In another embodiment, the present invention relates to the compound of general formula X I, wherein nitrogen-atoms is connected in 5 of heteroaryl by methylene radical.
In one embodiment, the present invention relates to the compound of general formula X I, wherein nitrogen-atoms is connected in 6 of heteroaryl by methylene radical.
In another embodiment, the present invention relates to the compound of general formula X I, wherein nitrogen-atoms is connected in 7 of heteroaryl by methylene radical.
In a further embodiment, the present invention relates to the compound of general formula X I, wherein W is a Sauerstoffatom.
In a further embodiment, the present invention relates to the compound of general formula X I, wherein W is a sulphur atom.
In a further embodiment, the present invention relates to the compound of general formula X I, wherein d is 0,1 or 2, is generally 0 or 1.
In a further embodiment, the present invention relates to the compound of general formula X I, wherein e is 0,1 or 2.
In a further embodiment, the present invention relates to the compound of general formula X I, wherein d+e is 0,1,2,3 or 4.
In a further embodiment, the present invention relates to the compound of general formula X I, wherein d and e are 0.
In a further embodiment, the present invention relates to by a substituent R 5The compound of the general formula X I that replaces.
In a further embodiment, the present invention relates to by two independent R that select 5The compound of the general formula X I that substituting group replaces.
In a further embodiment, the present invention relates to by three independent R that select 5The compound of the general formula X I that substituting group replaces.
Another aspect of the present invention relates to the compound or its salt of general formula X XXII:
Figure A20048001101900551
Wherein dotted line, j, q, s, T, U, X, Z, R 1, R 1 ', R 2, R 3And R 5Define suc as formula I.Any embodiment that relates to formula I also is the embodiment of formula XXXII.
In one embodiment, the present invention relates to the compound of general formula X XXII, wherein nitrogen-atoms is connected in shown in the heteroaryl 1 by methylene radical.
In another embodiment, the present invention relates to the compound of general formula X XXII, wherein nitrogen-atoms is connected in shown in the heteroaryl 2 by methylene radical.
In another embodiment, the present invention relates to the compound of general formula X XXII, wherein nitrogen-atoms is connected in shown in the heteroaryl 3 by methylene radical.
In a further embodiment, the present invention relates to the compound of general formula X XXII, wherein T is a Sauerstoffatom.
In a further embodiment, the present invention relates to the compound of general formula X XXII, wherein T is a nitrogen-atoms.
In a further embodiment, the present invention relates to the compound of general formula X XXII, wherein T represents NH.
In another embodiment, the present invention relates to the compound of general formula X XXII, wherein j is 0,1,2 or 3.
In a further embodiment, the present invention relates to the compound of general formula X XXII, wherein j is 0.
In a further embodiment, the present invention relates to by at least one substituent R 5The compound of the general formula X XXII that replaces.In aspect one, the compound of general formula X XXII shown in be substituted on 1.Its on the other hand in, the compound of general formula X XXII shown in be substituted on 2.At it aspect another in, the compound of general formula X XXII shown in be substituted on 3.At it aspect another in, T represents nitrogen-atoms, the compound of general formula X XXII is substituted on this position.
In a further embodiment, the present invention relates to by two independent R that select 5The compound of the general formula X XXII that substituting group replaces.
In a further embodiment, the present invention relates to by two or three R that independently selects 5The compound of the general formula X XXII that substituting group replaces.
In a further embodiment, the present invention relates to by three independent R that select 5The compound of the general formula X XXII that substituting group replaces.
One aspect of the present invention relates to compound and the salt thereof of general formula X XXIII:
Figure A20048001101900571
Wherein dotted line, k, q, s, L, U, X, Z, R 1, R 1 ', R 2, R 3And R 5Define suc as formula I.Any embodiment that relates to formula I also is the embodiment of formula XXXIII.
In one embodiment, the present invention relates to the compound of general formula X XXIII, wherein k is 0.
In another embodiment, the present invention relates to by a substituent R 5Replace (as the neighbour of nitrogen-atoms, or contraposition) the compound of general formula X XXIII.
In a preferred embodiment, the present invention relates to the contraposition of nitrogen-atoms by a substituent R 5The compound of the general formula X XXIII that replaces.
In one embodiment, the present invention relates to by two independent R that select 5Substituting group replaces the compound of the general formula X XXIII of (as in nitrogen-atoms neighbour and contraposition, or between nitrogen-atoms and contraposition, or at nitrogen-atoms an adjacent and position).
In another embodiment, the present invention relates to by three independent R that select 5The compound of the general formula X XXIII that substituting group replaces.
In one embodiment of the invention, preferred following compounds and its salt:
1.N-[4-chloro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
2.N-[4-chloro-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(3.[1-4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-the carboxylamine propyl ester;
(4.N-[1-4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-C-phenyl-Toluidrin;
5.4-fluoro-N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-benzamide;
(6.N-[1-4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(7.N-[1-4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-2-thiophene-2-yl acetamide;
(8.N-[1-4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
(9.3-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-1,1-di-isopropyl urea;
(10.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-morpholine-4-methane amide;
(11.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-tetramethyleneimine-1-methane amide;
(12.[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-carboxylamine 2-benzyloxy ethyl ester;
(13.3-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-1-methyl isophthalic acid-propyl group urea;
(14.[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-t-butyl carbamate;
(15.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-C-phenyl-Toluidrin;
(16.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butane-1-sulphonamide;
(17.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 4-fluorobenzamide;
(18.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
(19.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 2-phenoxy-acetamide;
(20.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(21.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
(22.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-cyclopentane formamide;
(23.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-thiophene-2-yl acetamide;
(24.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-Isonicotinamide;
(25.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-4-dimethylamino yl-benzamide;
(26.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
(27.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-IH-indoles-5-yl]-6-trifluoromethyl niacinamide;
28.1-the tertiary butyl-3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-urea;
(29.1-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 3-ethyl carbamide;
30.1-benzyl-3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-urea;
(31.1-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 3-phenthylcarbamide;
(32.1-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3-thiophene-2-base urea;
(33.1-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3-thiene-3-yl-urea;
34.2,2-dimethyl-N-[6-nitro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-propionic acid amide;
(35.N-[1-5-chlorothiophene-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
(36.2-4-fluorophenyl)-N-[6-nitro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
37.N-[6-amino-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
38.N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
39.N-[6-amino-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
40.N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide, or
(41.N-[1-5-chlorothiophene-2-ylmethyl)-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate.
In another embodiment of the invention, preferred following compounds and its salt:
1.N-[4-chloro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
2.N-[4-chloro-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(3.[1-4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-the carboxylamine propyl ester;
(4.N-[1-4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-C-phenyl-Toluidrin;
5.4-fluoro-N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-benzamide;
(6.N-[1-4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(7.N-[1-4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-2-thiophene-2-yl acetamide;
(8.N-[1-4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
(9.3-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-1,1-di-isopropyl urea;
(10.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-morpholine-4-methane amide;
(11.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-tetramethyleneimine-1-methane amide;
(12.[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-carboxylamine 2-benzyloxy ethyl ester;
(13.3-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-1-methyl isophthalic acid-propyl group urea;
(14.[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-t-butyl carbamate;
(15.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-C-phenyl-Toluidrin;
(16.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butane-1-sulphonamide;
(17.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 4-fluorobenzamide;
(18.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
(19.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 2-phenoxy-acetamide;
(20.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(21.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
(22.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-cyclopentane formamide;
(23.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-thiophene-2-yl acetamide;
(24.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-Isonicotinamide;
(25.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-4-dimethylamino yl-benzamide;
(26.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
(27.N-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-6-trifluoromethyl niacinamide;
28.1-the tertiary butyl-3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-urea;
(29.1-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 3-ethyl carbamide;
30.1-benzyl-3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-urea;
(31.1-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 3-phenthylcarbamide;
(32.1-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3-thiophene-2-base urea;
(33.1-[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3-thiene-3-yl-urea;
(34.[1-5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the carboxylamine propyl ester;
35.2,2-dimethyl-N-[6-nitro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-propionic acid amide;
(36.N-[1-5-chlorothiophene-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
(37.2-4-fluorophenyl)-N-[6-nitro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
(38.N-[1-5-chlorothiophene-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
(39.N-[1-5-chlorothiophene-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
40.N-[6-amino-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
41.N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
42.N-[6-amino-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
43.N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
44.N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
45.N-[6-amino-1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
46.N-[6-amino-1-(3-fluoro-4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(47.N-[1-5-chlorothiophene-2-ylmethyl)-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
48.N-[6-bromo-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
49.N-[6-bromo-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(50.N-[1-4-benzyl chloride base)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
51.3,3-dimethyl-N-[1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
(52.N-[1-4-isopropyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(53.N-[1-3-fluoro-4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(54.N-[1-the 6-chlorobenzene is [1,3] dioxole-5-ylmethyl also)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(55.N-[1-3,5-dimethyl-1-phenyl-1H-pyrazoles-4-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(56.N-[1-2-chloro-5-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
(57.N-{1-[5-4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-ylmethyl]-2,3-dihydro-1H-indoles-5-yl }-3, the 3-amide dimethyl butyrate;
58.3,3-dimethyl-N-[1-(6-is to tolyloxy-pyridin-3-yl methyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
(59.N-{1-[6-4-chloro-phenyl-sulfenyl)-pyridin-3-yl methyl]-2,3-dihydro-1H-indoles-5-yl }-3, the 3-amide dimethyl butyrate;
(60.N-{1-[6-4-cyano-benzene oxygen)-pyridin-3-yl methyl]-2,3-dihydro-1H-indoles-5-yl }-3, the 3-amide dimethyl butyrate;
61.3,3-dimethyl-N-[1-(6-5-flumethiazine-3-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
62.3,3-dimethyl-N-[1-(3-methyl-benzo [b] thiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
(63.N-[1-6-fluoro-4H-benzo [1,3] dioxine-8-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
64.3,3-dimethyl-N-[1-(6-phenoxypyridines-3-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
65.3,3-dimethyl-N-[1-(3-methyl-5-phenyl-isoxazole-4-base methyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
(66.N-1-benzo [b] thiophene-2-ylmethyl-2,3-dihydro-1H-indoles-5-yl)-3, the 3-amide dimethyl butyrate;
(67.N-{1-[1-4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-ylmethyl]-2,3-dihydro-1H-indoles-5-yl }-3, the 3-amide dimethyl butyrate;
68.3,3-dimethyl-N-[1-(5-thiotolene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
69.3,3-dimethyl-N-[1-(4-pyrroles-1-base-benzyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
(70.N-[1-4-benzyl chloride base)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
(71.2-4-fluorophenyl)-N-[1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
(72.2-4-fluorophenyl)-N-[1-(4-isopropyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
(73.2-4-fluorophenyl)-N-[1-(3-fluoro-4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
(74.N-[1-the 6-chlorobenzene is [1,3] dioxole-5-ylmethyl also)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
(75.N-[1-3,5-dimethyl-1-phenyl-1H-pyrazoles-4-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
(76.N-[1-2-chloro-5-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
(77.N-{1-[5-4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-ylmethyl]-2,3-dihydro-1H-indoles-5-yl }-2-(4-fluorophenyl)-ethanamide;
(78.N-{1-[6-4-cyano-benzene oxygen)-pyridin-3-yl methyl]-2,3-dihydro-1H-indoles-5-yl }-2-(4-fluorophenyl)-ethanamide;
(79.2-4-fluorophenyl)-N-[1-(3-methyl-benzo [b] thiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
(80.N-[1-6-fluoro-4H-benzo [1,3] dioxine-8-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
(81.2-4-fluorophenyl)-N-[1-(6-phenoxypyridines-3-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
(82.N-1-benzo [b] thiophene-2-ylmethyl-2,3-dihydro-1H-indoles-5-yl)-2-(4-fluorophenyl)-ethanamide;
(83.2-4-fluorophenyl)-N-{1-[1-(4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-ylmethyl]-2,3-dihydro-1H-indoles-5-yl }-ethanamide;
(84.2-4-fluorophenyl)-N-[1-(5-thiotolene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide; With
(85.2-4-fluorophenyl)-N-[1-(4-pyrroles-1-base-benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide.
According to an embodiment, the present invention relates to comprise the pharmaceutical composition of one or more pharmaceutical acceptable carriers or thinner and formula I compound or its salt, dotted line, s, q, U, X, Z, Y, R among the formula I 1, R 1 ', R 2And R 3As above definition, therefore any dotted line, a, b, c, d, e, f, g, h, j, k, s, q, L, T, U, X, Z, Y, W, R 1, R 1 ', R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'Define suc as formula I.Thereby pharmaceutical composition of the present invention can comprise one or more formulas I compound or its salt, for example a kind of formula I compound or its salt; Or two kinds of formula I compound or its salts; Or three kinds of formula I compound or its salts.
Thereby the invention provides a kind of pharmaceutical composition of oral or parenteral admin, described pharmaceutical composition comprises at least a formula I compound or its salt and one or more pharmaceutical acceptable carriers or the thinner for the treatment of significant quantity.
On the one hand, compound of the present invention can be used as the administration of unique treatment compounds effective.
On the other hand, compound of the present invention can be used as a part of administration of combination therapy, that is to say compound of the present invention can with the effective compound Combined Preparation of (as having anticonvulsant properties) of other treatment.These effects with other compounds of anticonvulsion performance can include but not limited to the activity for following system:
● ionic channel, as sodium, potassium or calcium channel;
● excitatory amino acid system, for example retardance of nmda receptor or adjusting;
● inhibitory nerve mediator system, for example retardance of the enhancing of GABA release or GABA absorption, or
● membrane stabilizing action.
Present anticonvulsant drug includes but not limited to tiagabine, Carbamzepine, Sodium Valproate, lamotrigine, gabapentin, lyrica, ethosuximide, Levetiracetam, Phenytoin Sodium Salt, topiramate, zonisamide and benzodiazepine class and Barbiturates.
In one aspect, found that compound of the present invention is effective to the potassium-channel of KCNQ family (particularly KCNQ2 hypotype).
In one embodiment, the present invention relates to the purposes of one or more compounds of the present invention in methods of treatment.By prevention, treatment or the disease that suppresses or the ion flow reaction of symptom in potassium-channel (as KCNQ family potassium-channel), increasing.The disease of these diseases or the preferred central nervous system of symptom or symptom.
Think that voltage that compound of the present invention can be used for being increased in Mammals (as the people) relies on the ionic current in the potassium-channel.
Think that compound of the present invention can be used for prevention, treatment or inhibition to responsive disease or the symptom of the mobile increase of potassium-channel (as KCNQ family potassium-channel) intermediate ion.The disease of these diseases or the preferred central nervous system of symptom or symptom.
Thereby think that compound of the present invention can be used for prevention, treatment or suppresses illness or disease such as epilepsy, neuralgia and migraine, anxiety disorder and neurodegenerative disease.
Thereby, think that compound of the present invention can be used for prevention, treatment or suppresses disease or illness such as convulsions, epilepsy, anxiety disorder, neurodynia and neurodegenerative disease.
Therefore special embodiment according to the present invention thinks that compound of the present invention can be used for prevention, treatment or suppresses epileptic seizures disease such as convulsions, epilepsy and epileptic state.
In one embodiment, think that compound of the present invention can be used for prevention, treatment and suppresses convulsions.
In another embodiment, think that compound of the present invention can be used for prevention, treatment and suppresses epilepsy, epilepsy syndromes and epileptic seizures.
In a further embodiment, think that compound of the present invention is used for prevention, treatment and inhibition anxiety disorder (as anxiety disorder) and disease and the illness relevant: panic attack with following situation, agoraphobia, the phobia that has agoraphobia, not with the phobia of agoraphobia, the agoraphobia of no phobia history, specific phobia disease, social phobia and other specific phobia diseases, obsessional idea and behavior disease, stress disease after the wound, gross stress reaction, generalized anxiety disorder, result from the anxiety disorder of whole body health situation, the anxiety disorder that material brings out, separation anxiety disorder, adjustment disorder, the behavior anxiety, hypochondriasis, result from the anxiety disorder of whole body health situation and anxiety disorder that material brings out and other not elsewhere specified anxiety disorders.
In a further embodiment, thinking that compound of the present invention can be used for preventing, treating and suppress after anxiety disorder such as anxiety, generalized anxiety disorder, panic anxiety disorder, obsessional idea and behavior disease, social phobia, behavior anxiety, the wound stress disease, gross stress reaction, adjustment disorder, hypochondriasis, separation anxiety disorder, agoraphobia, specificity anxiety, result from the anxiety disorder of whole body health situation and the anxiety disorder that material brings out.
In a further embodiment, think that also compound of the present invention can be used for prevention, treatment and suppresses neurodynia and migraine disease, as allodynia, hyperpathia pain, phantom pain, the neurodynia relevant and the neurodynia of being correlated with migraine with diabetic neuropathy.In a further embodiment, think that compound of the present invention can be used for prevention, treats and suppress neurodegenerative disease such as Alzheimer; Huntington Chorea; Multiple sclerosis; Amyotrophic lateral sclerosis; Creutzfeldt-Jakob disease; Parkinson's disease; Encephalopathic that AIDS-brings out or the encephalopathic that causes by rubella virus, simplexvirus, Borrelia and unknown pathogenic infection; The neurodegeneration that wound causes; As at the medicine withdrawal or because the drunk neuronal excitation transient state that causes; With the degenerative disease of peripheral nervous system, as polyneuropathy and polyneuritis.
In a further embodiment, think that compound of the present invention can be used for prevention, treats and suppress neurodegenerative disease such as Alzheimer; Huntington Chorea; Multiple sclerosis; Amyotrophic lateral sclerosis; Creutzfeldt-Jakob disease; Parkinson's disease; Encephalopathic that AIDS-brings out or the encephalopathic that causes by rubella virus, simplexvirus, Borrelia and unknown pathogenic infection; The neurodegeneration that wound causes.
In a further embodiment, think that compound of the present invention can be used for preventing, treating and suppresses as at the medicine withdrawal or because the drunk neuronal excitation transient state that causes.
The invention provides and in one or more following tests, show compounds effective:
● " by the relative discharge of KCNQ2 passage ", this test are used to measure the usefulness of compound at destination channel;
● " maximum electric shock ", the non-specific CNS that this test is used to measure by the electric shock mode stimulates the epilepsy of bringing out;
● " epilepsy that pilocarpine brings out ", be difficult to treat the epilepsy that pilocarpine brings out with existing antiepileptic drug, therefore consider " resistance epilepsy " model;
● " electric epilepsy threshold value test " and " chemical epilepsy threshold value test ", these model determinations the threshold value that begins of epilepsy, therefore can be used as the model whether each compound of detection has postponed the beginning of epilepsy;
● " amygdala are lighted and are brought out ", this test is used to measure progression of disease since these animals received more stimulation, compare with normal animal, the epilepsy in this model is more serious.
According to a special aspect of the present invention, described compound has the KCNQ2 activity, adopts following test " by the relative discharge of KCNQ2 passage " to measure EC 50Less than 15000nM, for example less than 10000nM.
According to another special aspect of the present invention, described compound has the KCNQ2 activity, adopts following test " by the relative discharge of KCNQ2 passage " to measure EC 50Less than 2000nM, for example less than 1500nM.
According to another special aspect of the present invention, described compound has the KCNQ2 activity, adopts following test " by the relative discharge of KCNQ2 passage " to measure EC 50Less than 200nM, for example less than 150nM.
According to a special aspect of the present invention, at the ED of compound described in " maximum electric shock " test as described below 50Less than 15mg/kg.
According to a special aspect of the present invention, at the ED of compound described in " maximum electric shock " test as described below 50Less than 5mg/kg.
According to a special aspect of the present invention, at the ED of compound described in " electric epilepsy threshold value test " as described below and " the chemical epilepsy threshold value test " 50Less than 5mg/kg.
Some compound almost is free from side effects or inapparent clinically side effect is only arranged.Therefore some compound is tested in the model that need not calmness, low temperature and imbalance mutual aid of this compound.
Some compound has the big therapeutic index between anticonvulsion effect and the side reaction (for example by motor capacity injury or ataxia reaction at the behavior determination on the revolving bar).This means before visible side reaction, can expect that described compound can be by the fine tolerance of patient, thereby allow high dosage.Therefore, can expect to have durable the being subjected to property of good treatment and can the high dosage administration, make that adopting other drugs to produce for those has more curative effect patient of side reaction.
Definition
The term heteroatoms is meant nitrogen, oxygen or sulphur atom.
Halogen is meant fluorine, chlorine, bromine or iodine.
Statement C 1-6-alkane (alkene/alkynes) base and C 1-6-(alkane/alkene/alkynes) base is meant C 1-6-alkyl, C 2-6-thiazolinyl or C 2-6-alkynyl.Term C 1-6-alkyl is meant alkyl branching or non-branching, and this alkyl comprises 1 to 6 carbon atom, includes but not limited to methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl group and 2-methyl isophthalic acid-propyl group.Similarly, C 2-6-thiazolinyl and C 2-6-alkynyl represents to have this class group of 2 to 6 carbon atoms respectively, comprises two keys and a triple bond respectively, includes but not limited to vinyl, propenyl, butenyl, ethynyl, proyl and butynyl.
Statement C 1-3-alkane (alkene/alkynes) base is meant C 1-3-alkyl, C 2-3-thiazolinyl or C 2-3-alkynyl.Term C 1-3-alkyl is meant alkyl branching or non-branching, and this alkyl comprises 1 to 3 carbon atom, includes but not limited to methyl, ethyl, 1-propyl group, 2-propyl group.Similarly, C 2-3-thiazolinyl and C 2-3-alkynyl represents to have this class group of 2 to 3 carbon atoms respectively, comprises two keys and a triple bond respectively, includes but not limited to vinyl, 1-propenyl, 2-propenyl, 3-propenyl, ethynyl, 1-proyl and 3-proyl.
Statement C 3-8-cycloalkanes (alkene) base and C 3-8-ring (alkane/alkene) base is meant C 3-8-cycloalkyl or cycloalkenyl group.Term C 3-8-cycloalkyl represents to have the monocycle or the two ring carbocyclic rings of 3 to 8 carbon atoms, includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.Term C 3-8-cycloalkenyl group is represented to have 3 to 8 carbon atoms and is comprised the monocycle or the two ring carbocyclic rings of two keys.
Statement C 3-6-cycloalkanes (alkene) base and C 3-6-ring (alkane/alkene) is meant C 3-6-cycloalkyl or cycloalkenyl group.Term C 3-6-cycloalkyl represents to have the monocycle or the two ring carbocyclic rings of 3 to 6 carbon atoms, includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
Term heterocycle alkane (alkene) basis representation monocycle or two member ring systems, wherein said ring is selected from 2 to 7 carbon atoms by 4 to 8 and 1 or 2 heteroatomic atom that is selected from N, S or O forms.
When two connected carbon atoms of substituting group form optionally when comprising 1 or 2 heteroatomic 3 to 8 yuan of saturated or unsaturated ring together, the monocycle system is selected from 1 to 8 carbon atom by 3 to 8 and 0 to 2 heteroatomic atom that is selected from N, S or O forms.The example of these member ring systems is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Term halo-C 1-6The C that-alkane (alkene/alkynes) basis representation is replaced by one or more halogen atoms 1-6-alkane (alkene/alkynes) base includes but not limited to trifluoromethyl.Similarly, halo-C 3-8The C that-cycloalkanes (alkene) basis representation is replaced by one or more halogen atoms 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base that halogenated heterocyclic alkane (alkene) basis representation is replaced by one or more halogen atoms.
Term NR 12R 12 '-C 1-6-alkane (alkene/alkynes) basis representation is by NR 12R 12 'The C that replaces 1-6-alkane (alkene/alkynes) base.Term NR 12R 12 '-C 3-8-cycloalkanes (alkene) basis representation is by NR 12R 12 'The C that replaces 3-8-cycloalkanes (alkene) base.Term NR 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) basis representation is by NR 12R 12 'The C that replaces 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.Work as NR 12R 12 '-C 1-6-alkane (alkene/alkynes) base, NR 12R 12 '-C 3-8-cycloalkanes (alkene) base and NR 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6When any in-alkane (alkene/alkynes) base is optionally substituted, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6In-alkane (alkene/alkynes) base any optional by one or more be C independently 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6The substituting group of-alkane (alkene/alkynes) base or aryl replaces.
Term acyl group used herein is meant formyl radical, C 1-6The basic carbonyl of-alkane (alkene/alkynes), C 3-8The basic carbonyl of-cycloalkanes (alkene), aryl-carbonyl, aryl-C 1-6Basic carbonyl of-alkane (alkene/alkynes) or C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-carbonyl, wherein C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and aryl as above define.
When two connected nitrogen-atoms of substituting group form together optional when comprising 1,2 or 3 other heteroatomic 4 to 8 yuan of saturated or unsaturated ring, the monocycle system by 4 to 8 be selected from nitrogen-atoms, 1 to 7 carbon atom and 0 to 3 be selected from N, S or OHeteroatomic atom form.The example of this member ring systems is azetidine, beta-lactam (lactame), tetramethyleneimine, piperidines, piperazine, morpholine, pyrroles, oxazolidine, thiazolidine, imidazolidine, azetidine, beta-lactam, tetrazolium and pyrazoles.
When two connected aryl of contiguous substituting group form optionally when comprising one or two heteroatomic 4 to 8 yuan of rings together, member ring systems is selected from 3 to 8 carbon atoms by 4 to 8 and 0 to 2 heteroatomic atom that is selected from N, S or O forms.The substituting group of two vicinities can form together:
(CH 2) N ' '-CH 2-,-CH=CH-(CH 2) M ' '-,-CH 2-CH=CH-(CH 2) P ' '-,-CH=CH-CH=CH-,-(CH 2) N ' '-O-,-O-(CH 2) M ' '-O-,-CH 2-O-(CH 2) P ' '-O-,-CH 2-O-CH 2-O-CH 2-,-(CH 2) N ' '-S-,-S-(CH 2) M ' '-S-,-CH 2-S-(CH 2) P ' '-S-,-CH 2-S-CH 2-S-CH 2-,-(CH 2) N ' '-NH-,-NH-(CH 2) M ' '-NH-,-CH 2-NH-(CH 2) P ' '-NH-,-CH=CH-NH-,-O-(CH 2) M ' '-NH-,-CH 2-O-(CH 2) P ' '-NH-or-O-(CH 2) P ' '-NH-CH 2-,-S-(CH 2) M ' '-NH-,-N=CH-NH-,-N=CH-O-or-N=CH-S-, wherein m ' ' is 1,2 or 3, n ' ' be 2,3 or 4 and p ' ' be 1 or 2.
Term aryl is meant the aromatic systems of optional 5 to 10 carbon atoms that replace, and wherein 0,1,2,3 or 4 carbon atom heteroatoms that can be independently selected from N, S or O replaces.The example of these aryl is the optional phenyl that replaces, the optional naphthyl that replaces, the optional pyridine that replaces, the optional pyrroles who replaces, the optional pyrimidine that replaces, the optional quinoline that replaces, the optional indoles that replaces, the optional thiophene that replaces, the optional furans that replaces, the optional thiazole that replaces and the optional De oxazole that replaces.Aryl can by one or more be hydroxyl, halogen, C independently 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8The basic oxygen base of-alkane (alkene/alkynes), acyl group, nitro or cyano group ,-CO-NH-C 1-6-alkane (alkene/alkynes) base ,-CO-N (C 1-6-alkane (alkene/alkynes) base) 2,-NH 2,-NH-C 1-6-alkane (alkene/alkynes) base ,-N (C 1-6-alkane (alkene/alkynes) base) 2 ,-S-C 1-6-alkane (alkene/alkynes) base ,-SO 2-C 1-6-alkane (alkene/alkynes) base ,-SO 2N (C 1-6-alkane (alkene/alkynes) base) 2With-SO 2NH-C 1-6The substituting group of-alkane (alkene/alkynes) base replaces; Or two connected aryl of contiguous substituting group form optional one or two heteroatomic 4 to 8 yuan saturated or unsaturation ring that comprises together.
Term C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8Cycloalkanes (alkene) base, aryl-heterocycle alkane (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 2-6-thiazolinyl oxygen base, C 2-6-alkynyloxy base, C 3-8The basic oxygen base of-cycloalkanes (alkene), C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 3-8-cycloalkanes (alkene) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes)-heterocycle alkane (alkene) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 1-6The basic carbonyl of-alkane (alkene/alkynes), C 3-8The basic carbonyl of-alkane (alkene/alkynes), aryl-carbonyl, aryl-C 1-6The basic carbonyl of-alkane (alkene/alkynes), C 3-8-cycloalkanes (alkene) base-C 1-6The basic carbonyl of-alkane (alkene/alkynes) ,-CO-C 1-6-alkane (alkene/alkynes) base ,-S-C 1-6-alkane (alkene/alkynes) base ,-SO 2-C 1-6-alkane (alkene/alkynes) base and-SO 2O-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-carbonyl of-cycloalkanes (alkene)-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, acyl group, acyl group-C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-cycloalkanes (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halogenated heterocyclic alkane (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-aryl, halo-heterocycle alkane (alkene) base-aryl, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group-C 1-6Expression such as-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base this class group, wherein C 1-6-alkane (alkene/alkynes) base, C 2-6-thiazolinyl, C 2-6-alkynyl, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, aryl, cyano group, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halogenated heterocyclic alkane (alkene) base and acyl group as above define.
The preferred pharmacy acceptable salt of salt of the present invention.These salt comprise pharmaceutically-acceptable acid addition, pharmaceutically acceptable metal-salt, ammonium salt, alkylating ammonium salt.
Pharmacy acceptable salt of the present invention is preferably acid salt.Acid salt of the present invention is preferably the pharmacy acceptable salt of compound of the present invention and non-toxic acid formation.Acid salt comprises mineral acid and organic acid salt.The representative example of suitable mineral acid comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, phosphoric acid and nitric acid etc.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, lactic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, oxalic acid, picric acid, pyruvic acid, Whitfield's ointment, succsinic acid, ethyl sulfonic acid, tartrate, xitix, pamoic acid, glyconic acid, citraconic acid, aspartic acid, stearic acid, palmitinic acid, EDTA, oxyacetic acid, para-amino benzoic acid, L-glutamic acid, dimethylene Whitfield's ointment (bis-methylene salicylic acid), methylsulfonic acid, ethionic acid, methylene-succinic acid, Phenylsulfonic acid, tosic acid, acetate theophylline and 8-halo theophylline (for example 8-bromine theophylline etc.).More pharmaceutically acceptable example inorganic or organic acid addition salt is listed in J.Pharm.Sci.1977, and in 66,2, it is combined in herein by reference.
The example of metal-salt comprises lithium, sodium, potassium, magnesium salts etc.
The example of ammonium salt and alkylated ammonium comprise ammonium, methyl-, dimethyl-, trimethylammonium-, ethyl-, hydroxyethyl-, diethyl-, normal-butyl-, sec-butyl-, the tertiary butyl-, tetramethyl ammonium etc.
The hydride that another kind of pharmaceutically-acceptable acid addition can form for this compound.
Compound of the present invention can have one or more chiral centres and any optical isomer, is included in the scope of the present invention as isolating, pure or partially purified optical isomer or its racemic mixture.
In addition, when having two keys or all or part of saturated member ring systems in the molecule, can form geometrical isomer.Any geometrical isomer all is included in scope of the present invention as isolating, pure or partially purified geometrical isomer or its mixture.Equally, have the molecule that rotates the key that limits and to form geometrical isomer.These are also included within scope of the present invention.
In addition, the form of the tautomer that some compound of the present invention can be different exists, and any tautomeric form that these compounds can form includes in scope of the present invention.
Compound of the present invention can non-solventization and is existed with the solvation form of solvent, and these solvents for example have water, ethanol etc.For purpose of the present invention, it has been generally acknowledged that the solvation form is equal to the non-solvent form.
Racemic form can be split as optically active enantiomorph with known method, for example by separating the diastereoisomeric salt that forms with the optics active acid, subsequently by discharge the optically active amine compound with alkaline purification.Another kind is to carry out chromatography on optically active matrix with the method that racemic modification is split as the optics optically active enantiomorph.Racemic compound of the present invention also can be split as its optically active enantiomorph by the fractional crystallization of for example d-or l-tartrate, mandelate or camsilate.Compound of the present invention also can split by forming non-mapping derivative.
Can use and well known to a person skilled in the art that other split the method for optical isomer.These methods comprise J.Jaques, and A.Collet and S.Wilen be middle those that describe in " enantiomer, racemic modification and fractionation " (" Enantiomers, Racemates, and Resolutions ", John Wiley and Sons, New York, 1981).
Also can be by the optically active compound of optically active feedstock production.
The present invention also comprises the prodrug of The compounds of this invention, produces chemical conversion by metabolism after the described prodrug administration, becomes pharmacological active substance.Usually, this prodrug is the functional derivatives of compound of formula I, VII, VIII, IX, X, XI, XXXII or XXXIII that is easy to be converted in vivo the compound of required formula I, VII, VIII, IX, X, XI, XXXII or XXXIIII.The conventional steps that is used to select and prepares suitable prodrug derivant for example is described in " prodrug design " (" Design of Prodrugs ", H.Bundgaard compiles, Elsevier, 1985).
The present invention also comprises the active metabolite of The compounds of this invention.
No matter when mention and formula I, VII, VIII, IX, X, XI, the term " epilepsy and various epilepsy " that the compound of XXXII or XXXIII is relevant is included in international anti-epileptic alliance: the suggestion of classifying about the clinical and electroencephalogram of revision epileptic seizures, international anti-epileptic alliance's classification and Technical Committee, Epilepsia, 198122:489-501 and international anti-epileptic alliance: about the suggestion of revision epilepsy and the syndromic classification of epilepsy, international anti-epileptic alliance's classification and Technical Committee, Epilepsia, 198930 (4): any epilepsy that proposes among the 389-399, epilepsy syndromes and epileptic seizures.
No matter when mention and formula I, VII, VIII, IX, X, XI, the relevant term anxiety disorder of XXXII or XXXIII compound comprises that anxiety disorder comprises and relates to the mental disorder diagnostic ﹠ statistical manual as Americanism association, 1994 the 4th editions: 110-113, the panic attack of 393-444 and 623-627 definition, agoraphobia, agoraphobia property paranoid fears (panic disorder withagoraphobia), the property paranoid fears that do not have that agoraphobia, the agoraphobia of no panic attack history, specific phobia disease, social phobia, obsessional idea and behavior disease, stress disease after the wound, gross stress reaction, generalized anxiety disorder, result from the anxiety disorder of whole body health situation, material inductive anxiety disorder, separation anxiety disorder, adjustment disorder and not elsewhere specified anxiety disorder.
Pharmaceutical composition
Compound of the present invention uses with free alkali or its pharmacy acceptable salt usually.Representative example as mentioned above.
As needs, pharmaceutical composition of the present invention can comprise formula I compound and other foregoing pharmacological active substances.
Compound of the present invention can be separately or in conjunction with pharmaceutically acceptable carrier or vehicle single dose or multiple dose administration.Medicinal compositions of the present invention can with pharmaceutically acceptable carrier or thinner and known other additives of any this area common process and vehicle allotment, as Remington:The Science and Practice of Pharmacy (the 19th edition, Gennaro compiles, Mack Publishing Co., Easton, PA, 1995) middle those disclosed.
Described medicinal compositions can specifically be allocated and be used for through any suitable administration, as mouth, rectum, nose, lung, part (comprising cheek and hypogloeeis), in skin, brain pond, intraperitoneal, vagina and parenteral (comprise in subcutaneous, intramuscular, the sheath, intravenously and intradermal) approach, the preferred oral approach.Preferred approach depends on by curer's whole body health situation and age, the character of being treated disease and selected active ingredient.
Pharmaceutical composition for oral administration comprises solid dosage such as capsule, tablet, drageeing, pill, lozenge, powder and granule.If needed, can be with its dressing (as enteric coating) or adopt the method keep as known in the art or to prolong release to be made into the preparation of the sustained release that activeconstituents is provided.
The liquid dosage form of oral administration comprises solution, emulsion, suspensoid, syrup and elixir.
The pharmaceutical composition of parenteral admin comprises aseptic aqueous solution and non-water injection solution, dispersion liquid, suspensoid or emulsion and with the preceding sterilized powder that is made into aseptic injectable solution or dispersion liquid again.Long acting injection is also in the scope that the present invention considers.
Other form of medication that are fit to comprise suppository, sprays, ointment, emulsion, gel, inhalation, transdermal patches and implant etc.
Pharmaceutical composition of the present invention or pharmaceutical composition prepared in accordance with the present invention can be by any suitable way administrations, for example with form oral administrations such as tablet, capsule, powder, syrups or with the form parenteral admin of injection solution agent.For these compositions of preparation, can use method well known in the art and use the normally used any pharmaceutically acceptable carrier in this area, thinner, vehicle or other additives.
Usually oral dosage is about 0.001 to about 100mg/kg body weight/day, and preferably about 0.01 to about 50mg/kg body weight/day, and more preferably from about 0.05 to about 10mg/kg body weight/day, list or multiple doses are as 1 to 3 dosed administration.Definite dosage will depend on seriousness and other conspicuous for a person skilled in the art factors of the complication of the body weight of the mode of administration and frequency, sex, age, treatment target and whole body health situation, sanatory character, treatment illness and any treatment.
Described preparation can exist with the unitary dose that is formed by method known to those skilled in the art easily.Be used for once a day or repeatedly the common unitary dose of (as every day 1 to 3 time) oral administration can contain 0.05 to about 1000mg, preferred about 0.1 to about 500mg, more preferably from about 0.5mg about 200mg extremely.
In outer approach of gi tract such as vein, the sheath, intramuscular and similar route of administration, be generally the oral administration using dosage pact half.
Compound of the present invention uses as free material or its pharmacologically acceptable salts usually.An example is the base addition salt with compound of free acid purposes.When compound of the present invention comprises free acid, can adopt solution or these salt of suspension preparation of the free acid of conventional method by handling compound of the present invention with stoichiometric pharmaceutically acceptable alkali.Representational example as previously mentioned.
For parenteral admin, can use the solution of novel cpd of the present invention in sterilized water, aqueous propylene glycol, moisture vitamin E or sesame oil or peanut oil.As needs, these aqueous solutions can suitably cushion and with enough salt or glucose liquid diluent are adjusted to etc. earlier and ooze.Described aqueous solution is particularly suitable for vein, intramuscular, subcutaneous and intraperitoneal administration.The aseptic aqueous medium that uses all easily obtains by standard technique known to those skilled in the art.
Can prepare injection solution by following method: activeconstituents and feasible additive are dissolved in the part solvent for injection, be preferably dissolved in the sterilized water, regulate described solution to volume required, described solution is sterilized, in the ampoule or phial that it is suitable that it is packed into.Routine be can add and any appropriate addn of this area such as tonicity agent (tonicityagents), sanitas, antioxidant etc. are used for.
Suitable pharmaceutical carrier comprises inert solid diluent or weighting agent, aseptic aqueous solution and various organic solvent.
The example of solid carrier is lower alkyl ether, yam starch, talcum, Magnesium Stearate, gelatin, lactose, natural gum of lactose, carclazyte, sucrose, cyclodextrin, talcum powder, agar, pectin, gum arabic, stearic acid and corn starch fibre element etc.
Can use any other auxiliary material or the additive that are used for these purposes, (as tinting material, correctives, sanitas etc.) condition is that itself and activeconstituents are compatible.
The example of liquid vehicle is syrup, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, polyoxyethylene and water.Similarly, described carrier or thinner can comprise any slow-release material known in the art, as glyceryl monostearate or distearin (separately or mix with wax use).
Novel cpd of the present invention then and pharmaceutically acceptable carrier mix the pharmaceutical composition of formation to be applicable to the various formulations administration easily of disclosed route of administration.The formulation that can prepare dosage unit by the known method of pharmaceutical field easily.
The preparation of the oral administration that the present invention is suitable can discrete units (as capsule or tablet) exist, every activeconstituents that comprises predetermined amount, and can comprise the vehicle that one or more are suitable.In addition, preparations for oral administration can be solution or the suspensoid in powder or granule, water or the on-aqueous liquid, perhaps is oil-in-water or water-in-oil liquid emulsion.
If solid carrier is used for oral administration, described preparation can be form with powder or piller and places the tablet of hard gelatin capsule or its to can be lozenge.
The scope of solid carrier amount is very wide, but is generally about 25mg to about 1g.
If use liquid vehicle, described preparation can be syrup, emulsion, soft gelatin capsule or aseptic injection liquid such as moisture or anhydrous liquid suspension or solution.
As needs, pharmaceutical composition of the present invention can comprise formula I, VII, VIII, IX, X or XI compound and foregoing other pharmacological active substances.
The representative instance of pharmaceutical formulation of the present invention is as follows:
1) contain the tablet of 5.0mg compound of the present invention (calculating) with free alkali:
Formula I, VII, VIII, IX, X or XI compound 5.0mg
Lactose 60mg
W-Gum 30mg
Hydroxypropylcellulose 2.4mg
Microcrystalline Cellulose 19.2mg
A type croscarmellose sodium 2.4mg
Magnesium Stearate 0.84mg
2) contain the tablet of 5.0mg compound of the present invention (calculating) with free alkali:
Formula I, VII, VIII, IX, X or XI compound 5.0mg
Lactose 46.9mg
W-Gum 23.5mg
Polyvidone 1.8mg
Microcrystalline Cellulose 14.4mg
A type croscarmellose sodium 1.8mg
Magnesium Stearate 0.63mg
3) every milliliter of syrup contains:
The compound 25mg of formula I, VII, VIII, IX, X or XI
Sorbyl alcohol 500mg
Hydroxypropylcellulose 15mg
Glycerine 50mg
Methyl p-hydroxybenzoate 1mg
Propylparaben 0.1mg
Ethanol 0.005mg
Essence 0.05mg
Soluble saccharin 0.5mg
Water adds to 1ml
4) every milliliter of injection solution contains:
The compound 0.5mg of formula I, VII, VIII, IX, X or XI
Sorbyl alcohol 5.1mg
Acetate 0.05mg
Soluble saccharin 0.5mg
Water adds to 1ml
The preparation of compound of the present invention
Scheme 1
Scheme 2
Figure A20048001101900812
The compound of the present invention of general formula I (wherein dotted line, q, s, U, Y, X, Z, R 1, R 1 ', R 2And R 3As above definition, therefore any dotted line, a, b, c, d, e, f, g, h, s, q, U, X, Z, Y, W, R 1, R 1 ', R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'Suc as formula the I definition) method preparation as described below shown in scheme 1 and scheme 2.
4 or 6 by R 2-(U) sThe general formula X II of-replacement and indoles and the indoline of XIII can commercially availablely obtain, existing in the literature describe or according to the known method preparation of this area chemical technology personnel [R.J.Sundberg " Pyrroles and their Benzo Derivatives:(iii) Synthesis and Applications (pyrroles and benzo derivative thereof: (iii) synthetic and use) ", Comprehensive Heterocyclic Chemistry, A.R.Katritzky, C.W.Rees (editor), the IV volume, the 313-376 page or leaf, Pergamon Press, 1984].By the known method of this area chemical technology personnel such as catalytic hydrogenation or use NaBH3CN reduction [S.M.Bromidge in suitable solvent (as acetate), S.Dabbs, D.T.Davies, D.M.Duckworth, J.Med.Chem.41 such as I.T.Forbes, 1998,1598-1612], the indoles of general formula X II can be converted into the indoline of general formula X III.By the known C-C linked reaction of this area chemical technology personnel (as Suzuki coupling, Stille coupling or other transition metal-catalyzed crosslinking reactions [D.W.Knight " Coupling Reactions Between sp2 Carbon Centers (linked reaction between the sp2 carbon center) ", Comprehensive Organic Synthesis, the 3rd volume, the 481-520 page or leaf, Pergamon Press 1991], s is 0 and R 2The general formula X II of the aryl that is specially but is not limited to replace as defined above or the heteroaryl of replacement or the compound of XIII can be by R 2Corresponding compounds preparation for I or Br.
By under suitable temperature, in the suitable solvent (as 1, the 2-ethylene dichloride), forming suitable blocking group (PG with reagent (as trifluoroacetic anhydride) reaction 1) [Protective Groups inOrganic Synthesis (blocking group in the organic synthesis); third edition T.W.Greene; P.G.M.Wuts; Wiley Interscience 1999]; protect the nitrogen of the compound indoline of general formula X III as trifluoroacetyl group (being the known TFA yls of this area chemical technology personnel) blocking group, the compound of preparation general formula X IV.
By the known method of this area chemical technology personnel [R.Behnisch " AromatischeNitro-Verbindungen ", Methoden der Organische Chemiel, Houben-Weyl, the 255th page, v.E16d, Thieme:1992] as under suitable temperature, in the suitable solvent (as diacetyl oxide, acetate, the vitriol oil or its mixture), reacting with concentrated nitric acid, 5 of the nitrated indoline of regioselectivity part are converted into the compound of the general formula X IV that obtains the compound of general formula X V like this.By the substitution reaction of the known nucleophilic aromatic of this area chemical technology personnel, for example with form-(U) s-R 2The suitable nucleophilic reagent of group (as thiophenol, alkyl sulfur compounds, alcohol, phenol, amine and the aniline of neutrality or deprotonation form) reaction, the nitro-compound of general formula X V (R wherein 2For halogen, especially be 0 for fluorine and s) (wherein U is O, NR can be converted into the compound of general formula X V 11Or S and R 2As above definition).By the known method for oxidation of this area chemical technology personnel, for example use catalyzer RuCl 3NaIO under existing 4Oxidation or with the oxidation of 3-chlorine peroxybenzoic acid, (wherein U is SO can to obtain general formula X V compound by the compound (wherein U is S) of general formula X V 2).
Under suitable temperature or supersound process, in the suitable solvent (as methyl alcohol, ethanol or tetrahydrofuran (THF)), in the presence of the suitable hydrogenation catalyst (as palladium carbon), in the presence of acid (as acetate or hydrochloric acid), hydrogen or ammonium formiate, can use appropriate reductant (as zinc or iron powder), with the nitroreduction in the compound of general formula X V, obtain the aniline of general formula X VI.Perhaps, under the condition that this area chemical technology personnel know, can use tindichloride or sodium hyposulfate as reductive agent.
Under suitable temperature (as room temperature or reflux temperature), suitable solvent is (as acetonitrile, tetrahydrofuran (THF), 1,2-ethylene dichloride or methylene dichloride) in, add or do not add alkali (as magnesium oxide, salt of wormwood, sodium hydride, trialkylamine, sodium alkoxide or potassium alcoholate or pyridine), by with suitable formation R 3-(Z) qThe electrophilic reagent of-X group (as the assorted aromatic ester of alkyl chloroformate, chloroformic acid aryl ester or chloroformic acid or urea chloride, acyl chlorides, acylbromide, acyl iodides, SULPHURYL CHLORIDE, isocyanic ester, carbonic anhydride, usefulness activator such as carbodiimide or the known activator activatory of other this areas chemical technology personnel carbonic acid) reaction, by the compound of the compound general formula X VII of general formula X VI, react for this area chemical technology personnel known.Remove blocking group PG according to this area known method of chemical technology personnel then 1[T.W.Greene, P.G.M.Wuts, WileyInterscience 1999 for Protective Groups in Organic Synthesis (blocking group in the organic synthesis), the third edition] obtain the compound of general formula X VIII.For example work as PG 1During for TFA, can be under suitable temperature, remove this group with the wet chemical hydrolysis in the suitable solvent (as methyl alcohol).
At last, under suitable temperature, in the suitable solvent (as methyl alcohol, ethanol, tetrahydrofuran (THF), acetonitrile or its mixture), appropriate reductant is (as NaBH 3CN) under the existence, add or do not add the acid (as acetate) of catalytic amount, by of aldehyde (wherein the Y as above define) reaction of the known reductive alkylation reaction of this area chemical technology personnel, form the compound of the present invention (R wherein of general formula I with aniline and the general formula YCHO of the general formula X VIII that obtains 1And R 1 'Be hydrogen).Perhaps, under the known condition of this area chemical technology personnel, by with general formula (Y) (R 1) (R 1 ') nucleophilic substitution reaction of suitable electrophilic reagent (wherein LG is suitable leavings group, as iodine, bromine or sulfonate radical (sulphonate)) of C-LG introduces (Y) (R 1) (R 1 ') the C-group, obtain the compound of the present invention of general formula I.
Perhaps, the compound of general formula X IX is commercially available, described or can be by the compound of general formula X V by going the protection preparation as mentioned above according to document.Then with the aldehyde generation reductive alkylation of itself and general formula YCHO or with aforesaid general formula (Y) (R 1) (R 1 ') the electrophilic reagent generation nucleophilic substitution reaction of C-LG, obtain the compound of general formula X X.As previously mentioned with nitroreduction, form the compound of general formula X XI then.Finally, be converted into the method for the compound of general formula X VII, obtain having the compound of the present invention of the general formula I of indoline part by above-mentioned compound with general formula X VI.
Choose wantonly under suitable temperature, in the suitable solvent (as toluene or dimethylbenzene), by the known dehydrogenation of this area chemical technology personnel, as use suitable reagent (as 2,3,5,6-tetrachloro-[1,4] benzoquinones, MnO 2) oxidation or at catalyzer (as palladium carbon or RuCl 2(PPh 3) 3) existence under catalytic dehydrogenation, can obtain having the compound of the present invention of the general formula I of indoles part by the indoline of general formula I.
Perhaps, compound of Formula I (wherein-(U) s-R 2Be connected 6 of indoline part) can be prepared as follows according to the route shown in the scheme 2:
Adopt the method identical,, obtain the compound of general formula X XII with suitable blocking group (as the TFA yl) protection 5-nitro indoline with the compound of above-mentioned general formula X IV.The method of compound that adopts above-mentioned preparation general formula X VI then obtains the compound of general formula X XIII with nitroreduction.Adopt the method for the compound of above-mentioned preparation general formula X VII then, use suitable formation R 3-(Z) qThe electrophilic reagent of-X is translated into the compound of general formula X XIV.By the electric aromatics replacement of in suitable solvent (as acetate), knowing through this area chemical technology personnel of regioselectivity parent with suitable electrophilic reagent (as N-chloro-succinimide, bromine, iodine, iodine chloride (iodochloride)), perhaps adopt the condition of the compound for preparing general formula X V nitrated, (wherein s is 0, and R to obtain the compound of general formula X XV 2Be NO 2Or halogen atom such as Cl, Br or I).
(wherein s is 0 to the compound of general formula X XV, and R 2Be the aryl that replaces as defined above or the heteroaryl of replacement) can be by the corresponding compounds of same general formula (R wherein 2Be I or Br) through the known C-C linked reaction preparation of aforesaid this area chemical technology personnel.Remove blocking group then as mentioned above, obtain the compound of general formula X XVI.
Finally, the compound of the present invention that has the general formula I of indoline part by the compound of general formula X XVI by aforesaid reductive alkylation or nucleophilic substitution reaction preparation.Equally can obtain having the compound of the present invention of the general formula I of indoles part by dehydrogenation as mentioned above by the indoline of general formula I.
Embodiment
The LC-MS analytical data derives from the PE Sciex API 150EX instrument that APPI (normal pressure photo-ionization) ion source and Shimadzu LC-8A/SLC-10A LC system are housed.Post: 30 * 4.6mm Waters Symmetry C18 post, packing material size is 3.5 μ m; Solvent system: A=water/trifluoroacetic acid (100: 0.05), B=water/acetonitrile/trifluoroacetic acid (5: 95: 0.03); Method: in 4 minutes with the flow velocity of 2ml/min 90%A-100%B linear gradient elution.Integration with UV (254nm) and ELSD trace is determined purity.Retention time (RT) in minute.
On identical instrument, be prepared type LC-MS purifying.Post: 50 * 20mm YMCODS-A post, packing material size are 5 μ m; Method: in 7 minutes with the flow velocity of 22.7ml/min 80%A-100%B linear gradient elution.Detect the collection cut by shunting MS.
Record under Bruker Avance DRX500 instrument, 500.13MHz 1H NMR wave spectrum.Use deuterochloroform (99.8%D) or methyl-sulphoxide (99.8%D) as solvent.With TMS as interior mark.Chemical displacement value is with the ppm value representation.Use following abbreviation to represent multiple NMR signal: s=is unimodal, d=doublet, t=triplet, q=quartet, the qui=quintet, h=septet, dd=doublet of doublet, dual three peaks of dt=, dual four peaks of dq=, triple three peaks of tt=, m=multiplet, br.=broad peak.
The preparation of intermediate
The preparation of general formula X XII and XIV intermediate
1-trifluoroacetyl group-5-nitro indoline
(5.51g 33.56mmol) 1, adds trifluoroacetic anhydride (20ml) in the suspension in the 2-ethylene dichloride (15ml) toward 5-nitro indoline.After 60 minutes with heptane (200ml) with the solution quencher that obtains, (two crops) filtering separation title compound obtains 7.12g in two batches, yield is 81.5%. 1H NMR(DMSO-d 6)：3.34(t，2H)，4.38(t，2H)，8.19(m，3H)。
1-trifluoroacetyl group-4-chlorine indoline
Similarly by 4-chlorine indoline preparation [S.M.Bromidge, S.Dabbs, D.T.Davies, D.M.Duckworth .J.Med.Chem.41 such as I.T.Forbes, 1998,1598-1612]. 1H NMR(DMSO-d 6)：3.26(t，2H)，4.34(t，2H)，7.27(d，1H)，7.34(t，1H)，8.01(d，1H)。
The preparation of general formula X V intermediate
1-trifluoroacetyl group-4-chloro-5-nitro indoline
(197mg 0.838mmol) adds the HNO of being fuming in the solution in diacetyl oxide (3ml) and acetate (0.3ml) toward 1-trifluoroacetyl group-4-chlorine indoline in a small amount of gradation in 5 hours 3Solution (0.4ml).In the reaction mixture impouring ice that obtains, with saturated NaHCO 3Aqueous solution neutralization, and use ethyl acetate extraction.Through SiO 2(10g) plunger filters this organic solution, and vacuum-evaporation is also passed through the flash chromatography on silica gel purifying, with heptane-ethyl acetate/heptane (1: 4) gradient elution, obtains the title compound 70mg of yellow solid shape, and yield is 31%.
1H NMR(DMSO-d 6)：3.33(t，2H)，4.42(t，2H)，8.10(s，2H)。
The preparation of general formula X X intermediate
1-(5-chlorothiophene-2-ylmethyl)-5-nitro indoline
(3.23g, 19.67mmol) (4.2g drips NaBH in solution 28.6mmol) with 5-chlorothiophene-2-formaldehyde toward the 5-nitro indoline in methyl alcohol (45ml) and acetate (8ml) in 10 minutes 3Methyl alcohol (8ml) solution of CN (0.9g).The reaction mixture stirring that obtains is spent the night.By filtering, methyl alcohol separates with water washing and vacuum-drying, finally obtains red crystalline solid shape title compound 4.6g, and yield is 79.3%.LC/MS (m/z) 293.9 ([M] +); RT=3.59, (UV, ELSD) 98%, 99.8% 1H NMR (DMSO-d 6): 3.04 (t, 2H), 3.62 (t, 2H), 4.68 (s, 2H), 6.72 (d, 1H), 6.98 (d, 1H), 7.01 (d, 1H), 7.85 (do not resolve m, 1H), 8.00 (dd, 1H).
Use suitable aldehyde to be prepared as follows compound similarly:
1-(4-luorobenzyl)-5-nitro indoline
Obtain yellow spicule 3.66g, yield is 72.2%.LC/MS(m/z)272.0([M] +)；RT＝3.35，(UV，ELSD)99％，100％。 1H NMR (DMSO-d 6): 3.06 (t, 2H), 3.61 (t, 2H), 4.52 (s, 2H), 6.63 (d, 1H), 7.18 (m, 2H), 7.35 (m, 2H), 7.83 (do not resolve m, 1H), 7.97 (dd, 1H).
The preparation of general formula X XI, XXII and XVI intermediate
The amino indoline of 1-(5-diuril phenol-2-ylmethyl)-5-
(4.013g, 13.62mmol) a small amount of gradation adds zinc powder (25g) in the solution, keeps temperature to be lower than 40 ℃ toward cold (ice/water-bath) intensively stirred 1-(5-chlorothiophene-2-ylmethyl)-5-nitro indoline in THF (100ml) and acetate (15ml).Remove the low temperature bath and at room temperature continue to stir and finish (1 hour) up to reaction.To obtain suspension through SiO 2(25g) plunger filters, and uses ethyl acetate as elutriant.And with the solution for vacuum evaporation that obtains.With the residue that obtains with saturated NaHCO 3The aqueous solution is handled, and uses ethyl acetate extraction, through Na 2SO 4Dry also vacuum-evaporation obtains deep green oily title compound 3.30g, and yield is 91.5%.
LC/MS(m/z)265.9([M+1] +)；RT＝1.85，(UV，ELSD)93％，100％。 1HNMR (DMSO-d 6): 2.73 (t, 2H), 3.08 (t, 2H), 4.25 (s, 2H), 4.40 (br.s, 2H, NH 2), 6.30 (dd, 1H), 6.41 (d, 1H), 6.43 (do not resolve m, 1H), 6.89 (d, 1H), 6.95 (d, 1H).
Be prepared as follows compound similarly:
The amino indoline of 1-(4-luorobenzyl)-5-
Will be through SiO 2The crude product that obtains after the filtration is dissolved in a spot of methyl alcohol, uses saturated NaHCO 3Aqueous solution chilling, after filtration, washing and vacuum-drying separate, and obtain the title compound 2.40g of intense violet color solid state, and yield is 93.2%.
LC/MS(m/z)265.9([M+1] +)；RT＝1.74，(UV，ELSD)87％，98％. 1H NMR(DMSO-d 6)：2.72(t，2H)，3.01(t，2H)，4.04(s，2H)，4.36(br.s，2H，NH 2)，6.28(d，1H)，6.34(d，1H)，6.44(s，1H)，7.14(t，2H)，7.38(t，2H).
The amino indoline of 1-trifluoroacetyl group-5-
By 1-trifluoroacetyl group-5-nitro indoline (6.67g, 25.65mmol) preparation title compound.Through SiO 2Crude product after the filtration does not need purifying to be used for next step.Obtain title compound 6.11g, yield is 100%.
LC/MS(m/z)230.1([M] +)；RT＝1.29，(UV，ELSD)97％，98％. 1H NMR(DMSO-d 6)：3.10(t，2H)，4.18(t，2H)，5.18(br.s，2H，NH 2)，6.43(dd，1H)，6.53(s，1H)，7.75(d，1H).
The amino indoline of 1-trifluoroacetyl group-4-chloro-5-
1H NMR(CDCl 3)：3.23(t，2H)，4.28(t，2H)，6.67(d，1H)，7.93(d，1H).
The preparation of general formula X XIV and XVII intermediate
3,3-dimethyl-N-[1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-butyryl Amine
Toward the 1-trifluoroacetyl group-5-of cold (ice/water-bath) amino indoline (2.69g, CH 11.7mmol) 2Cl 2(1.88g 14mmol), adds Et subsequently to add tertiary butyl Acetyl Chloride 98Min. in the solution 3N (4ml).Use saturated NaHCO after 5 minutes 3The aqueous solution is with this reaction mixture quencher and stirred 30 minutes.Organic layer is through SiO 2(20g) plunger filters, with ethyl acetate as elutriant and be evaporated to a little volume.Use the heptane chilling, separate obtaining white solid title compound 3.10g after filtration, yield is 81%.
LC/MS(m/z)329.2([M+1] +)；RT＝3.04，(UV，ELSD)97％，100％. 1H MR(DMSO-d 6)：1.02(s，9H)，2.18(s，2H)，3.22(t，2H)，4.26(t，2H)，7.38(dd，1H)，7.72(s，1H)，7.96(d，1H)，9.86(s，1H，NHCO).
Be prepared as follows compound by amino indoline of 1-trifluoroacetyl group-5-and suitable acyl chlorides or chloro-formic ester similarly:
N-[4-chloro-1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-dimethyl Butyramide
By the amino indoline preparation of 1-trifluoroacetyl group-4-chloro-5-.With the evaporation of described reaction mixture and need not to identify and be used for next step.
2,2-dimethyl-N-[1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-propionyl Amine
1H NMR(DMSO-d 6)：1.22(s，9H)，3.23(t，2H)，4.28(t，2H)，7.47(dd，1H)，7.71(s，1H)，7.96(d，1H)，9.26(s，1H，NHCO).
2-(4-fluorophenyl)-N-[1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-second Acid amides
LC/MS(m/z)367.0([M+1] +)；RT＝3.00，UV，ELSD)92％，99％. 1H NMR(DMSO-d 6)：3.22(t，2H)，3.63(s，2H)，4.27(t，2H)，7.15(t，2H)，7.36(dd，2H)，7.39(dd，1H)，7.69(s，1H)，7.97(d，1H)，10.24(s，1H，NHCO).
[1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-urethanum
Use 1, the 2-ethylene dichloride prepares title compound as solvent and pyridine as alkali.
LC/MS(m/z)302.1([M] +)；RT＝2.85(UV，ELSD)79％，100％. 1H NMR(DMSO-d 6)：1.24(t，3H)，3.22(t，2H)，4.12(q，2H)，4.26(t，2H)，7.31(br.d(unresolved dd)，1H)，7.49(s，1H)，7.94(d，1H)，9.70(s，1H，NHCO).
[1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-carboxylamine propyl ester
Use 1, the 2-ethylene dichloride prepares title compound as solvent and pyridine as alkali.
LC/MS(m/z)315.9([M] +)；RT＝3.11(UV，ELSD)89％，99％. 1H NMR(DMSO-d 6)：0.93(t，3H)，1.64(m，2H)，3.22(t，2H)，4.03(t，2H)，4.26(t，2H)，7.32(br.d(unresolved dd)，1H)，7.50(s，1H)，7.94(d，1H)，9.71(s，1H，NHCO).
The preparation of general formula X XV and XXVI intermediate
3,3-dimethyl-N-(6-nitro-2,3-dihydro-1H-indoles-5-yl)-butyramide
In 5 minutes toward 3 of the stirring of cold (ice/water-bath); 3-dimethyl-N-[1-(2,2, the 2-trifluoroacetyl group)-2; 3-dihydro-1H-indoles-5-yl]-(1.96g 5.98mmol) drips the HNO of being fuming to butyramide in the solution in diacetyl oxide (30ml) and acetate (5ml) 3(650mg, acetate 10.3mmol) (5ml) solution.To also use solid NaHCO in this reaction mixture impouring ice after 5 minutes 3Neutralization (a small amount of gradation adds and stirs up to stopping to produce gas).Filter, washing and vacuum-drying obtain 3 of yellow solid shape, 3-dimethyl-N-[6-nitro-1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-butyramide.
LC/MS(m/z)374.0([M+1] +)；RT＝3.45(UV，ELSD)94％，99％. 1H NMR(DMSO-d 6)：1.03(s，9H)，2.23(s，2H)，3.35(t，2H)，4.36(t，2H)，7.66(s，1H)，7.51(s，1H)，10.17(s，1H，NHCO).
This solid is dissolved in the methyl alcohol (30ml) again, adds K subsequently 2CO 3Water (2.0g) (7ml) solution.Color becomes scarlet by yellow immediately.Stir after 15 minutes, in this reaction mixture impouring ice/water, filtering separation obtains the title compound 1.52g of purple solid state, and yield is 91.8%.
LC/MS(m/z)277.0([M] +)；RT＝2.30(UV，ELSD)91％，99％. 1H NMR(CDCl 3)：1.10(s，9H)，2.29(s，2H)，3.10(t，2H)，3.63(t，2H)，4.80(very br.s，NH)，7.30(s，1H)，8.46(s，1H)，10.14(s，1H，NHCO).
Be prepared as follows compound similarly:
2,2-dimethyl-N-(6-nitro-2,3-dihydro-1H-indoles-5-yl)-propionic acid amide
LC/MS(m/z)264.1([M+1] +)；RT＝2.19(UV，ELSD)96％，95％. 1H NMR(DMSO-d 6)：1.19(s，9H)，3.00(t，2H)，3.51(dt，2H)，5.98(br.s，NH)，6.97(s，1H)，7.44(s，1H)，9.57(s，1H，NHCO).
2-(4-fluorophenyl)-N-(6-nitro-2,3-dihydro-1H-indoles-5-yl)-ethanamide
LC/MS(m/z)315.0([M] +)；RT＝2.33(UV，ELSD)87％，99％. 1H NMR(DMSO-d 6)：2.99(t，2H)，3.49(dt，2H)，3.62(s，2H)，6.00(br.s，NH)，6.91(s，1H)，7.15(t，2H)，7.28(s，1H)，7.33(dd，2H)，9.95(s，1H，NHCO).
[6-nitro-2,3-dihydro-1H-indoles-5-yl]-urethanum
LC/MS(m/z)250.9([M] +)；RT＝1.92(UV，ELSD)93％，98％. 1H NMR(DMSO-d 6)：1.19(t，3H)，2.99(t，2H)，3.50(dt，2H)，4.06(q，2H)，5.96(br.s，NH)，6.92(s，1H)，7.24(s，1H)，9.22(s，1H，NHCO).
[6-nitro-2,3-dihydro-1H-indoles-5-yl]-carboxylamine propyl ester
LC/MS(m/z)264.9([M] +)；RT＝2.36(UV，ELSD)93％，99％. 1H NMR(DMSO-d 6)：0.89(t，3H)，1.59(m，2H)，2.99(t，2H)，3.50(t，2H)，3.97(t，2H)，5.96(br.s，NH)，6.92(s，1H)，7.24(s，1H)，9.22(s，1H，NHCO).
3,3-dimethyl-N-(6-bromo-2,3-dihydro-1H-indoles-5-yl)-butyramide
Toward 3 of stirring, 3-dimethyl-N-[1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-(0.624g adds bromine (0.195ml, 1 equivalent) to butyramide in acetate 1.90mmol) (20ml) solution.Add more bromines (0.195ml) after 45 minutes.With this reaction mixture impouring Na 2SO 3In water (5g) (100ml) solution.After filtration, use saturated NaHCO 3The aqueous solution and water washing separated product finally obtain the N-[6-bromo-1-(2,2, the 2-trifluoroacetyl group)-2 of colorless solid shape, 3-dihydro-1H-indoles-5-yl]-3,3-amide dimethyl butyrate 0.555g, yield are 71%.
LC/MS(m/z)409.0([M+1] +)；RT＝3.38(UV，ELSD)97.5％，85.5％. 1H NMR(DMSO-d 6)：1.05(s，9H)，2.25(s，2H)，3.22(t，2H)，4.30(t，2H)，7.55(s，1H)，8.25(s，1H)，9.37(s，1H，NHCO).
This solid (100mg) is dissolved in the methyl alcohol (10ml) again, adds K subsequently 2CO 3Water (0.52g) (5ml) solution.After stirring 5 minutes under 50 ℃, in this reaction mixture impouring ice/water mixture, obtain colorless solid shape title compound 0.057g by filtering separation, yield is 75%.
LC/MS(m/z)313.0([M+1] +)；RT＝1.71，(UV，ELSD)97.5％，98.9％.
The preparation of general formula X VIII intermediate
N-(4-chloro-2,3-dihydro-1H-indoles-5-yl)-3, the 3-amide dimethyl butyrate
Toward rough N-[4-chloro-1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-3, add K in MeOH (10ml) solution of 3-amide dimethyl butyrate (about 100mg) 2CO 3Water (0.5g) (2ml) solution.50 ℃ with the mixture heating up that obtains 5 minutes, use ethyl acetate and water quencher subsequently.This organic solution is through SiO 2(5g) filter also vacuum-evaporation, obtain title compound 20mg.This thick product does not need purifying to be used for next step.
LC/MS(m/z)267.1([M+1] +)；RT＝1.61(UV，ELSD)45％，78％.
N-(2,3-dihydro-1H-indoles-5-yl)-2-(4-fluorophenyl)-ethanamide
Toward 2-(4-fluorophenyl)-N-[1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-(1.3g adds K in methyl alcohol 3.55mmol) (50ml) solution to ethanamide 2CO 3Water (7.6g) (20ml) solution.This reaction mixture in the impouring water, separates obtaining title compound 0.742g subsequently after filtration 50 ℃ of insulations 5 minutes, and yield is 77.4%.
LC/MS(m/z)271.0([M+1] +)；RT＝1.42，(UV，ELSD)94.5％，98.7％. 1H NMR(DMSO-d 6)：2.85(t，2H)，3.36(t，2H)，3.55(s，2H)；5.28(br，1H，NH)；6.41(d，1H)；7.06(dd，1H)；7.12(t，2H)；7.28(d，1H)；7.35(dd，2H)；9.75(s，1H，NHCO).
Similarly by 3,3-dimethyl-N-[1-(2,2, the 2-trifluoroacetyl group)-2,3-dihydro-1H-indoles-5-yl]-butyramide is prepared as follows compound:
N-(2,3-dihydro-1H-indoles-5-yl)-3,3-dimethyl-butyramide
LC/MS(m/z)232.9([M+1] +)；RT＝1.43，(UV，ELSD)94.4％，88.1％. 1H NMR(DMSO-d 6)：1.00(s，9H)；2.09(s，2H)；2.84(t，2H)；3.37(t，2H)；5.25(br，1H，NH)；6.41(d，1H)；7.02(dd，1H)；7.29(d，1H)；9.34(s，1H，NHCO).
Compound of the present invention
Embodiment 1
1a N-[4-chloro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-diformazan The base butyramide
Toward N-(4-chloro-2,3-dihydro-1H-indoles-5-yl)-3, add NaBH in methyl alcohol (0.3ml) solution of 3-amide dimethyl butyrate (10mg), 4-trifluoromethylated benzaldehyde (0.06ml) and acetate (0.03ml) 3CN (100mg).After 60 minutes, with reaction mixture at ethyl acetate and saturated NaHCO 3Distribute between the aqueous solution.This organic layer is through SiO 2(2g) plunger filters, evaporation, and, obtain the title compound 11mg of colorless solid shape by preparation type LC/MS purifying.
LC/MS(m/z)425.2([M+1] +)；RT＝4.01，(UV，ELSD)95％，99％. 1H NMR(DMSO-d 6)：1.03(s，9H)，2.16(s，2H)，2.97(t，2H)，3.40(t，2H)，4.41(s，2H)，6.48(d，1H)，7.03(d，1H)，7.56(d，2H)，7.72(d，2H)，9.12(s，1H，NHCO).
Use 5-chloro-2 thiophene carboxaldehyde to be prepared as follows compound similarly:
1b N-[4-chloro-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3,3-two Methylbutyryl amine
LC/MS(m/z)397.0(M+1] +)；RT＝3.91，(UV，ELSD)97％，99％. 1H NMR(DMSO-d 6)：1.03(s，9H)，2.17(s，2H)，2.92(t，2H)，3.37(t，2H)，4.46(s，2H)，6.60(d，1H)，6.95(d，1H)，6.99(d，1H)，7.07(d，1H)，9.12(s，1H，NHCO).
Embodiment 2
2a[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-the carboxylamine propyl ester(0.2M, 0.15ml) the middle propyl chloroformate (0.02ml or about 20mg) that adds adds pyridine (0.03ml) to the acetonitrile solution of the amino indoline of the 1-(4-luorobenzyl) of past cold (ice/water-bath)-5-subsequently.At room temperature this reaction mixture was placed 60 minutes vacuum-evaporation subsequently.Separate by preparation type LC/MS, obtain title compound 5.8mg, yield is 59%.LC/MS(m/z)329.1([M+1] +)；RT＝2.68，(UV，ELSD)94％，99％。
Similarly by amino indoline of corresponding 5-and commercially available suitable chloro-formic ester, urea chloride, SULPHURYL CHLORIDE, acyl chlorides, tert-Butyl dicarbonate (Boc 2O) or isocyanic ester obtain following compound, these compounds are listed in the following table 1.Under the situation of using chloro-formic ester, urea chloride and SULPHURYL CHLORIDE, use pyridine as alkali.Under the situation of using acyl chlorides, use triethylamine as alkali.Using isocyanic ester and Boc 2Under the situation of O, do not use alkali.
2b N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-C-phenyl-Toluidrin
LC/MS(m/z)395.3([M-1] +)；RT＝3.17，(UV，ELSD)80％，100％。
2c 4-fluoro-N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-benzamide
LC/MS(m/z)365.4([M+1] +)；RT＝2.90，(UV，ELSD)96％，100％。
2d N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate
LC/MS(m/z)341.1([M+1] +)；RT＝2.79，(UV，ELSD)94％，100％。
2e N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-2-thiophene-2-yl acetamide
LC/MS(m/z)367.1([M+1] +)；RT＝2.72，(UV，ELSD)93％，100％。
2f N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide
LC/MS(m/z)379.3([M+1] +)；RT＝2.82，(UV，ELSD)95％，100％。
2g 3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-1, the 1-diisopropyl The base urea
LC/MS(m/z)392.3([M+1] +)；RT＝3.14，(UV，ELSD)75％，89％。
2h N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-morpholine-4-first Acid amides
LC/MS(m/z)378.2([M+1] +)；RT＝2.33，(UV，ELSD)97％，100％。
2i N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-tetramethyleneimine-1-first Acid amides
LC/MS(m/z)362.0([M+1] +)；RT＝2.48，(UV，ELSD)83％，99％。
2j [1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-carboxylamine 2-benzyl Oxygen base ethyl ester
LC/MS(m/z)442.1([M] +)；RT＝3.52，(UV，ELSD)62％，86％。
2k 3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-1-methyl isophthalic acid-third The base urea
LC/MS(m/z)364.3([M+1] +)；RT＝2.73，(UV，ELSD)94％，100％。
2l [1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-carboxylamine uncle fourth Ester
LC/MS(m/z)364.3([M] +)；RT＝3.50，(UV，ELSD)97％，100％。
2m N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-C-phenyl-first Sulphonamide
LC/MS(m/z)418.2([M] +)；RT＝3.44，(UV，ELSD)98％，100％。
2n N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butane-1-sulphur Acid amides
LC/MS(m/z)384.1([M] +)；RT＝3.43，(UV，ELSD)98％，100％。
2o N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 4-fluorobenzoyl Amine
LC/MS(m/z)386.0([M] +)；RT＝3.35，(UV，ELSD)91％，100％。
2p N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2, the 2-dimethyl Propionic acid amide
LC/MS(m/z)349.0([M+1] +)；RT＝3.21，(UV，ELSD)94％，100％。
2q N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-phenoxy group second Acid amides
LC/MS(m/z)398.0([M] +)；RT＝3.46，(UV，ELSD)80％，100％。
2r N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-dimethyl Butyramide
LC/MS(m/z)362.1([M] +)；RT＝3.34，(UV，ELSD)84％，99％。
2s N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide
LC/MS(m/z)335.0([M+1] +)；RT＝2.95，(UV，ELSD)78％，99％。
2t N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the pentamethylene formyl Amine
LC/MS(m/z)361.1([M+1] +)；RT＝3.22，(UV，ELSD)84％，99％。
2u N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-thiophene-2-base Ethanamide
LC/MS(m/z)388.1([M] +)；RT＝3.22，(UV，ELSD)76％，98％。
2v N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-Isonicotinamide
LC/MS(m/z)370.0([M+1] +)；RT＝2.22，(UV，ELSD)96％，100％。
2w N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 4-dimethyl Aminobenzamide
LC/MS(m/z)412.0([M+1] +)；RT＝3.09，(UV，ELSD)87％，100％。
2x N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorobenzene Base)-ethanamide
LC/MS(m/z)401.0([M+1] +)；RT＝3.31，(UV，ELSD)84％，100％。
2y N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 6-trifluoromethyl Niacinamide
LC/MS(m/z)437.1([M] +)；RT＝3.46，(UV，ELSD)90％，99％。
The 2z 1-tertiary butyl-3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-urea
LC/MS(m/z)364.3([M+1] +)；RT＝2.80，(UV，ELSD)97％，100％。
2aa 1-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 3-ethyl carbamide
LC/MS(m/z)335.1([M] +)；RT＝2.34，(UV，ELSD)96％，100％。
2ab 1-benzyl-3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-urea
LC/MS(m/z)398.2([M+1] +)；RT＝2.85，(UV，ELSD)84％，100％。
2ac 1-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 3-phenthylcarbamide
LC/MS(m/z)411.9([M+1] +)；RT＝3.00，(UV，ELSD)87％，97％。
2ad 1-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3-thiophene-2- The base urea
LC/MS(m/z)390.0([M+1] +)；RT＝3.01，(UV，ELSD)94％，92％。
2ae 1-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3-thiophene-3- The base urea
LC/MS(m/z)390.2([M+1] +)；RT＝2.98，(UV，ELSD)96％，100％。
2af [1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-carboxylamine third Ester
LC/MS(m/z)351.2([M] +)；RT＝3.48，(UV，ELSD)94.0％，98.0％. 1H NMR(DMSO-d 6)：0.92(t，3H)；1.62(sextet，2H)；2.84(t，2H)；3.22(t，2H)，3.89(t，2H)，4.38(s，2H)，6.59(d，1H)；6.92(d，1H)；6.98(d，1H)；7.07(br.d(dd)，1H)；7.18(br.s，1H)；9.20(brs，1H，NH).
The chloro-formic ester that table 1. uses in the preparation of 2a-2af compound of the present invention, SULPHURYL CHLORIDE, urea chloride, acyl chlorides and isocyanic ester
Compound of the present invention Reagent Molecular weight Manufacturer Catalog number (Cat.No.)
2a The chloroformic acid n-propyl 122.55 Aldrich 24，946-7
2b α-toluene sulfonyl chloride 190.649 Aldrich 15，971-9
2c The 4-fluorobenzoyl chloride 158.559 Aldrich 11，994-6
2d Tertiary butyl Acetyl Chloride 98Min. 134.605 Aldrich B8，880-2
2e Thiophene-2-Acetyl Chloride 98Min. 160.624 Aldrich 19，599-5
2f 4-fluorophenyl Acetyl Chloride 98Min. 172.585 Aldrich 46，695-6
2g The diisopropylaminoethyl formyl chloride 163.647 Aldrich S31，027-1
2h Morpholine-4-formyl chloride 149.576 Aldrich 34，829-5
2i 1-pyrrolidine formyl chlorine 133.577 Aldrich 20，635-0
2j Chloroformic acid 2-benzyloxy ethyl ester 214.647 Aldrich 52，514-6
2k N-sec.-propyl-N-methyl-urea chloride 135.59 Lundbeck C0005221
2l Tert-Butyl dicarbonate 218.247 Fluka 34660
2m α-toluene sulfonyl chloride 190.649 Aldrich 15，971-9
2n The fourth SULPHURYL CHLORIDE 156.632 Aldrich 26，360-5
2o The 4-fluorobenzoyl chloride 158.559 Aldrich 11，994-6
2p Trimethyl-acetyl chloride 120.578 Aldrich T7，260-5
2q The phenoxy group Acetyl Chloride 98Min. 170.594 Aldrich 15，862-3
2r Tertiary butyl Acetyl Chloride 98Min. 134.605 Aldrich B8，880-2
2s Butyryl chloride 106.551 Aldrich 10，961-4
2t The pentamethylene formyl chloride 132.589 Aldrich 32，831-6
2u Thiophene-2-Acetyl Chloride 98Min. 160.624 Aldrich 19，599-5
2v Different nicotinoyl chlorine hydrochloride 178.018 Aldrich 22，875-3
2w 4-dimethylamino Benzoyl chloride 183.637 Aldrich 52，611-8
2x 4-fluorophenyl Acetyl Chloride 98Min. 172.585 Aldrich 46，695-6
2y 6-(trifluoromethyl) nicotinoyl chlorine 209.554 Fluorochem 9368
2z Tert-butyl isocyanate 99.132 Aldrich 14，445-2
2aa Ethyl isocyanate 71.08 Aldrich E3，330-0
2ab Benzyl mustard oil 133.149 Aldrich 22，726-9
2ac Isocyanic acid phenenyl B ester 147.176 Aldrich 45，617-9
2ad Isocyanic acid 2-thiophene ester 125.151 Maybridge CC13006
2ae Isocyanic acid 3-thiophene ester 125.151 Maybridge CC13106
2af The chloroformic acid n-propyl 122.55 Aldrich 24，946-7
Embodiment 3
3a 2,2-dimethyl-N-[6-nitro-1-(4-trifluoromethyl benzyl)-2, and 3-dihydro-1H-indoles- The 5-yl]-propionic acid amide
In 3 hours, be divided into 4 parts toward 2 of stirring, 2-dimethyl-N-(6-nitro-2,3-dihydro-1H-indoles-5-yl)-(0.379g adds 4-trifluoromethylated benzaldehyde (0.8ml), acetate (0.8ml) and NaBH to propionic acid amide in methyl alcohol 1.44mmol) (25ml) solution 3Methyl alcohol (10ml) solution of CN (0.8g) is up to reacting completely.The reaction mixture vacuum concentration that obtains to small volume, is used saturated NaHCO 3Aqueous solution chilling and supersound process several minutes.Separate after filtration, obtain the title compound 0.574g of red solid shape, yield is 95%.
LC/MS(m/z)422.1([M+1] +)；RT＝4.11，(UV，ELSD)96％，99％. 1H NMR (DMSO-d 6)：1.20(s，9H)，3.04(t，2H)，3.42(t，2H)，4.49(s，2H)，7.09(s，1H)，7.48(s，1H)，7.57(d，2H)，7.73(d，2H)，9.62(s，1H，NHCO).
Be prepared as follows compound similarly:
3b N-[1-(5-chlorothiophene-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indoles-5-yl]-2,2- The dimethyl propylene acid amides
LC/MS(m/z)394.0([M+1] +；RT＝4.07，(UV，ELSD)97％，98％. 1H NMR(DMSO-d 6)：1.20(s，9H)，3.00(t，2H)，3.41(t，2H)，4.55(s，2H)，6.97(d，1H)，7.01(d，1H)，7.22(s，1H)，7.47(s，1H)，9.62(s，1H，NHCO).
3c 2-(4-fluorophenyl)-N-[6-nitro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles -5-yl]-ethanamide
LC/MS(m/z)474.2([M+1] +)；RT＝3.89，(UV，ELSD)80％，97％.
3d N-[1-(5-chlorothiophene-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indoles-5-yl]-2- (4-fluorophenyl)-ethanamide
LC/MS(m/z)445.1([M] +)；RT＝3.88，(UV，ELSD)79.8％，98.9％. 1H NMR(DMSO-d 6)：2.98(t，2H)；3.41(t，2H)，3.63(s，2H)，4.54(s，2H)，6.96(d，1H)；7.0(d，1H)；7.16(t，2H)；7.17(s，1H)；7.31(s，1H)；7.34(dd，2H)；10.03(s，1H，NH).
3e N-[1-(5-chlorothiophene-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indoles-5-yl]-3,3- Amide dimethyl butyrate
LC/MS(m/z)407.1([M] +)；RT＝4.07，(UV，ELSD)72.4％，98.7％. 1H NMR(DMSO-d 6)：1.01(s，9H)；2.16(s，2H)；2.99(t，2H)；3.41(t，2H)，4.54(s，2H)，6.98(d，1H)；7.01(d，1H)；7.14(s，1H)；7.23(s，1H)；9.76(s，1H，NH).
Embodiment 4
4a N-[6-amino-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3,3- Amide dimethyl butyrate
Toward 3, add NaBH in methyl alcohol (5ml) solution of 3-dimethyl-N-(6-nitro-2,3-dihydro-1H-indoles-5-yl)-butyramide (15mg), 5-chloro-2 thiophene carboxaldehyde (50mg) and acetate (0.1ml) 3CN (200mg).After 30 minutes, this reaction mixture is concentrated into small volume in a vacuum, between ethyl acetate and water, distributes subsequently.With 1M hydrochloric acid and saturated NaHCO 3This organic solution of solution washing and evaporation in a vacuum.
The resistates that obtains is dissolved in tetrahydrofuran (THF) (10ml) and the acetate (2ml), adds zinc powder (1g) subsequently.With the suspension supersound process that obtains 5 minutes, add zinc powder (0.5g) again and continued supersound process 2 minutes.Through SiO 2(2g) plunger filters resulting suspension, and evaporation separates by preparation type LC/MS, obtains the title compound 6.5mg of colorless solid shape, and yield is 32%.
LC/MS (m/z) 378.0 ([M+1] +); RT=2.36, (UV, ELSD) 93%, 98%.%. 1H NMR (DMSO-d 6): 1.03 (s, 9H), 2.17 (s, 2H), 2.82 (t, 2H), 3.30 (t, 2H), 3.55 (very wide s, NH 2Water), 4.38 (s, 2H), 6.27 (s, 1H), 6.81 (s, 1H), 6.93 (d, 1H), 7.00 (d, 1H), 9.27 (br.s, 1H, NHCO).
4b N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2,2-two Methyl propanamide
Method according to the amino indoline of above-mentioned preparation 1-(5-chlorothiophene-2-ylmethyl)-5-(referring to the preparation of general formula X XI intermediate), by above-mentioned 2,2-dimethyl-N-[6-nitro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-propionic acid amide (referring to embodiment 3) is by zinc powder reduction prepared in reaction title compound.Through SiO 2After the filtration, handle thick solid residue with ethyl acetate and heptane, and obtain colorless solid shape title compound 0.375g by filtering separation, yield is 71%.
LC/MS(m/z)392.3([M+1] +)；RT＝2.38，(UV，ELSD)97％，99％. 1H NMR(DMSO-d 6)：1.20(s，9H)，2.77(t，2H)，3.25(t，2H)，4.28(s，2H)，4.34(s，2H，NH 2)，5.96(s，1H)，6.64(s，1H)，7.56(d，2H)，7.71(d，2H)，8.47(s，1H，NHCO).
Corresponding various 6-nitro indoline by general formula X XV are prepared as follows compound in two steps similarly, adopt embodiment 3 described methods with suitable aldehyde reductive alkylation, subsequently according to above-mentioned method zinc powder reduction.
4c N-[6-amino-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2,2- The dimethyl propylene acid amides
LC/MS(m/z)364.2([M+1] +)；RT＝2.19，(UV，ELSD)98％，99％. 1H NMR(DMSO-d 6)：1.20(s，9H)，2.72(t，2H)，3.21(t，2H)，4.33(s，2H)，4.39(br.s，2H，NH 2)，6.07(s，1H)，6.64(s，1H)，6.91(d，1H)，6.98(d，1H)，8.48(s，1H，NHCO).
4d N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorine Phenyl)-ethanamide
LC/MS(m/z)444.0([M+1] +)；RT＝2.65，(UV，ELSD)95％，99％. 1H NMR(DMSO-d 6)：2.76(t，2H)，3.24(t，2H)，3.57(s，2H)，4.26(s，2H)，4.51(br.s，2H，NH 2)，5.92(s，1H)，6.73(s，1H)，7.14(t，2H)，7.36(dd，2H)，7.55(d，2H)，7.71(dd，2H)，9.08(s，1H，NHCO).
4e N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3,3-two Methylbutyryl amine
LC/MS(m/z)406.0([M+1] +)；RT＝2.58，(UV，ELSD)97.4％，99.0％. 1H NMR(DMSO-d 6)：1.02(s，9H)；2.12(s，2H)；2.78(t，2H)；3.24(t，2H)；4.28(s，2H)，4.48(s，2H，NH 2)；5.93(s，1H)；6.74(s，1H)；7.56(d，2H)；7.71(d，2H)；8.81(s，1H，NH).
4f N-[6-amino-1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-dimethyl butyrate Acid amides
LC/MS(m/z)356.0([M+1] +)；RT＝2.26，(UV，ELSD)96.7％，98.9％. 1H NMR(DMSO-d 6)：1.02(s，9H)；2.13(s，2H)；2.73(t，2H)；3.18(t，2H)；4.16(s，2H)，4.48(s，2H，NH 2)；5.98(s，1H)；6.71(s，1H)；7.17(t，2H)；7.36(dd，2H)；8.80(s，1H，NH).
4g N-[6-amino-1-(3-fluoro-4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]- 3, the 3-amide dimethyl butyrate
LC/MS(m/z)424.0([M+1] +)；RT＝2.58，(UV，ELSD)92.0％，98.8％. 1H NMR(DMSO-d 6)：1.01(s，9H)；2.12(s，2H)；2.79(t，2H)；3.28(t，2H)；4.27(s，2H)，4.48(s，2H，NH 2)；5.90(s，1H)；6.75(s，1H)；7.39(d，1H)；7.45(d，1H)；7.78(t，1H)；8.80(s，1H，NH).
Embodiment 5
5a N-[1-(5-chlorothiophene-2-ylmethyl)-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate
Toward N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the methyl-sulphoxide-d of 3-amide dimethyl butyrate (20mg) 6(0.6ml) add 2,3,5 in the solution, 6-tetrachloro [1,4] benzoquinones (65mg).Under 70 ℃,, allow its cooling, impouring NaHSO with the mixture heating up that obtains 5 minutes 3In water (1g) (5ml) solution, add 25% the ammoniacal liquor (5ml) and 10% the NaOH aqueous solution (5ml) subsequently.Use CH 2Cl 2(3 * 10ml) extract this mixture, and water and 1M HCl wash the organic solution of this merging, through SiO 2(10g) plunger filters, and with ethyl acetate/heptane (1: 1) wash-out.Crude product after the evaporation obtains the title compound 5mg of colorless solid shape by preparation type LC/MS purifying.
LC/MS(m/z)361.1([M+1] +)；RT＝3.43，(UV，ELSD)96％，99％. 1H NMR (DMSO-d 6)：1.03(s，9H)，2.16(s，2H)，5.51(s，2H)，6.41(d，1H)，6.95(d，1H)，6.98(d，1H)，7.21(dd，1H)，7.41(d，1H)，7.44(d，1H)，7.87(d，1H)，9.60(s，1H，NHCO).
Embodiment 6
6a N-[6-bromo-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-diformazan The base butyramide
According to method described in the embodiment 1, by 3,3-dimethyl-N-(6-bromo-2,3-dihydro-1H-indoles-5-yl)-butyramide (25mg) and 4-trifluoromethylated benzaldehyde (64mg) prepare title compound 16.7mg.LC/MS(m/z)469.1([M+1] +)；RT＝3.99，(UV，ELSD)97.4％，95.1％。
Use suitable aldehyde to be prepared as follows compound similarly:
6b N-[6-bromo-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3,3-two Methylbutyryl amine
Obtain title compound 16.8mg.LC/MS(m/z)443.1([M+1] +)；RT＝3.92，(UV，ELSD)96.3％，94.9％。
Embodiment 7
Universal method: in acetaldehyde (25mg or 0.025ml) and the suitable mixture of indoline (7mg) in methyl alcohol (0.5ml), add NaBH 3Methyl alcohol (0.2ml) solution of CN (20mg) adds acetate (0.05ml) subsequently.With the solution that obtains or suspension supersound process 5 minutes and in 50 ℃ of insulations 60 minutes down, evaporation in a vacuum subsequently.Resistates is dissolved in DMSO (2.5ml) and the water (100ml).By preparation type LC/MS separated product.
By N-(2,3-dihydro-1H-indoles-5-yl)-3,3-dimethyl-butyramide (7a-7z compound) or N-(2,3-dihydro-1H-indoles-5-yl)-2-(4-fluorophenyl)-ethanamide (7aa-7aw compound) and suitable aldehyde (seeing table 2) are prepared as follows compound:
7a N-[1-(4-benzyl chloride base)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate
LC/MS(m/z)357.2([M+1] +)；RT＝3.17，(UV，ELSD)77.1％，97.2％。
7b 3,3-dimethyl-N-[1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-Ding Acid amides
LC/MS(m/z)391.4([M+1] +)；RT＝3.44，(UV，ELSD)91.8％，99.6％。
7c N-[1-(4-isopropyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3,3-dimethyl butyryl Amine
LC/MS(m/z)365.4([M+1] +)；RT＝3.13，(UV，ELSD)89.4％，99.2％。
7d N-[1-(3-fluoro-4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-diformazan The base butyramide
LC/MS(m/z)409.2([M+1] +)；RT＝3.60，(UV，ELSD)69.6％，98.2％。
7e N-[1-(the 6-chlorobenzene is [1,3] dioxole-5-ylmethyl also)-2,3-dihydro-1H-indoles -5-yl]-3, the 3-amide dimethyl butyrate
LC/MS(m/z)401.0([M+1] +)；RT＝3.22，(UV，ELSD)94.6％，99.5％。
7f N-[1-(3,5-dimethyl-1-phenyl-1H-pyrazoles-4-ylmethyl)-2,3-dihydro-1H-indoles -5-yl]-3, the 3-amide dimethyl butyrate
LC/MS(m/z)417.2([M+1] +)；RT＝2.23，(UV，ELSD)93.3％，98.9％。
7g N-[1-(2-chloro-5-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-diformazan The base butyramide
LC/MS(m/z)425.2([M+1] +)；RT＝3.79，(UV，ELSD)75.4％，98.4％。
7h N-{1-[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-ylmethyl]-2, the 3-dihydro -1H-indoles-5-yl }-3, the 3-amide dimethyl butyrate
LC/MS(m/z)467.3([M+1] +)；RT＝2.71，(UV，ELSD)95.2％，99.8％。
7j 3,3-dimethyl-N-[1-(6-is to tolyloxy-pyridin-3-yl methyl)-2,3-dihydro-1H- Indoles-5-yl]-butyramide
LC/MS(m/z)430.2([M+1] +)；RT＝3.15，(UV，ELSD)76.6％，97.9％。
7k N-{1-[6-(4-chloro-phenyl-sulfenyl)-pyridin-3-yl methyl]-2,3-dihydro-1H-indoles-5- Base }-3, the 3-amide dimethyl butyrate
LC/MS(m/z)466.0([M+1] +)；RT＝3.45，(UV，ELSD)69.3％，97.1％。
7l N-{1-[6-(4-cyano-benzene oxygen)-pyridin-3-yl methyl]-2,3-dihydro-1H-indoles-5- Base }-3, the 3-amide dimethyl butyrate
LC/MS(m/z)441.4([M+1] +)；RT＝2.98，(UV，ELSD)79.8％，98.9％。
7m 3,3-dimethyl-N-[1-(6-5-flumethiazine-3-ylmethyl)-2,3-dihydro-1H-Yin Diindyl-5-yl]-butyramide
LC/MS(m/z)392.4([M+1] +)；RT＝3.10，(UV，ELSD)82.5％，99.5％。
7p 3,3-dimethyl-N-[1-(3-methyl-benzo [b] thiophene-2-ylmethyl)-2,3-dihydro-1H- Indoles-5-yl]-butyramide
LC/MS(m/z)393.3([M+1] +)；RT＝3.56，(UV，ELSD)72.8％，97.9％。
7q N-[1-(6-fluoro-4H-benzo [1,3] dioxine-8-ylmethyl)-2,3-dihydro-1H- Indoles-5-yl]-3, the 3-amide dimethyl butyrate
LC/MS(m/z)399.2([M+1] +)；RT＝2.75，(UV，ELSD)84.9％，99.3％。
7s 3,3-dimethyl-N-[1-(6-phenoxypyridines-3-ylmethyl)-2, and 3-dihydro-1H-indoles- The 5-yl]-butyramide
LC/MS(m/z)416.2([M+1] +)；RT＝2.98，(UV，ELSD)67.5％，96.5％。
7u 3,3-dimethyl-N-[1-(3-methyl-5-phenyl-isoxazole-4-base methyl)-2, and the 3-dihydro- 1H-indoles-5-yl]-butyramide
LC/MS(m/z)404.4([M+1] +)；RT＝3.24，(UV，ELSD)97.6％，99.9％。
7v N-(1-benzo [b] thiophene-2-ylmethyl-2,3-dihydro-1H-indoles-5-yl)-3, the 3-diformazan The base butyramide
LC/MS(m/z)379.3([M+1] +)；RT＝3.44，(UV，ELSD)71.8％，97.6％。
7w N-{1-[1-(4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-ylmethyl]-2,3-dihydro-1H- Indoles-5-yl }-3, the 3-amide dimethyl butyrate
LC/MS(m/z)421.4([M+1] +)；RT＝2.24，(UV，ELSD)79.5％，98.9％。
7y 3,3-dimethyl-N-[1-(5-thiotolene-2-ylmethyl)-2,3-dihydro-1H-indoles-5- Base]-butyramide
LC/MS(m/z)343.1([M+1] +)；RT＝2.84，(UV，ELSD)59.9％，89.1％。
7z 3,3-dimethyl-N-[1-(4-pyrroles-1-base-benzyl)-2,3-dihydro-1H-indoles-5-yl]- Butyramide
LC/MS(m/z)388.3([M+1] +)；RT＝3.03，(UV，ELSD)81.1％，99.5％。
7aa N-[1-(4-benzyl chloride base)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide
LC/MS(m/z)395.1([M+1] +)；RT＝2.99，(UV，ELSD)93.4％，93.1％。
7ab 2-(4-fluorophenyl)-N-[1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]- Ethanamide
LC/MS(m/z)429.1([M+1] +)；RT＝3.24，(UV，ELSD)76.6％，87.4％。
7ac 2-(4-fluorophenyl)-N-[1-(4-isopropyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-second Acid amides
LC/MS(m/z)403.1([M+1] +)；RT＝2.96，(UV，ELSD)91.5％，83.7％。
7ad 2-(4-fluorophenyl)-N-[1-(3-fluoro-4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles- The 5-yl]-ethanamide
LC/MS(m/z)447.2([M+1] +)；RT＝3.36，(UV，ELSD)79.3％，90.4％。
7ae N-[1-(the 6-chlorobenzene is [1,3] dioxole-5-ylmethyl also)-2,3-dihydro-1H-Yin Diindyl-5-yl]-2-(4-fluorophenyl)-ethanamide
LC/MS(m/z)439.0([M+1] +)；RT＝3.02，(UV，ELSD)94.0％，92.2％。
7af N-[1-(3,5-dimethyl-1-phenyl-1H-pyrazoles-4-ylmethyl)-2,3-dihydro-1H-Yin Diindyl-5-yl]-2-(4-fluorophenyl)-ethanamide
LC/MS(m/z)455.0([M+1] +)；RT＝2.14，(UV，ELSD)97.1％，91.4％。
7ag N-[1-(2-chloro-5-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorine Phenyl)-ethanamide
LC/MS(m/z)463.1([M+1] +)；RT＝3.53，(UV，ELSD)98.3％，95.3％。
7ah N-{1-[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-ylmethyl]-2,3-two Hydrogen-1H-indoles-5-yl }-2-(4-fluorophenyl)-ethanamide
LC/MS(m/z)503.3([M-1] +)；RT＝2.55，(UV，ELSD)92.3％，90.5％。
7ai N-{1-[6-(4-cyano-benzene oxygen)-pyridin-3-yl methyl]-2,3-dihydro-1H-indoles-5- Base }-2-(4-fluorophenyl)-ethanamide
LC/MS(m/z)479.1([M+1] +)；RT＝2.81，(UV，ELSD)84.1％，87.1％。
7al 2-(4-fluorophenyl)-N-[1-(3-methyl-benzo [b] thiophene-2-ylmethyl)-2, the 3-dihydro- 1H-indoles-5-yl]-ethanamide
LC/MS(m/z)431.2([M+1] +)；RT＝3.34，(UV，ELSD)60.2％，88.8％。
7am N-[1-(6-fluoro-4H-benzo [1,3] dioxine-8-ylmethyl)-2, the 3-dihydro- 1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide
LC/MS(m/z)437.0([M+1] +)；RT＝2.62，(UV，ELSD)79.7％，83.6％。
7ao 2-(4-fluorophenyl)-N-[1-(6-phenoxypyridines-3-ylmethyl)-2,3-dihydro-1H-Yin Diindyl-5-yl]-ethanamide
LC/MS(m/z)454.3([M+1] +)；RT＝2.81，(UV，ELSD)77.9％，83.1％。
7ar N-(1-benzo [b] thiophene-2-ylmethyl-2,3-dihydro-1H-indoles-5-yl)-2-(4-fluorobenzene Base)-ethanamide
LC/MS(m/z)417.2([M+1] +)；RT＝3.22，(UV，ELSD)80.2％，89.4％。
7as 2-(4-fluorophenyl)-N-{1-[1-(4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-ylmethyl]- 2,3-dihydro-1H-indoles-5-yl }-ethanamide
LC/MS(m/z)459.3([M+1] +)；RT＝2.15，(UV，ELSD)91.5％，88.7％。
7au 2-(4-fluorophenyl)-N-[1-(5-thiotolene-2-ylmethyl)-2,3-dihydro-1H-indoles- The 5-yl]-ethanamide
LC/MS(m/z)381.1([M+1] +)；RT＝2.71，(UV，ELSD)76.6％，82.9％。
7av 2-(4-fluorophenyl)-N-[1-(4-pyrroles-1-base-benzyl)-2,3-dihydro-1H-indoles-5- Base]-ethanamide
LC/MS(m/z)426.1([M+1] +)；RT＝2.87，(UV，ELSD)92.2％，88.2％。
The aldehyde that table 2. uses in the compound of 7a-7av of the present invention
Compound of the present invention Aldehyde Molecular weight Manufacturer Catalog number (Cat.No.)
7a The 4-chlorobenzaldehyde 140.568 Aldrich
7b 4-(trifluoromethyl)-phenyl aldehyde 174.12 Aldrich
7c 4-isopropyl benzene formaldehyde 148.204 Aldrich
7d 3-fluoro-4-(trifluoromethyl) phenyl aldehyde 192.111 ABCR AV20008
7e 6-chlorine piperonylaldehyde 184.577 ABCR AV13607
7f 3,5-dimethyl-1-phenylpyrazole-4-formaldehyde 200.24 Acros Organics 40852-0050
7g 2-chloro-5-(trifluoromethyl) phenyl aldehyde 208.566 Aldrich 37，682-5
7h 5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-formaldehyde 250.684 Bionet Research 11F-431S
7j 6-(4-methylphenoxy) nicotine aldehyde 213.235 Bionet Research 5L-355S
7k The 6-[(4-chloro-phenyl-) sulfenyl] nicotine aldehyde 249.72 Bionet Research 5L-356S
7l 4-[(5-formyl radical-2-pyridyl) oxygen base] cyanobenzene 224.218 Bionet Research 6L-309S
7m 6-(trifluoromethyl) pyridine-3-formaldehyde 175.109 Fluorochem 9397
7p 3-methyl benzo [b] thiophene-2-formaldehyde 176.238 ABCR AV11375
7q 5-fluoro-4H-1,3-benzo dioxine-5-formaldehyde 182.149 Maybridge CC 01904
7s 6-phenoxy group nicotine aldehyde 199.208 Maybridge CC 19604
7u 3-methyl-5-phenyl-4-isoxazole formaldehyde 187.197 Maybridge CC 20304
7v 1-thionaphthene-2-formaldehyde 162.211 Specs 942/25034639
7w 1-(4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-formaldehyde 204.203 Maybridge MO 00310
7y 5-methyl-2 thiophene carboxaldehyde 126.178 Aldrich M8，441-0
7z 4-(1H-pyrroles-1-yl) phenyl aldehyde 171.198 Maybridge N/A
7aa The 4-chlorobenzaldehyde 140.568 Aldrich
7ab 4-(trifluoromethyl) phenyl aldehyde 174.12 Aldrich
7ac 4-isopropyl benzene formaldehyde 148.204 Aldrich
7ad 3-fluoro-4-(trifluoromethyl) phenyl aldehyde 192.111 ABCR AV20008
7ae 6-chlorine piperonylaldehyde 184.577 ABCR AV13607
7af 3,5-dimethyl-1-phenylpyrazole-4-formaldehyde 200.24 Acros Organics 40852-0050
7ag 2-chloro-5-(trifluoromethyl) phenyl aldehyde 208.566 Aldrich 37，682-5
7ah 5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-formaldehyde 250.684 Bionet Research 11F-431S
7ai 4-[(5-formyl radical-2-pyridyl) oxygen base] cyanobenzene 224.218 Bionet Research 6L-309S
Compound of the present invention Aldehyde Molecular weight Manufacturer Catalog number (Cat.No.)
7al 3-methyl benzo [b] thiophene-2-formaldehyde 176.238 ABCR AV11375
7am 5-fluoro-4H-1,3-benzo dioxine-5-formaldehyde 182.149 Maybridge CC 01904
7ao 6-phenoxy group nicotine aldehyde 199.208 Maybridge CC 19604
7ar 1-thionaphthene-2-formaldehyde 162.211 Specs 942/25034639
7as 1-(4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-formaldehyde 204.203 Maybridge MO 00310
7au 5-methyl-2 thiophene carboxaldehyde 126.178 Aldrich M8，441-0
7av 4-(1H-pyrroles-1-yl) phenyl aldehyde 171.198 Maybridge N/A
External and in vivo test
Compound of the present invention has tested and has demonstrated effect in the model below one or more:
Relative discharge by the KCNQ2 passage
This illustration be used to assess the KCNQ2 screening scheme of The compounds of this invention.Described analysis to measure through the relative discharge of KCNQ2 passage, according to Tang etc. (Tang, W. etc., J.Biomol.Screen.2001,6,325-331) following improvement is carried out and carried out to the method that is used for the hERG potassium channel of Miao Shuing.
The same day Chinese hamster ovary celI flat board of the q.s of the valtage-gated KCNQ2 passage of stably express was cultivated the density that enough generations singly converge layer in test.Test the day before yesterday with cell inoculation and load 1 μ Ci/ml[ 86Rb] spend the night.Washed these cells with the damping fluid that contains HBSS the same day in test.With medicine pre-cultured cell 30 minutes, and in the presence of medicine continues, with the inferior peak concentration stimulation of 15mMKCl [ 86Rb +] flow 30 minutes.Behind one section suitable incubation time, remove supernatant liquid, and in liquid scintillation counter (Tricarb), count.Use the 2mMNaOH dissolved cell, and counting 86The amount of Rb+.Following calculating relative discharge:
((CPM super/(CPM super+CPM cell))C mpd/
(CPM super/(CPM super+CPM cell))15mM KCl)*100-100.
The EC of compound of the present invention 50Less than 20000nM, in most of the cases less than 2000nM, in many cases less than 200nM.Therefore, think that compound of the present invention can be used for treating and the relevant disease of KCNQ family potassium channel.
Electrophysiological patch clamp record
Use traditional patch clamp recording (Pfl ü gers Arch 1981 such as Hamill OP; 391:85-100) the KCNQ2 electric current of the voltage-activated of the mammiferous Chinese hamster ovary celI of the full cell patch pincers of record configuration.Under normal cell culture condition, at CO 2Cultivate in the incubator stably express voltage-activated the KCNQ2 electric current Chinese hamster ovary celI and after flat board is cultivated 1 to 7 day, be used for the electrophysiology record.Resting membrane potential (membraneholding potential) from-100mV to-40mV is that 5-20mV (or slope stimulation mode) progressively is increased to+80mV (JNeuroscience2001 such as TatulianL with the increment; 21 (15): 5535-5545) the KCNQ2 potassium-channel is activated.Various parameters with the KCNQ2 electric current of voltage activated are estimated by the electrophysiological effect of compound inductive.Particularly studied to the activation threshold value of electric current with to the influence of maximum inductive electric current.
Some compounds in the compound of the present invention in this test, have been tested.Expection activation threshold value moving to left (left-ward) or maximum increase of inducing potassium current will reduce activity in the neural network, and thereby make compound can be used for and the relevant disease (as epilepsy) of neural activity increase
Maximum electric shock
Use Corneal electrode (corneal electrode) on each male mice group, to carry out this test, in order to bring out epilepsy, use rectangular wave current effect 0.4 second (people such as Wlaz, the Epilepsy Research 1998 of 26mA with THE feature, 30,219-229).
The epilepsy that pilocarpine brings out
By bringing out the epilepsy that pilocarpine brings out, and observe and cause the epileptic seizures situation of forgetting oneself in 30 minutes to male mice group peritoneal injection 250mg/kg pilocarpine.(people such as Starr, Pharmacology Biochemistry and Behavior 1993,45,321-325)
The test of electricity epilepsy threshold value
Use to raise and reduce (up-and-down) method (people such as Kimball, RadiationResearch 1957, improving one's methods 1-12) measured the meta threshold value of the THE of inducing male mice group response cornea electric shock.Give first mouse 14mA (0.4s, electric shock 50Hz), and observation epileptic seizures of each group.Epilepsy occurs if observe, then that next mouse is used electric current reduces 1mA, epilepsy do not occur if still observe, and then electric current is increased 1mA.
15 mouse for this treatment group are repeated this step.
The test of chemistry epilepsy threshold value
The threshold dose of bringing out the required pentetrazole of clonism by regularly toward male mice tail lateral vein inject pentetrazole measure (5mg/mL, 0.5ml/min) (people such as Nutt, J.Pharmacy and Pharmacology 1986,38,697-698).
Amygdala are lighted and are brought out
Rat is undergone surgery, be implanted into three utmost point electrodes at tergolateral amygdala.After the operation, allow these animal rehabilitations, organize the test compounds or the pharmaceutical carrier of various dosage then to rat.Stimulate with initial ADT value+25 μ A every day, continue 3-5 week, write down time length (the Racine.Electroencephalography and Clinical Neurophysiology1972 of epileptic seizures severity, epilepsy time length and back discharging current under the various situations, 32,281-294).
Side effect
The central nervous system side effect by mouse rest on time on rotating rod (rotarod) device measure (people such as Capacio, Drug and Chemical Toxicology 1992,15,177-201); Perhaps the light beam number of infrared light that passes the test cage by calculating is measured the mobility of mouse (people such as Watson, Neuropharmacology 1997,36,1369-1375).Maybe can measure by rectal thermometer temperature implantation this compound of wireless remote control sensor determination to the cooling behavior of animal subject temperature (people such as Keeney, Physiology and Behaviour2001,74,177-184).
Pharmacokinetics
The pharmacokinetics character of described compound is measured through 20 hours blood samplings then by giving Spraque Dawley rat through vein and oral administration.Use LC/MS/MS to measure plasma concentration.

Claims (30)

1. the indoles of the replacement of a general formula I or indolin derivatives or its salt,
Figure A2004800110190002C1
Wherein
Dotted line is represented the key chosen wantonly;
R 1And R 1 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Or
R 1And R 1 'Connected carbon atom forms 3 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1 or 2 heteroatoms;
S is 0 or 1;
U is O, NR 11, S, SO 2, SO 2NR 11, CO-O or CO-NR 11R wherein 11Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Or R 2And R 11Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
R 2Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-bad alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-NO 2, NR 10R 10 '-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 3-8-cycloalkanes (alkene) base and NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 10And R 10 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 10And R 10 'Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
Condition is to work as R 2Be NO 2, when halogen or cyano group, s is 0; With
Condition is to work as R 2For hydrogen atom or acyl group and s are 1 o'clock, U is NR 11, O or S;
Group-(U) wherein s-R 2Be connected indoles or indoline 4 or 6;
Q is 0 or 1;
Z is O or S;
X is CO or SO 2Condition be when X be SO 2The time, q is 0;
R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-heterocycle alkane (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 3-8-cycloalkanes (alkene) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes)-heterocycle alkane (alkene) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-carbonyl of-cycloalkanes (alkene)-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-heterocycle alkane (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-aryl, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-cycloalkanes (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base and-NR 12R 12 ', the optional NR that replaces 12R 12 '-C 1-6-alkane (alkene/alkynes) base, the optional NR that replaces 12R 12 '-C 3-8-cycloalkanes (alkene) base, the optional NR that replaces 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 12And R 12 'Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
Condition is to work as R 3Be NR 12R 12 'The time, q is 0;
With
The group of Y expression II, III, IV, V, VI, XXX and XXXI:
Figure A2004800110190005C1
Or
Figure A2004800110190005C2
Wherein
Straight line is represented key that the group shown in the Y is connected with carbon atom;
W is O or S;
T is N, NH or O;
L is N, C or CH;
A is 0,1,2 or 3;
B is 0,1,2,3 or 4;
C is 0 or 1;
D is 0,1,2 or 3;
E is 0,1 or 2;
F is 0,1,2,3,4 or 5;
G is 0,1,2,3 or 4;
H is 0,1,2 or 3;
J is 0,1,2 or 3; Condition is when T is nitrogen-atoms, and j is 0,1,2 or 3; With when T is NH or Sauerstoffatom, j is 0,1 or 2;
K is 0,1,2,3 or 4; And
R 5Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-sulfenyl, aryl-oxygen base, acyl group, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8The basic oxygen base of-cycloalkanes (alkene), C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes), halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-CO-NR 6R 6 ', cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-NR 7R 7 ',-S-R 8With-SO 2R 8, or two adjacent R 5Connected aryl forms optional one or two heteroatomic 4 to 8 yuan of rings that comprise together;
R 6And R 6 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and aryl;
R 7And R 7 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl and acyl group;
With
R 8Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl and-NR 9R 9 'R wherein 9And R 9 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Condition is to work as R 8For-NR 9R 9 'The time, R 5Be not-S-R 8
Condition is that formula I compound is not following compound or its salt:
N-[1-(phenyl methyl)-1H-indoles-5-yl]-Toluidrin;
The N-[1-[(4-fluorophenyl) methyl]-1H-indoles-5-yl]-Toluidrin;
N-[2,3-dihydro-1-(phenyl methyl)-1H-indoles-5-yl]-Toluidrin;
N-[1-(phenyl methyl)-1H-indoles-5-yl]-N '-4-quinolyl-urea;
N-[1-(phenyl methyl)-1H-indoles-5-yl]-N '-4-quinolyl-urea; Or
1-(1-benzyl-5-indolinyl)-3-phenyl-urea.
2. the compound of claim 1, wherein R 1Or R 1 'In at least one is a hydrogen atom.
3. each compound, wherein R in the claim 1 and 2 1And R 1 'Be hydrogen atom.
4. each compound among the claim 1-3, wherein s is 0.
5. each compound among the claim 1-3, wherein s is 1.
6. each compound, wherein R among the claim 1-5 2Be hydrogen atom.
7. each compound, wherein R among the claim 1-4 2Be NO 2Or halogen atom.
8. each compound among claim 1-3 and the 5-7, wherein U is NR 11
9. the compound of claim 8, wherein R 11Be hydrogen atom.
10. each compound among the claim 1-9, wherein X is CO.
11. each compound among the claim 1-9, wherein X is SO 2
12. each compound among the claim 1-11, wherein q is 0.
13. each compound among the claim 1-11, wherein q is 1.
14. the compound of claim 13, wherein Z is a Sauerstoffatom.
15. each compound, wherein R among the claim 1-14 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base and-NR 12R 12 'Condition is to work as R 3Be NR 12R 12 'The time, q is 0.
16. the compound of claim 15, wherein R 3Be NR 12R 12 ', q is 0, R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, aryl and aryl-C 1-6-alkane (alkene/alkynes) base, or R 12And R 12 'Connected nitrogen-atoms forms optional 1,2 or 3 other heteroatomic 4 to 8 yuan of saturated or unsaturated ring that comprises together.
17. each compound among the claim 1-16, wherein Y is formula II, III, V, XXX or XXXI.
18. each compound among the claim 1-17, wherein Y is that formula II or III and W are sulphur atom.
19. each compound among the claim 1-17, wherein Y is that formula XXX and T are nitrogen-atoms or Sauerstoffatom.
20. each compound among the claim 1-17, wherein Y is that formula XXXI and L are C or CH.
21. each compound, wherein R among the claim 1-20 5Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, aryl, aryl-sulfenyl, aryl-oxygen base, halogen and halo C 1-6-alkane (alkene/alkynes) base, the perhaps R of two vicinities 5Connected aryl forms optional one or two heteroatomic 4 to 8 yuan of rings that comprise together.
22. each compound among the claim 1-21, described compound are selected from following compound or its pharmacy acceptable salt:
1) N-[4-chloro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
2) N-[4-chloro-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
3) [1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-carboxylamine propyl ester;
4) N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-C-phenyl-Toluidrin;
5) 4-fluoro-N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-benzamide;
6) N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
7) N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-2-thiophene-2-yl acetamide;
8) N-[1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
9) 3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-1,1-di-isopropyl urea;
10) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-morpholine-4-methane amide;
11) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-tetramethyleneimine-1-methane amide;
12) [1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-carboxylamine 2-benzyloxy ethyl ester;
13) 3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-1-methyl isophthalic acid-propyl group urea;
14) [1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-t-butyl carbamate;
15) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-C-phenyl-Toluidrin;
16) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butane-1-sulphonamide;
17) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 4-fluorobenzamide;
18) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
19) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 2-phenoxy-acetamide;
20) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
21) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
22) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-cyclopentane formamide;
23) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-thiophene-2-yl acetamide;
24) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-Isonicotinamide;
25) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-4-dimethylamino yl-benzamide;
26) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
27) N-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-6-trifluoromethyl niacinamide;
28) the 1-tertiary butyl-3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-urea;
29) 1-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 3-ethyl carbamide;
30) 1-benzyl-3-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-urea;
31) 1-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-the 3-phenthylcarbamide;
32) 1-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3-thiophene-2-base urea;
33) 1-[1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3-thiene-3-yl-urea;
34) [1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-carboxylamine propyl ester;
35) 2,2-dimethyl-N-[6-nitro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-propionic acid amide;
36) N-[1-(5-chlorothiophene-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
37) 2-(4-fluorophenyl)-N-[6-nitro-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
38) N-[1-(5-chlorothiophene-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
39) N-[1-(5-chlorothiophene-2-ylmethyl)-6-nitro-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
40) N-[6-amino-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
41) N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
42) N-[6-amino-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2,2-dimethyl propylene acid amides;
43) N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
44) N-[6-amino-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
45) N-[6-amino-1-(4-luorobenzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
46) N-[6-amino-1-(3-fluoro-4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
47) N-[1-(5-chlorothiophene-2-ylmethyl)-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
48) N-[6-bromo-1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
49) N-[6-bromo-1-(5-chlorothiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
50) N-[1-(4-benzyl chloride base)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
51) 3,3-dimethyl-N-[1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
52) N-[1-(4-isopropyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
53) N-[1-(3-fluoro-4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
54) N-[1-(the 6-chlorobenzene is [1,3] dioxole-5-ylmethyl also)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
55) N-[1-(3,5-dimethyl-1-phenyl-1H-pyrazoles-4-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
56) N-[1-(2-chloro-5-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
57) N-{1-[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-ylmethyl]-2,3-dihydro-1H-indoles-5-yl }-3, the 3-amide dimethyl butyrate;
58) 3,3-dimethyl-N-[1-(6-is to tolyloxy-pyridin-3-yl methyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
59) N-{1-[6-(4-chloro-phenyl-sulfenyl)-pyridin-3-yl methyl]-2,3-dihydro-1H-indoles-5-yl }-3, the 3-amide dimethyl butyrate;
60) N-{1-[6-(4-cyano-benzene oxygen)-pyridin-3-yl methyl]-2,3-dihydro-1H-indoles-5-yl }-3, the 3-amide dimethyl butyrate;
61) 3,3-dimethyl-N-[1-(6-5-flumethiazine-3-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
62) 3,3-dimethyl-N-[1-(3-methyl-benzo [b] thiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
63) N-[1-(6-fluoro-4H-benzo [1,3] dioxine-8-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-3, the 3-amide dimethyl butyrate;
64) 3,3-dimethyl-N-[1-(6-phenoxypyridines-3-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
65) 3,3-dimethyl-N-[1-(3-methyl-5-phenyl-isoxazole-4-base methyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
66) N-(1-benzo [b] thiophene-2-ylmethyl-2,3-dihydro-1H-indoles-5-yl)-3, the 3-amide dimethyl butyrate;
67) N-{1-[1-(4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-ylmethyl]-2,3-dihydro-1H-indoles-5-yl }-3, the 3-amide dimethyl butyrate;
68) 3,3-dimethyl-N-[1-(5-thiotolene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
69) 3,3-dimethyl-N-[1-(4-pyrroles-1-base-benzyl)-2,3-dihydro-1H-indoles-5-yl]-butyramide;
70) N-[1-(4-benzyl chloride base)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
71) 2-(4-fluorophenyl)-N-[1-(4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
72) 2-(4-fluorophenyl)-N-[1-(4-isopropyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
73) 2-(4-fluorophenyl)-N-[1-(3-fluoro-4-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
74) N-[1-(the 6-chlorobenzene is [1,3] dioxole-5-ylmethyl also)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
75) N-[1-(3,5-dimethyl-1-phenyl-1H-pyrazoles-4-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
76) N-[1-(2-chloro-5-trifluoromethyl benzyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
77) N-{1-[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-ylmethyl]-2,3-dihydro-1H-indoles-5-yl }-2-(4-fluorophenyl)-ethanamide;
78) N-{1-[6-(4-cyano-benzene oxygen)-pyridin-3-yl methyl]-2,3-dihydro-1H-indoles-5-yl }-2-(4-fluorophenyl)-ethanamide;
79) 2-(4-fluorophenyl)-N-[1-(3-methyl-benzo [b] thiophene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
80) N-[1-(6-fluoro-4H-benzo [1,3] dioxine-8-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-2-(4-fluorophenyl)-ethanamide;
81) 2-(4-fluorophenyl)-N-[1-(6-phenoxypyridines-3-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide;
82) N-(1-benzo [b] thiophene-2-ylmethyl-2,3-dihydro-1H-indoles-5-yl)-2-(4-fluorophenyl)-ethanamide;
83) 2-(4-fluorophenyl)-N-{1-[1-(4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-ylmethyl]-2,3-dihydro-1H-indoles-5-yl }-ethanamide;
84) 2-(4-fluorophenyl)-N-[1-(5-thiotolene-2-ylmethyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide; With
85) 2-(4-fluorophenyl)-N-[1-(4-pyrroles-1-base-benzyl)-2,3-dihydro-1H-indoles-5-yl]-ethanamide.
23. a pharmaceutical composition, described pharmaceutical composition comprise among one or more pharmaceutically acceptable carriers or thinner and the claim 1-22 each compound.
24. a pharmaceutical composition is used for increasing for example purposes of the ion flow of people's potassium channel of Mammals, described pharmaceutical composition comprises the compound or its salt of one or more pharmaceutically acceptable carriers or thinner and general formula I,
Figure A2004800110190014C1
Wherein
Dotted line is represented the key chosen wantonly;
R 1And R 1 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Or
R 1And R 1 'Connected carbon atom forms 3 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1 or 2 heteroatoms;
S is 0 or 1;
U is O, NR 11, S, SO 2, SO 2NR 11, CO-O or CO-NR 11R wherein 11Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Or R 2And R 11Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
R 2Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-NO 2, NR 10R 10 '-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 3-8-cycloalkanes (alkene) base and NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
Wherein
R 10And R 10 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 10And R 10 'Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
Condition is to work as R 2Be NO 2, when halogen or cyano group, s is 0; With
Condition is to work as R 2For hydrogen atom or acyl group and s are 1 o'clock, U is NR 11, O or S;
Group-(U) wherein s-R 2Be connected indoles or indoline 4 or 6;
Q is 0 or 1;
Z is O or S;
X is CO or SO 2Condition be when X be SO 2The time, q is 0;
R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-heterocycle alkane (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, aryl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-C of-cycloalkanes (alkene) 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 3-8-cycloalkanes (alkene) base, C 1-6The basic oxygen base of-alkane (alkene/alkynes)-heterocycle alkane (alkene) base, aryl-oxygen base-C 1-6-alkane (alkene/alkynes) base, aryl-C 1-6The basic oxygen base-C of-alkane (alkene/alkynes) 1-6-alkane (alkene/alkynes) base, C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, C 3-8The basic oxygen base-carbonyl of-cycloalkanes (alkene)-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base-carbonyl of-alkane (alkene/alkynes)-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-heterocycle alkane (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-aryl, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-aryl, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-aryl, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-cycloalkanes (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base and-NR 12R 12 ', the optional NR that replaces 12R 12 '-C 1-6-alkane (alkene/alkynes) base, the optional NR that replaces 12R 12 '-C 3-8-cycloalkanes (alkene) base, the optional NR that replaces 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-C 3-8-cycloalkanes (alkene) base, aryl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 12And R 12 'Connected nitrogen-atoms forms 4 to 8 yuan of saturated or unsaturated rings together, and described ring is chosen wantonly and comprised 1,2 or 3 other heteroatoms;
Condition is to work as R 3Be NR 12R 12 'The time, q is 0;
With
The group of Y expression II, III, IV, V, VI, XXX and XXXI:
Or
Wherein
Straight line is represented key that the group shown in the Y is connected with carbon atom;
W is O or S;
T is N, NH or O;
L is N, C or CH;
A is 0,1,2 or 3;
B is 0,1,2,3 or 4;
C is 0 or 1;
D is 0,1,2 or 3;
E is 0,1 or 2;
F is 0,1,2,3,4 or 5;
G is 0,1,2,3 or 4;
H is 0,1,2 or 3;
J is 0,1,2 or 3; Condition is when T is nitrogen-atoms, and j is 0,1,2 or 3; With when T is NH or Sauerstoffatom, j is 0,1 or 2;
K is 0,1,2,3 or 4; And
R 5Be selected from C independently of one another 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl, aryl-C 1-6-alkane (alkene/alkynes) base, aryl-sulfenyl, aryl-oxygen base, acyl group, C 1-6The basic oxygen base of-alkane (alkene/alkynes), C 3-8The basic oxygen base of-cycloalkanes (alkene), C 3-8-cycloalkanes (alkene) base-C 1-6The basic oxygen base of-alkane (alkene/alkynes), halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-CO-NR 6R 6 ', cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-NR 7R 7 ',-S-R 8With-SO 2R 8, or two adjacent R 5Connected aryl forms optional one or two heteroatomic 4 to 8 yuan of rings that comprise together;
R 6And R 6 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and aryl;
R 7And R 7 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl and acyl group;
With
R 8Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, aryl and-NR 9R 9 'R wherein 9And R 9 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Condition is to work as R 8For-NR 9R 9 'The time, R 5Be not-S-R 8
25. the purposes of claim 24, described purposes is for prevention, treatment or suppress disease to the ion flow sensitivity that increases in the potassium channel, and this class disease is preferably central nervous system disease.
26. the purposes of claim 25, wherein said disease is selected from the epileptic seizures disease, as convulsions, epilepsy and epileptic state.
27. the purposes of claim 25 is characterized in that described disease is selected from neurodynia and migraine disease, as allodynia, hyperpathia pain, phantom pain, the neurodynia relevant with diabetic neuropathy and the neurodynia of being correlated with migraine.
28. the purposes of claim 25, it is characterized in that described disease is selected from anxiety disorder, as stress disease, gross stress reaction, insufficiency of accommodation, hypochondriasis, separation anxiety disorder, agoraphobia, specific phobia disease after anxiety, generalized anxiety disorder, panic anxiety, obsessional idea and behavior disease, social phobia, behavior anxiety, the wound, result from the anxiety disorder of whole body health situation and the anxiety disorder that material brings out.
29. the purposes of claim 25, it is characterized in that described disease is selected from neurodegenerative disease, the neurodegeneration that the encephalopathic of bringing out as alzheimer's disease, Huntington Chorea, multiple sclerosis, amyotrophic lateral sclerosis, AIDS-and other encephalopathic, Creutzfeldt-Jakob disease, Parkinson's disease, wounds that is caused by rubella virus, simplexvirus, Borrelia and unknown pathogenic infection cause.
30. the purposes of claim 25 is characterized in that described disease is selected from the nervous excitation transient state, for example at medicine withdrawal or because the drunk neuronal excitation transient state that causes.
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BR (1) BRPI0409317A (en)
CA (1) CA2523102A1 (en)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103508960A (en) * 2012-06-29 2014-01-15 上海先声药物研究有限公司 Benzoheterocyclic derivatives
CN108863893A (en) * 2018-07-09 2018-11-23 湖南博隽生物医药有限公司 Indolinyl derivative and its application in drug
CN112010808A (en) * 2019-05-31 2020-12-01 上海挚盟医药科技有限公司 tetrahydro-1H-benzazepine compounds as potassium channel modulators, and preparation and application thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103508960A (en) * 2012-06-29 2014-01-15 上海先声药物研究有限公司 Benzoheterocyclic derivatives
CN103508960B (en) * 2012-06-29 2017-12-12 江苏先声药业有限公司 Benzheterocyclic derivatives
CN108863893A (en) * 2018-07-09 2018-11-23 湖南博隽生物医药有限公司 Indolinyl derivative and its application in drug
CN112010808A (en) * 2019-05-31 2020-12-01 上海挚盟医药科技有限公司 tetrahydro-1H-benzazepine compounds as potassium channel modulators, and preparation and application thereof
WO2020238917A1 (en) * 2019-05-31 2020-12-03 上海挚盟医药科技有限公司 Tetrahydro-1h-benzazepine compound as potassium channel modulator, preparation method and use thereof
CN112010808B (en) * 2019-05-31 2021-11-30 上海挚盟医药科技有限公司 tetrahydro-1H-benzazepine compounds as potassium channel modulators, and preparation and application thereof
CN113767091A (en) * 2019-05-31 2021-12-07 上海挚盟医药科技有限公司 tetrahydro-1H-benzazepine compounds as potassium channel modulators, and preparation and application thereof

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KR20060004957A (en) 2006-01-16
CA2523102A1 (en) 2004-11-11
EA200501669A1 (en) 2006-04-28
BRPI0409317A (en) 2006-04-25
UA80190C2 (en) 2007-08-27
AR044517A1 (en) 2005-09-14
NZ541999A (en) 2009-03-31
ZA200507186B (en) 2006-11-29

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