CN1732162A - 1,2,4-triaminobenzenderivater nyttige for behandling AV forstyrrelser i sentralnervesystemet - Google Patents
1,2,4-triaminobenzenderivater nyttige for behandling AV forstyrrelser i sentralnervesystemet Download PDFInfo
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- CN1732162A CN1732162A CNA2003801076953A CN200380107695A CN1732162A CN 1732162 A CN1732162 A CN 1732162A CN A2003801076953 A CNA2003801076953 A CN A2003801076953A CN 200380107695 A CN200380107695 A CN 200380107695A CN 1732162 A CN1732162 A CN 1732162A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/28—Halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
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Abstract
The present invention concerns 1,2,4-triaminobenzene derivatives of the general formula I or pharmaceutically acceptable salts thereof and the use thereof.
Description
Invention field
The present invention relates to novel 1,2 as KCNQ family potassium channel openers, 4-triaminobenzene derivative.These compounds are used for prevention, treatment and/or suppress central nervous system 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 the different potassium channel hypotype of more than 70 kind of 26S Proteasome Structure and Function (Jentsch NatureReviews Neuroscience 2000,1,21-30).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, with epileptic seizures with propagate relevant (people such as Cooper, Proceedings National Academy of Science USA2000,97,4914-4919).
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.Therefore, in the epilepsy and disease illnesss such as (as epilepsy and neuralgias) that with the over-drastic neuronal activity are feature, these KCNQ channel openers will reduce the over-drastic neuronal activity.
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 KCNQ2/3 K (+) 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 is 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, Neuropharmacology2001,40,888-898; Blackburn-Munro and Jensen European Journal ofPharmacology 2003,460,109-116).In addition, be reported in localization people such as (, Society for Neuroscience Abstracts 2003,53.8) Goldstein of KCNQ passage mRNA in the brain relevant and other central nervous system zones with pain.
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 be regulated 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 OfPharmacology 1996,303,163-169).
Give up the anticonvulsion compound (for example benzodiazepine and 5-chloromethyl thiazole (chlorme thiazole)) of ethanol syndromes and the very effective anticonvulsion compound of other animal models (for example gabapentin) (people such as Watson by being used for clinical treatment in this syndromes, Neuropharmacology 1997,36,1369-1375), 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, Journalofneuroscietice 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 Psychopharmacology2003,17 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, insufficiency of accommodation, 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's disease, Huntington Chorea, multiple sclerosis, amyotrophic lateral sclerosis, the encephalopathic that AIDS-brings out and other are by rubella virus, simplexvirus, the encephalopathic that Borrelia and other unknown pathogenic infections cause, Creutzfeldt-Jakob disease, Parkinson's disease, the neurodegeneration that wound causes and at the medicine withdrawal with because the drunk neuronal excitation transient state that causes, the degenerative disease of peripheral nervous system (as polyneuropathy and polyneuritis (polyneuritides)).
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 pharmacotherapy to patient,
● reduce side effect,
● increase therapeutic index,
● improve tolerance, and/or
● improve compliance.
Summary of the invention
Therefore, one object of the present invention is for providing a kind of novel compound, and this compound is effective opener of KCNQ family potassium channel.
Compound of the present invention is 1,2 of a general formula I, 4-triaminobenzene derivative or its pharmacy acceptable salt:
R wherein
1, R
2, R
2 ', R
3, X, Z, Y and q be as giving a definition.
The invention still further relates to medicinal compositions that comprises formula I compound and uses thereof.
Invention is described
The present invention relates to the novel 1,2 of formula I, 4-triaminobenzene derivative or its pharmacy acceptable salt:
Wherein
R
1Be 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, acyl group, hydroxyl-C
1-6-alkane (alkene/alkynes) base and hydroxyl-C
3-8-cycloalkanes (alkene) base;
R
2And R
2 'Be independently selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, 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, acyl group, hydroxyl-C
1-6-alkane (alkene/alkynes) base and hydroxyl-C
3-8-cycloalkanes (alkene) base;
R
3Be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, 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, hydroxyl-C
1-6-alkane (alkene/alkynes) base, aryl-C
3-8-cycloalkanes (alkene) base, NR
10R
10 '-C
1-6-alkane (alkene/alkynes) base, NR
10R
10 '-C
3-8-cycloalkanes (alkene) base and hydroxyl-C
3-8-cycloalkanes (alkene) 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 'The nitrogen-atoms that connects with them forms optional 1,2 or 3 other the saturated or unsaturated ring of heteroatomic 4-8 unit that comprises;
X is CO or SO
2
Z is O or NR
4, wherein:
R
4Be 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 and hydroxyl-C
3-8-cycloalkanes (alkene) base; Or
R
3And R
4The nitrogen-atoms that connects with them forms optional 1,2 or 3 other the saturated or unsaturated ring of heteroatomic 4-8 unit that comprises, and is described by R
3And R
4And the ring that nitrogen-atoms forms is optional by one or more C that are independently selected from
1-6-alkane (alkene/alkynes) base, aryl and aryl-C
1-6The substituting group of-alkane (alkene/alkynes) base replaces;
Q is 0 or 1;
And
Y represents the heteroaryl of formula II or III:
Wherein:
W is O or S;
M is 0,1,2 or 3;
N is 0,1,2,3 or 4;
P is 0 or 1; And
R
5Independently be selected from C separately
1-6-alkane (alkene/alkynes) base, 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, acyl group, halogen, halo-C
1-6-alkane (alkene/alkynes) base, C
1-6The basic oxygen base of-alkane (alkene/alkynes) ,-CO-NR
6R
6 ', cyano group, nitro ,-NR
7R
7 ',-S-R
8,-SO
2R
8And SO
2OR
8
Wherein:
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; And
R
8Be 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, 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.
When q is 0, R
3Be connected in X, and when q is 1, R
3Be connected in the Z that links to each other with X.So X-(Z)
q-R
3Can represent X-R
3, X-O-R
3Or X-NR
3R
4
In a specific embodiment, the present invention relates to compound or its pharmaceutically-acceptable acid addition of formula I, wherein:
R
1, R
2, R
2 ', X and q as above define; And
R
3Be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, 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, hydroxyl-C
1-6-alkane (alkene/alkynes) base and hydroxyl-C
3-8-cycloalkanes (alkene) base; And
Z as above defines, and condition is R
4Be 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 and hydroxyl-C
3-8-cycloalkanes (alkene) base; And
Y as above defines, and condition is R
5Independently be selected from C separately
1-6-alkane (alkene/alkynes) base, 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, acyl group, halogen, halo-C
1-6-alkane (alkene/alkynes) base ,-CO-NR
6R
6 ', cyano group, nitro ,-NR
7R
7 ',-S-R
8,-SO
2R
8And SO
2OR
8
In one embodiment, R
1Be selected from acyl group, hydroxyl-C
1-6-alkane (alkene/alkynes) base and hydroxyl-C
3-8-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein R
1Be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base and C
3-8-cycloalkanes (alkene) base-C
1-6The compound of-alkane (alkene/alkynes) base.
In a preferred embodiment, the present invention relates to wherein R
1Be selected from hydrogen and C
1-6The compound of-alkane (alkene/alkynes) base.
In a specific embodiment, the present invention relates to wherein R
1Compound for hydrogen atom.
In another specific embodiment, the present invention relates to wherein R
1Be C
1-6The compound of-alkane (alkene/alkynes) base.
In one embodiment, R
2And R
2 'In at least one is selected from aryl, aryl-C
1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C
1-6-alkane (alkene/alkynes) base and hydroxyl-C
3-8-cycloalkanes (alkene) base.
In another embodiment, R
2And R
2 'In at least one is 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 another embodiment, the present invention relates to wherein substituent R
2And R
2 'In at least one is the compound of hydrogen atom.
In another embodiment, the present invention relates to wherein R
2And R
2 'Be the compound of hydrogen atom.
In one embodiment, R
3Be selected from hydroxyl-C
1-6-alkane (alkene/alkynes) base, aryl-C
3-8-cycloalkanes (alkene) base, NR
10R
10 '-C
1-6-alkane (alkene/alkynes) base, NR
10R
10 '-C
3-8-cycloalkanes (alkene) base and hydroxyl-C
3-8-cycloalkanes (alkene) 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 'The nitrogen-atoms that connects with them forms optional 1,2 or 3 other the saturated or unsaturated ring of heteroatomic 4-8 unit that comprises.
In another embodiment, the present invention relates to wherein that q is 1, Z is NR
4, and R
3Compound for hydrogen atom.
In another embodiment, the present invention relates to wherein R
3It is not the compound of hydrogen atom.
In another embodiment, R
3Be selected from C
1-6-alkane (alkene/alkynes) base, 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.
In another embodiment, the present invention relates to wherein R
3Be selected from C
1-6-alkane (alkene/alkynes) base and aryl-C
1-6The compound of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R
3Be C
1-6The compound of-alkane (alkene/alkynes) base.
In another embodiment, R
3Be C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R
3Be aryl-C
1-6The compound of-alkane (alkene/alkynes) base.
In one embodiment, the present invention relates to wherein, X is SO
2Compound.
In another embodiment, the present invention relates to wherein, X is the compound of CO.
In one embodiment, q is 0.
In another embodiment, the present invention relates to wherein that X is CO, and q is 0 compound.
In another embodiment, the present invention relates to wherein that X is CO, q is 0 and R
3The compound that is different from aryl.
In another embodiment, q is 1.
In one embodiment, the present invention relates to wherein q be 1 and Z be NR
4Compound.
In one embodiment, q is 1, and Z is NR
4, and R
3And R
4The nitrogen-atoms that connects with them forms optional 1,2 or 3 other the saturated or unsaturated ring of heteroatomic 4-8 unit that comprises, and is described by R
3And R
4And the ring that nitrogen-atoms forms is optional by one or more C that are independently selected from
1-6-alkane (alkene/alkynes) base, aryl and aryl-C
1-6The substituting group of-alkane (alkene/alkynes) base replaces;
In another embodiment, q is 1, and Z is NR
4And R
4Be 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 and hydroxyl-C
3-8-cycloalkanes (alkene) base.
In another embodiment, q is 1, and Z is NR
4And R
4Be hydrogen atom.
In one embodiment, q is 1, and Z is NR
4, and R
3And R
4In at least one is different from hydrogen atom.
In another embodiment, the present invention relates to wherein q and be 1 and Z be the compound of Sauerstoffatom.
In another embodiment, the present invention relates to wherein that X is CO, q be 1 and Z be the compound of Sauerstoffatom.
In another embodiment, the present invention relates to wherein R
2And R
2 'Be hydrogen atom, X is CO, q be 1 and Z be the compound of Sauerstoffatom.
In another embodiment, the present invention relates to wherein, W is the compound of Sauerstoffatom.
In another embodiment, the present invention relates to wherein, W is the compound of sulphur atom.
In another embodiment, the present invention relates to wherein, W is that sulphur atom and X are the compound of CO.
In another embodiment, the present invention relates to wherein, W is that sulphur atom and q are 0 compound.
In another embodiment, the present invention relates to wherein that W is a sulphur atom, X is that CO and q are 0 compound.
In another embodiment, the present invention relates to wherein that W is a sulphur atom, q be 1 and Z be the compound of Sauerstoffatom.
In another embodiment, the present invention relates to wherein that W is a sulphur atom, X is CO, q be 1 and Z be the compound of Sauerstoffatom.
In another embodiment, m is 0.
In another embodiment, m is 1.
In another embodiment, m is 2.
In one embodiment, m is 3.
In another embodiment, n is 0.
In another embodiment, n is 1.
In one embodiment, n is 2,3 or 4;
In one embodiment, p is 0.
In another embodiment, p is 1.
In one embodiment, at least one R
5Be selected from acyl group ,-CO-NR
6R
6 ', nitro ,-S-R
8And SO
2OR
8
In another embodiment, R
5Independently be selected from C separately
1-6-alkane (alkene/alkynes) base, 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, halogen, halo-C
1-6-alkane (alkene/alkynes) base, C
1-6The basic oxygen base of-alkane (alkene/alkynes), cyano group, NR
7R
7 'With-SO
2R
8
In another embodiment, R
5Independently be selected from C separately
1-6-alkane (alkene/alkynes) base, aryl, halogen, C
1-6The basic oxygen base of alkane (alkene/alkynes) ,-NR
7R
7 'With-SO
2R
8
In another embodiment, the present invention relates to wherein R
5Independently be selected from C separately
1-6-alkane (alkene/alkynes) base, halogen and-SO
2R
8, R wherein
8Compound for aryl.
In another embodiment, at least one substituent R
5Be C
1-6-alkane (alkene/alkynes) base.
In another embodiment, at least one substituent R
5Be aryl.
In another embodiment, at least one substituent R
5Be C
1-6The basic oxygen base of-alkane (alkene/alkynes).
In another embodiment, at least one substituent R
5For-SO
2R
8
In another embodiment, at least one substituent R
5Be halogen atom.
In another embodiment, at least one substituent R
5For being selected from the halogen atom of chlorine, bromine and iodine.
In another embodiment, at least one substituent R
5Be fluorine.
In another embodiment, at least one substituent R
5Be chlorine.
In another embodiment, at least one substituent R
5Be bromine.
In another embodiment, at least one substituent R
5For-NR
7R
7 '
In one embodiment, at least one substituent R
5For-NR
7R
7 ', and R
7And R
7 'In at least one is aryl or acyl group.
In one embodiment, at least one substituent R
5For-NR
7R
7 ', and R
7And R
7 'In at least one is 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 another embodiment, at least one substituent R
5For-NR
7R
7 ', and R
7And R
7 'In at least one is selected from hydrogen and C
1-6-alkane (alkene/alkynes) base.
In another embodiment, at least one substituent R
5For-NR
7R
7 ', and R
7And R
7 'In at least one is C
1-6-alkane (alkene/alkynes) base.
In another embodiment, at least one substituent R
5For-NR
7R
7 ', and R
7And R
7 'Be C
1-6-alkane (alkene/alkynes) base.
In one embodiment, at least one substituent R
5For-SO
2R
8, and R
8For-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.
In one embodiment, at least one substituent R
5For-SO
2R
8, and R
8Be 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 and aryl.
In another embodiment, at least one substituent R
5For-SO
2R
8And R
8Be aryl.
In another embodiment, the present invention relates to wherein, Y is the compound of formula II.
In another embodiment, the present invention relates to wherein, Y is the compound of formula III.
In another embodiment, the present invention relates to wherein, Y is the compound of formula IIb or IIIb:
Wherein W, m, n, p and R
5As above definition.
In another embodiment, the present invention relates to wherein, Y is the compound of formula IIb.
In another embodiment, the present invention relates to wherein m and be 0 and Y be the compound of formula IIb.
In another embodiment, the present invention relates to wherein, Y is the compound of formula III b.
In another embodiment, the present invention relates to wherein n and be 0 and Y be the compound of formula III b.
In another embodiment, the present invention relates to wherein p and be 0 and Y be the compound of formula III b.
In another embodiment, the present invention relates to wherein that n is 0, p be 0 and Y be the compound of formula III b.
In another embodiment, the present invention relates to wherein that Y is that formula III b and n+p are 1 compound, under a kind of concrete situation, n be 1 and p be 0, under the concrete situation of another kind, n be 0 and p be 1.
In another embodiment, the present invention relates to wherein that Y is that formula III b and n+p are 2 compound, under a kind of concrete situation, n be 2 and p be 0, under the concrete situation of another kind, n be 1 and p be 1.
In another embodiment, the present invention relates to wherein, Y is Formula Il b
1, IIb
2, IIb
3, IIIb
1, IIIb
2, IIIb
3Or IIIb
4Compound:
Wherein
W as mentioned above;
R is 0,1 or 2;
S is 0,1,2 or 3; And
R
5 'And R
5 "Independently as R
5Definition, R
5Independent separately as above definition.
In another embodiment, the present invention relates to the wherein compound of each group as giving a definition:
● m be 0 and Y be formula IIb; Or
● n be 0 and Y be formula III b; Or
● p be 0 and Y be formula III b; Or
● n is 0, p be 0 and Y be formula III b; Or
● Y is that formula III b and n+p are 1, under a kind of concrete situation, and n
Be 1 and p be 0, under the concrete situation of another kind, n be 0 and p be 1; Or
● Y is that formula III b and n+p are 2, under a kind of concrete situation, and n
Be 2 and p be 0, under the concrete situation of another kind, n be 1 and p be 1; Or
● Y is formula IIb
1, IIb
2, IIb
3, IIIb
1, IIIb
2, IIIb
3Or IIIb
4
In another embodiment, the present invention relates to wherein, Y is formula IIb
1, IIb
2Or IIb
3Compound; Or wherein m be 0 and Y be the compound of formula IIb.
In another embodiment, the present invention relates to wherein, Y is formula IIb
1Compound.
In another embodiment, the present invention relates to wherein, Y is formula IIb
2Compound.
In another embodiment, the present invention relates to wherein, Y is formula IIb
3Compound.
In another embodiment, the present invention relates to the wherein compound of each group as giving a definition:
● Y is formula III b
1, IIIb
2, IIIb
3Or IIIb
4Or
● n be 0 and Y be formula III b; Or
● p be 0 and Y be formula III b; Or
● n is 0, p be 0 and Y be formula III b; Or
● Y is that formula III b and n+p are 1, under a kind of concrete situation, and n
Be 1 and p be 0, under the concrete situation of another kind, n be 0 and p be 1; Or
● Y is that formula III b and n+p are 2, under a kind of concrete situation, and n
Be 2 and p be 0, under the concrete situation of another kind, n be 1 and p be 1.
In another embodiment, the present invention relates to wherein, Y is formula III b
1Compound.
In another embodiment, the present invention relates to wherein, Y is formula III b
2Compound.
In another embodiment, the present invention relates to wherein, Y is formula III b
3Compound.
In another embodiment, the present invention relates to wherein, Y is formula III b
4Compound.
In another embodiment, the present invention relates to wherein, Y is the compound of formula IIc or IIIc:
Wherein W, m, n, p and R
5As above definition.
In another embodiment, the present invention relates to wherein, Y is the compound of formula IIc.
In another embodiment, the present invention relates to wherein m and be 0 and Y be the compound of formula IIc.
In another embodiment, the present invention relates to wherein, Y is the compound of formula III c.
In another embodiment, the present invention relates to wherein n and be 0 and Y be the compound of formula III c.
In another embodiment, the present invention relates to wherein p and be 0 and Y be the compound of formula III c.
In another embodiment, the present invention relates to wherein that n is 0, p be 0 and Y be the compound of formula III c.
In another embodiment, the present invention relates to wherein that Y is that formula III c and n+p are 1 compound, under a kind of concrete situation, n be 1 and p be 0, under the concrete situation of another kind, n be 0 and p be 1.
In another embodiment, the present invention relates to wherein that Y is that formula III c and n+p are 2 compound, under a kind of concrete situation, n be 2 and p be 0, under the concrete situation of another kind, n be 1 and p be 1.
In another embodiment, the present invention relates to wherein, Y is Formula Il c
1, IIc
2, IIc
3, IIIc
1, IIIc
2, IIIc
3Or IIIc
4Compound:
Wherein:
W as above defines;
R is 0,1 or 2;
S is 0,1,2 or 3; And
R
5 'And R
5 "Independently as R
5Definition, R
5Independent separately as above definition.
In another embodiment, the present invention relates to the wherein compound of each group as giving a definition:
● m be 0 and Y be formula IIc; Or
● n be 0 and Y be formula III c; Or
● p be 0 and Y be formula III c; Or
● n is 0, p be 0 and Y be formula III c; Or
● Y is that formula III c and n+p are 1, under a kind of concrete situation, and n
Be 1 and p be 0, under the concrete situation of another kind, n be 0 and p be 1; Or
● Y is that formula III c and n+p are 2, under a kind of concrete situation, and n
Be 2 and p be 0, under the concrete situation of another kind, n be 1 and p be 1; Or
● Y is formula IIc
1, IIc
2, IIc
3, IIIc
1, IIIc
2, IIIc
3Or IIIc
4
In another embodiment, the present invention relates to wherein, Y is formula IIc
1, IIc
2Or IIc
3Compound; Or m be 0 and Y be the compound of formula IIc.
In another embodiment, the present invention relates to wherein, Y is formula IIc
1Compound.
In another embodiment, the present invention relates to wherein, Y is formula IIc
2Compound.
In another embodiment, the present invention relates to wherein, Y is formula IIc
3Compound.
In another embodiment, the present invention relates to the wherein compound of each group as giving a definition:
● Y is formula III c
1, IIIc
2, IIIc
3Or IIIc
4Or
● n be 0 and Y be formula III c; Or
● p be 0 and Y be formula III c; Or
● n is 0, p be 0 and Y be formula III c; Or
● Y is that formula III c and n+p are 1, under a kind of concrete situation, and n
Be 1 and p be 0, under the concrete situation of another kind, n be 0 and p be 1; Or
● Y is that formula III c and n+p are 2, under a kind of concrete situation, and n
Be 2 and p be 0, under the concrete situation of another kind, n be 1 and p be 1.
In another embodiment, the present invention relates to wherein, Y is formula III c
1Compound.
In another embodiment, the present invention relates to wherein, Y is formula III c
2Compound.
In another embodiment, the present invention relates to wherein, Y is formula III c
3Compound.
In another embodiment, the present invention relates to wherein, Y is formula III c
4Compound.
In another embodiment, the present invention relates to r wherein and be 0 compound.
In another embodiment, the present invention relates to r wherein and be 1 compound.
In another embodiment, the present invention relates to r wherein and be 2 compound.
In another embodiment, the present invention relates to s wherein and be 0 compound.
In another embodiment, the present invention relates to s wherein and be 1,2 or 3 compound.
In another embodiment, the Y that the present invention relates to its Chinese style II represents the compound of following group:
● IIb
1, IIb
2, IIb
3, IIc
1, IIc
2Or IIc
3Or
● the group of formula IIb, wherein m is 0; Or
● the group of formula IIc, wherein m is 0.
In another embodiment, the Y that the present invention relates to its Chinese style II represents the compound of following group:
● IIb
1, IIb
2Or IIb
3Or
● the group of formula IIb, wherein m is 0; Or
● the group of formula IIc, wherein m is 0.
In another embodiment, the present invention relates to the compound that the Y of formula III wherein represents following group:
● IIIb
1, IIIb
2, IIIb
3, IIIb
4, IIIc
1, IIIc
2, IIIc
3Or IIIc
4
Or
● the group of formula III b, wherein n is 0; Or
● the group of formula III b, wherein p is 0; Or
● the group of formula III b, wherein n be 0 and p be 0; Or
● the group of formula III b, wherein n+p is 1, in a kind of concrete situation
Down, n be 1 and p be 0, under the concrete situation of another kind, n be 0 and p be
1; Or
● Y is that formula III b and n+p are 2, under a kind of concrete situation, and n
Be 2 and p be 0, under the concrete situation of another kind, n be 1 and p be 1;
● the group of formula III c, wherein n is 0; Or
● the group of formula III c, wherein p is 0; Or
● the group of formula III c, wherein n be 0 and p be 0; Or
● the group of formula III c, wherein n+p is 1, in a kind of concrete situation
Down, n be 1 and p be 0, under the concrete situation of another kind, n be 0 and p be
1; Or
● Y is that formula III c and n+p are 2, under a kind of concrete situation, and n
Be 2 and p be 0, under the concrete situation of another kind, n be 1 and p be 1.
In another embodiment, the present invention relates to the compound that the Y of formula III wherein represents following group:
● IIIb
2Or IIIc
2Or
● the group of formula III b, wherein n be 0 and p be 0; Or
● the group of formula III c, wherein n be 0 and p be 0.
In another embodiment, the present invention relates to wherein m and be 0 and Y be the compound of formula II, under a kind of concrete situation, Y is formula IIb or IIc.
In another embodiment, m is 1, and Y is formula II, and under a kind of concrete situation, Y is formula IIb, and under situation more specifically, Y is formula IIb
1, IIb
2Or IIb
3
In another embodiment, m is 1, R
5Be selected from C
1-6-alkane (alkene/alkynes) base and halogen and Y are formula II, and under a kind of concrete situation, Y is formula IIb, and under situation more specifically, Y is formula IIb
1, IIb
2Or IIb
3
In another embodiment, the present invention relates to wherein that m is 1, R
5Be C
1-6-alkane (alkene/alkynes) base and Y are the compound of formula II, and under a kind of concrete situation, Y is formula IIb, and under situation more specifically, Y is formula IIb
1Or IIb
3
In another embodiment, the present invention relates to wherein that m is 1, R
5Be in halogen atom (as bromine, chlorine or fluorine), and Y is the compound of formula II that under a kind of concrete situation, Y is formula IIb, under situation more specifically, Y is formula IIb
1, IIb
2Or IIb
3
In another embodiment, the present invention relates to wherein that m is 1, R
5Be bromine or chlorine, and Y is the compound of formula II, under a kind of concrete situation, Y is formula IIb, and under situation more specifically, Y is formula IIb
1, IIb
2Or IIb
3
In another embodiment, the present invention relates to wherein that m is 1, R
3Be C
1-6-alkane (alkene/alkynes) base, and Y is the compound of formula II, under a kind of concrete situation, Y is formula IIb, under situation more specifically, Y is formula IIb
1, IIb
2Or IIb
3, under the most concrete a kind of situation, Y is formula IIb
3
In another embodiment, the present invention relates to wherein R
1Be C
1-6-alkane (alkene/alkynes) base, m is 1, R
5Be C
1-6-alkane (alkene/alkynes) base or halogen and Y are the compound of formula II, and under a kind of concrete situation, Y is formula IIb, and under a kind of situation more specifically, Y is formula IIb
3
In another embodiment, the present invention relates to wherein that n is 0, p be 0 and Y be the compound of formula III, under concrete situation, Y is formula III b or IIIc.
In another embodiment, the present invention relates to wherein n and be 1 and Y be the compound of formula III, under concrete situation, Y is formula III b or IIIc, under situation more specifically, Y is formula III b
2, IIIb
3Or IIIc
2
In another embodiment, the present invention relates to wherein n+p and be 1 and Y be the compound of formula III, under a kind of concrete situation, Y is formula III c, under a kind of situation more specifically, Y is formula III c
2
In another embodiment, the present invention relates to wherein n+p and be 2 and Y be the compound of formula III, under a kind of concrete situation, Y is formula III b, under a kind of situation more specifically, Y is formula III b
2Or IIIb
3
In another embodiment, when W was Sauerstoffatom, Y was not formula II.
In another embodiment, the compound of formula I comprises no more than 3 aryl as defined above.
Preferred following compounds and pharmacy acceptable salt thereof:
1.{2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-methyl-amino]-phenyl }-urethanum;
2.{2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
3.{2-amino-4-[(5-methyl-thiophene-2-ylmethyl)-methyl-amino]-phenyl }-urethanum;
4.{2-amino-4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
5.{2-amino-4-[(6-chloro-3-methoxyl group-benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
6.{2-amino-4-[(benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
7.{2-amino-4-[(5-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
8.{2-amino-4-[(4-bromo-3-methoxyl group-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
9.{2-amino-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
10.{2-amino-4-[(3-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
11. (2-amino-4-[4-(4-chloro-benzene sulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-phenyl)-urethanum;
12.{2-amino-4-[(3-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
13.{2-amino-4-[(5-fluoro-cumarone-3-ylmethyl)-amino]-phenyl }-urethanum;
14.{2-amino-4-[(thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
15.{2-amino-4-[(4-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
16.{2-amino-4-[(5-ethyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
17.{2-amino-4-[(thiene-3-yl-methyl)-amino]-phenyl }-urethanum;
18.{2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-ethyl-amino]-phenyl }-urethanum;
19.{2-amino-4-[(benzo [b] thiene-3-yl-methyl)-amino]-phenyl }-urethanum;
20.{2-amino-4-[(5-dimethyl-amino-benzo [b] thiene-3-yl-methyl)-amino]-phenyl }-urethanum;
21.{2-amino-4-[(5-dimethyl-amino-3-methyl-benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
22.{2-amino-4-[(5-fluoro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
23.{2-amino-4-[(benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-the carboxylamine propyl ester;
24.{2-amino-4-[(benzo [b] thiene-3-yl-methyl)-amino]-phenyl }-the carboxylamine propyl ester;
25.N-{2-amino amino-4-[(5-chloro-thiophene-2-ylmethyl)]-phenyl }-2-(4-fluoro-phenyl)-ethanamide; With
26.N-{{2-amino amino-4-[(5-chloro-thiophene-2-ylmethyl)]-phenyl }-3,3-dimethyl-butyramide
One concrete aspect, preferred following compounds and pharmaceutically-acceptable acid addition thereof:
1.{2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-methyl-amino]-phenyl }-urethanum;
2.{2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
3.{2-amino-4-[(5-methyl-thiophene-2-ylmethyl)-methyl-amino]-phenyl }-urethanum;
4.{2-amino-4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
5.{2-amino-4-[(6-chloro-3-methoxyl group-benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
6.{2-amino-4-[(benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
7.{2-amino-4-[(5-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
8.{2-amino-4-[(4-bromo-3-methoxyl group-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
9.{2-amino-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
10.{2-amino-4-[(3-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
11. (2-amino-4-{[4-(4-chloro-benzene sulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-phenyl)-urethanum;
12.{2-amino-4-[(3-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
13.{2-amino-4-[(5-fluoro-cumarone-3-ylmethyl)-amino]-phenyl }-urethanum;
14.{2-amino-4-[(thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
15.{2-amino-4-[(4-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
16.{2-amino-4-[(5-ethyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
17.{2-amino-4-[(thiene-3-yl-methyl)-amino]-phenyl }-urethanum;
18.{2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-ethyl-amino]-phenyl }-urethanum.
On the one hand, the invention provides a kind of medicinal compositions, described composition comprises compound or its pharmacy acceptable salt of at least a I of formula as defined above that treats significant quantity, and one or more carrier of pharmaceutically accepting or thinners.
One concrete aspect, the invention provides a kind of medicinal compositions, described composition comprises compound or its pharmaceutically-acceptable acid addition of at least a I of formula as defined above that treats significant quantity, and one or more carrier of pharmaceutically accepting or thinners.
The invention provides a kind of medicinal compositions that is used for oral administration or parenteral admin, described medicinal compositions comprises the compound or its salt of at least a formula I that treats significant quantity, and one or more pharmaceutically acceptable carriers or thinner.
In one embodiment, compound of the present invention can be used as unique treatment active compound administration.
In another embodiment, compound of the present invention can be used as a part of administration of conjoint therapy, and compound promptly of the present invention can for example have the treatment active compound administration of anticonvulsion performance with other.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, and/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.
Think that compound of the present invention can be used for increasing the ion flow in the pressure-dependent potassium channel.
Think that compound of the present invention can be used for prevention, treatment and/or inhibition obstacle or the disease in response to the ion flow that increases in the potassium channel (as KCNQ family potassium-channel).
In one aspect, found that compound of the present invention is effective to the potassium-channel of KCNQ family (particularly KCNQ2 hypotype).
According to an aspect, think that compound of the present invention can be used for prevention, treats and/or suppresses various nervus centralis diseases, for example epileptic seizures disease is as convulsions, epilepsy and epileptic state; Anxiety disorder, as stress disease after anxiety, generalized anxiety disorder, panic anxiety, obsessional idea and behavior disease, social phobia, behavior anxiety, the wound, gross stress reaction, insufficiency of accommodation, hypochondriasis, separation anxiety disorder, agoraphobia and specific phobia disease.
Therefore, think that compound of the present invention can be used for prevention, treats and/or suppresses various nervus centralis diseases, for example:
● the epileptic seizures disease, as convulsions, epilepsy and epileptic state;
● neurodynia, as allodynia, hyperpathia pain, phantom pain, the neurodynia relevant and the neurodynia of being correlated with migraine with diabetic neuropathy;
● anxiety disorder, as stress disease after anxiety, generalized anxiety disorder, panic anxiety, obsessional idea and behavior disease, social phobia, behavior anxiety, the wound, gross stress reaction, insufficiency of accommodation, hypochondriasis, separation anxiety disorder, agoraphobia and specific phobia disease;
● 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 other unknown pathogenic infections cause; And
● the neuronal excitation transient state, for example at the medicine withdrawal with because the drunk neuronal excitation transient state that causes; The degenerative disease of peripheral nervous system is as polyneuropathy and polyneuritis.
Therefore, think that compound of the present invention can be used for prevention, treatment and/or suppresses epileptic seizures disease, neurodynia and disease or illnesss such as migraine disease, anxiety disorder and neurodegenerative disease.
According to a concrete aspect of the present invention, think that compound of the present invention can be used for prevention, treatment and/or suppresses the epileptic seizures disease, as convulsions, epilepsy and epileptic state.
According to a concrete aspect of the present invention, think that compound of the present invention can be used for prevention, treatment and/or suppresses neurodynia and migraine, as allodynia, hyperpathia pain, phantom pain, the neurodynia relevant and the neurodynia of being correlated with migraine with diabetic neuropathy.
Think that also compound of the present invention can be used for prevention, treatment and/or suppresses anxiety disorder, as stress disease, gross stress reaction, insufficiency of accommodation, hypochondriasis, separation anxiety disorder, agoraphobia 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 anxiety disorder and the specific phobia disease that material brings out.
Think that also compound of the present invention can be used for prevention, treatment and/or suppresses neurodegenerative disease, neurodegeneration and nervous excitation transient state 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 other unknown pathogenic infections cause are for example at medicine withdrawal and because the drunk neuronal excitation transient state that causes.
In yet another aspect, the invention provides all cpds that below one or more, demonstrates effect in the test:
● " 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 concrete 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.
According to a concrete 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 1500nM.
According to another concrete 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 150nM.
According to another concrete 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 another concrete 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 another concrete 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 chemical combination almost is free from side effects or inapparent clinically side effect is only arranged.Therefore some compound need not to carry out calmness, cooling and the ataxia model trial of this compound.
The clearance rate that some chemical combination has the suitable transformation period and is fit to this means that the patient for example only needs once a day or takes tablet twice.The patient is easy to remember, and helps to comply with pharmacological agent.
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 medicines to produce for those has more curative effect patient of side reaction.
Definition
Term " heteroatoms " is meant nitrogen, oxygen or sulphur atom.
" halogen " is meant fluorine, chlorine, bromine or iodine.
" C
1-6-alkane (alkene/alkynes) base " be meant C
1-6-alkyl, C
2-6-thiazolinyl or C
2-6-alkynyl.
Term " C
1-6-alkyl " be meant the branching with 1-6 carbon atom or the alkyl of non-branching, include but not limited to methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl group, 2-2-dimethyl-1-propyl group and 2-methyl isophthalic acid-propyl group.
Similarly, " C
2-6-thiazolinyl " and " C
2-6-alkynyl " be meant respectively have a 2-6 carbon atom comprise two keys and such group of triple-linked respectively, include but not limited to vinyl, propenyl, butenyl, ethynyl, proyl and butynyl.
" C
3-8-cycloalkanes (alkene) base " be meant C
3-8-cycloalkyl or cycloalkenyl group.
Term " C
3-8-cycloalkyl " be monocycle or bicyclic carbocyclic with 3-8 carbon atom, include but not limited to cyclopropyl, cyclopentyl, cyclohexyl etc.
Term " C
3-8-cycloalkenyl group " be monocycle or the bicyclic carbocyclic that has 3-8 carbon atom and comprise two keys.
The nitrogen-atoms that connects with their when two substituting groups forms optional when comprising 1,2 or 3 other heteroatomic 4-8 units saturated or unsaturated ring, and then described monocycle member ring systems is selected from the individual heteroatomic atom that is selected from N, S or O of nitrogen-atoms, a 1-7 carbon atom and 0-3 by 4-8 and forms.The example of this member ring systems is azetidine, beta-lactam (lactame), tetramethyleneimine, piperidines, piperazine, morpholine, pyrroles, oxazolidine, thiazolidine, imidazolidine, tetrazolium and pyrazoles.
Term " aryl " is meant the optional aryl system that is replaced by one or more substituting groups, for example pyridine, thiazole, oxazole, phenyl, naphthyl, thiophene and furans, and described substituting group independently is hydroxyl, halogen, 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, halo-C
1-6-alkane (alkene/alkynes) base, C
1-6-alkoxyl group, C
3-8-alkoxyl group, acyl group, nitro, cyano group ,-CO-NH-C
1-6-alkane (alkene/alkynes) base ,-CO-N (C
1-6-alkane (alkene/alkynes) base)
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
2O-C
1-6-alkane (alkene/alkynes) base ,-NH
2,-SO
2N (C
1-6-alkane (alkene/alkynes) base)
2Or-SO
2NH-C
1-6-alkane (alkene/alkynes) base; Or
Two adjacent substituting groups can form the optional first ring of one or two heteroatomic 4-8 that comprises with the aryl that they connect.
The aryl that connects with their when two adjacent substituting groups forms optional when comprising one or two heteroatomic 4-8 unit ring, and described member ring systems is selected from 3-8 carbon atom by 4-8 and the individual heteroatomic atom that is selected from N, S or O of 0-2 forms.Two adjacent substituting groups 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-,-O-(CH
2)
P "-NH-CH
2-,-S-(CH
2)
M "-NH-,-N=CH-NH-,-N=CH-O-or-N=CH-S-, wherein m " be 1,2 or 3, n " be 2,3 or 4 and p " be 1 or 2.
Term used herein " acyl group " 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
1-6The basic carbonyl of-alkane (alkene/alkynes), wherein C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base and aryl as above define.
Term " halo-C
1-6-alkane (alkene/alkynes) base " be meant the C that is replaced by one or more halogen atoms
1-6-alkane (alkene/alkynes) base includes but not limited to trifluoromethyl.Similarly, " halo-C
3-8-cycloalkanes (alkene) base " be meant the C that is replaced by one or more halogen atoms
3-8-cycloalkanes (alkene) base, " halo-C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base " be meant the C that is replaced by one or more halogen atoms
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base.
Term " C
3-8-cycloalkanes (alkene) base-C
1-6-alkane (alkene/alkynes) base ", " C
3-8-cycloalkanes (alkene) base " and " C
1-6-alkane (alkene/alkynes) base " as above definition.
In addition, term such as hydroxyl-C
1-6-alkane (alkene/alkynes) base, hydroxyl-C
3-8-cycloalkanes (alkene) base, aryl-C
1-6-alkane (alkene/alkynes) base, C
1-6The basic oxygen base of-alkane (alkene/alkynes), C
3-8The basic oxygen base of-cycloalkanes (alkene), C
1-6The basic carbonyl of-alkane (alkene/alkynes), C
3-8The basic carbonyl of-cycloalkanes (alkene), 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), aryl-C
3-8-cycloalkanes (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, 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 and NR
10R
10 '-C
3-8-cycloalkanes (alkene) base etc. is meant wherein C
1-6-alkane (alkene/alkynes) base, C
3-8-cycloalkanes (alkene) base and aryl be group as defined above.
Salt of the present invention is preferably pharmacy acceptable salt.This salt comprises pharmaceutically-acceptable acid addition, pharmaceutically acceptable metal-salt, ammonium salt and alkylating ammonium salt.
Pharmacy acceptable salt of the present invention is preferably acid salt.
Acid salt comprises mineral acid and organic 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.
The example of this organic salt has and toxilic acid, fumaric acid, phenylformic acid, xitix, succsinic acid, oxalic acid, dimethylene Whitfield's ointment (bis-methylene salicylic acid), methylsulfonic acid, ethyl sulfonic acid, acetate, propionic acid, tartrate, Whitfield's ointment, citric acid, glyconic acid, lactic acid, oxysuccinic acid, tussol, styracin, citraconic acid, aspartic acid, stearic acid, palmitinic acid, methylene-succinic acid, oxyacetic acid, para-amino benzoic acid, L-glutamic acid, the salt that Phenylsulfonic acid and acetate theophylline and 8-halo theophylline (as 8-bromo theophylline) form.
The example of this inorganic salt has the salt that forms with spirit of salt, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid and nitric acid.This acid salt can be by well known to a person skilled in the art the method preparation.Pharmaceutically acceptable other examples inorganic or organic acid addition salt are included in J.Pharm.Sci.1977, the pharmacy acceptable salt of listing in 66,2, and the document is combined in herein by reference.
The hydride that another kind of pharmaceutically-acceptable acid addition can form for this compound.
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 category 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 category 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 at category of the present invention.
In addition, compound of the present invention can non-solventization and the solvation form of pharmaceutically acceptable solvent exist, 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.
Some compound of the present invention comprises chiral centre, and these compounds exist with isomer (being optically active isomer) form.The present invention includes all these isomer and any mixture (comprising racemic mixture) thereof.
Racemic form can be split as optically active enantiomorph with known method, for example by separating diastereoisomeric salt 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 1-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 general formula I that is easy to be converted in vivo the compound of required general formula I.The conventional steps that is used to select and prepares suitable prodrug derivant for example is described in " prodrug design " (" Design ofProdrugs ", H.Bundgaard compiles, Elsevier, 1985).
The present invention also comprises the active metabolite of The compounds of this invention.
The term relevant with the compound of formula I " epilepsy and various epilepsy " 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, 1981 22:489-501 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, 1,989 30 (4): any epilepsy that proposes among the 389-399, epilepsy syndromes and epileptic seizures.
Medicinal compositions
Compound of the present invention is used with free alkali or with the form of its pharmacy acceptable salt usually.Representative example as mentioned above.
If desired, pharmaceutical composition of the present invention can comprise the combination of compound and other the aforesaid pharmacological active substances of formula I.
Described medicinal compositions can specifically be allocated 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, muscle, the sheath, intravenously and intradermal) approach, the preferred oral approach.Preferred approach depends on by curer's general body state and age, the character of being treated disease and selected active ingredient.
Medicinal compositions of the present invention or those medicinal compositionss prepared in accordance with the present invention can pass through any suitable administration, for example with form oral administrations such as tablet, capsule, powder, granule, pill, coated tablet, pill or lozenge, solution in water or on-aqueous liquid or suspensoid, oil-in-water or water-in-oil liquid emulsion, elixir, syrup, or with the injection solution form through parenteral admin.Other medicinal compositionss that are used for parenteral admin comprise 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 category 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.
Method well known in the art can be used for preparing this composition, and can use conventional any pharmaceutically acceptable carrier, thinner, vehicle or other additives that uses in this area.
Compound of the present invention is carried out administration with the unitary dose that contains the described compound of about 0.01-100mg.Usually total per daily dose scope is about 0.05-500mg or even 0.05-1500mg or 0.05-3000mg, the most preferably from about active compound of the present invention of 0.1-50mg.For the parenteral approach (as in intravenously, the sheath, intramuscular and similarly administration), dosage is about half of oral administration dosage usually.
Compound of the present invention can be individually dosed or be combined with one-pack type or multi-form administration with pharmaceutically acceptable carrier or vehicle.Medicinal compositions of the present invention can with pharmaceutically acceptable carrier or thinner and any according to known other additives of this area common process and vehicle allotment, as Remington:The Science and Practice ofPharmacy (the 19th edition, Gennaro compiles, Mack Publishing Co., Easton, PA, 1995) middle those disclosed.Described preparation can provide with unit dosage by the pharmaceutical field known method.
Can use any other auxiliary material or the additive that are generally used for painted, seasoning, purpose such as anticorrosion, as tinting material, seasonings, sanitas etc., condition is that they and active ingredient are compatible.
Pharmaceutical preparation of the present invention can be according to the ordinary method preparation of this area.For example, with activeconstituents and common various assistant agents and/or mixing diluents, this mixture of compacting can prepare tablet in the tabletting machine of routine subsequently.The example of assistant agent or thinner comprises: W-Gum, yam starch, talcum, Magnesium Stearate, gelatin, lactose, natural gum etc.Can use any other to be generally used for the assistant agent or the additive of painted, seasoning, purpose such as anticorrosion, as tinting material, seasonings, sanitas etc., condition is that they can be compatible with described activeconstituents.
In appropriate circumstances, can prepare the solid dosage of dressing (as enteric coating) according to methods known in the art, perhaps allotment is so that provide the controlled release (discharging as continuing or prolonging) of activeconstituents.
If used liquid vehicle, described preparation can be syrup, emulsion, soft capsule or aseptic injection liquid (as water or on-aqueous liquid suspension or solution).
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.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 (tonicity agents), sanitas, antioxidant etc. are used for.Therefore, if desired, this aqueous solution can suitably be cushioned, and at first diluent is given etc. with the salt of capacity or glucose and being oozed.The aqueous solution is specially adapted to intravenously, intramuscular, subcutaneous and intraperitoneal administration.The aseptic aqueous medium that uses easily obtains through well known to a person skilled in the art standard technology.
The pharmaceutical carrier that is fit to comprises inert solid diluent or filler, aseptic aqueous solution and various organic solvent.The example of liquid vehicle has syrup, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, polyoxyethylene and water.Similarly, described carrier or thinner can comprise any extended release material well known in the art, for example use the mixture of Zerol or Stearic diglyceride or itself and wax separately.
The representative instance of the prescription of preparation of the present invention is as follows:
1) tablet contains 5.0mg compound of the present invention, calculates with free alkali:
| The compound of formula I | 5.0mg |
| Lactose | 60mg |
| W-Gum | 30mg |
| Hydroxypropylcellulose | 2.4mg |
| Microcrystalline Cellulose | 19.2mg |
| Croscarmellose sodium A type | 2.4mg |
| Magnesium Stearate | 0.84mg |
2) tablet contains 0.5mg compound of the present invention, calculates with free alkali:
| The compound of formula I | 0.5mg |
| Lactose | 46.9mg |
| W-Gum | 23.5mg |
| Polyvidone | 1.8mg |
| Microcrystalline Cellulose | 14.4mg |
| Croscarmellose sodium A type | 1.8mg |
| Magnesium Stearate | 0.63mg |
3) syrup, every milliliter contains:
| The compound of formula I | 25mg |
| Sorbyl alcohol | 500mg |
| Hydroxypropylcellulose | 15mg |
| Glycerine | 50mg |
| Methyl p-hydroxybenzoate | 1mg |
| Propylparaben | 0.1mg |
| Ethanol | 0.005ml |
| Seasonings | 0.05mg |
| Soluble saccharin | 0.5mg |
| Water | 1ml |
4) injection solution, every milliliter contains:
| The compound of formula I | 0.5mg |
| Sorbyl alcohol | 5.1mg |
| Acetate | 0.05mg |
| Soluble saccharin | 0.5mg |
| Water | Add to 1ml |
The preparation of The compounds of this invention
The The compounds of this invention of general formula I, wherein R
1, R
2, R
2 ', R
3, X, Y, Z and q as above define, by the preparation of the method shown in the flow process, and be described below:
Hereinafter, any R
1, R
2, R
2 ', R
3, R
4, R
5, R
6, R
6 ', R
7, R
7 ', R
8, R
9, R
9 ', R
10, R
10 ', X, Y, Z, W, m, n, p and q as above define.
The compound of general formula VII according to this area chemical technology personnel known method preparation (Sonderdruck 103,3-15), are summarized as follows for people such as v.Bebenburg, Chemiker Zeitung 1979:
The compound of general formula I V prepares by the following method: in the suitable temperature (as room temperature or reflux temperature) that obtains by conventional heating or microwave radiation, the solvent that is fit to is (as ethyl acetate diox, tetrahydrofuran (THF), acetonitrile or ether) in, add or do not add alkali (as trialkylamine, salt of wormwood or lithium, the alkoxide of sodium or potassium) under, by 4-N-methyl-p-nitroaniline and the electrophilic reagent that is fit to (such as but not limited to acyl chlorides, acylbromide, acyl iodides, SULPHURYL CHLORIDE, isocyanic ester, carbonic acid gas, active ester and halo alkyl formate) reaction, then in suitable temperature, the hydrogenation catalyst (draping over one's shoulders carbon as palladium) that is fit to exists down, in the solvent (as methyl alcohol or ethanol) that is fit to, use the reductive agent that is fit to (as V-Brite B, iron powder in the spirit of salt or zinc powder or hydrogen) the reduction nitro.
The compound of general formula V is by under the temperature that is fit to, in the solvent (as Glacial acetic acid) that is fit to, by the compound of general formula I V and reagent (as the Tetra hydro Phthalic anhydride) prepared in reaction that forms blocking group on anilino.
The compound of general formula VI is by under the temperature that is fit to, in the solvent (as Glacial acetic acid) that is fit to, by the compound of general formula V according to the known nitration reaction preparation of this area chemical technology personnel, for example with the nitrosonitric acid prepared in reaction.
The compound of general formula VII by under the temperature that is fit to, the solvent (such as the diox that are fit to) in, go protection to obtain aniline functional group by the compound of general formula VI with hydrazine hydrate.
Perhaps, the compound of general formula VII can be by 2-nitro-1, and the 4-diaminobenzene is described below with three step preparations shown in the flow process.The first step; under the temperature that is fit to, in the solvent (as acetonitrile) that is fit to; react by reagent (as tert-Butyl dicarbonate) with the formation blocking group that is fit to; with the nitrogen on the less and more active aniline of steric hindrance with suitable blocking group PG (as tert-butoxycarbonyl; Boc) protection (see " protecting group in the organic synthesis " (" ProtectiveGroups in Organic Synthesis); the 3rd edition; T.W.Greene; P.G.M.Wuts; WileyInterscience 1999), obtain the compound of general formula X I.
The compound of general formula X II under the temperature (room temperature or reflux temperature) that is fit to that obtains by routine heating or microwave radiation, the solvent that is fit to is (as acetonitrile, tetrahydrofuran (THF), 1,2-ethylene dichloride or methylene dichloride) in, add or do not add under the alkali (as magnesium oxide, salt of wormwood, trialkylamine, pyridine or sodium bicarbonate) of the compound that is used for above-mentioned general formula I V, by the compound of general formula X I with form R
3-(Z) the suitable electrophilic reagent of q-X group (as chloroformyl alkyl ester, chloroformyl aryl ester, chloroformyl heteroaryl ester, urea chloride, acyl chlorides, acylbromide, acyl iodides, SULPHURYL CHLORIDE, isocyanic ester, carbonic anhydride, active carbonic acid) and activator be (as carbodiimide or other activators reactions well known by persons skilled in the art.
Adopt this area chemical technology personnel known method to remove described blocking group.Specifically, in suitable temperature, do not exist or exist under the solvent (as methylene dichloride or toluene), handle with the acid (as trifluoroacetic acid) that is fit to and to remove the Boc group, obtain the compound of general formula VII.
The preparation of the compound of general formula VIII:
Under the temperature that is fit to, in the solvent (as methyl alcohol, ethanol, tetrahydrofuran (THF), water, diox or its mixture) that is fit to, add or do not add under the acid (as acetate) of catalytic amount, use the aldehyde (R wherein of reductive agent (as sodium borohydride or sodium cyanoborohydride) and general formula I Ia or IIIa
5, W, m, n and p as above define) compound of mutual-through type VII carries out the known reductive alkylation reaction of this area chemical technology personnel, forms the compound of general formula VIII, wherein R
1Be hydrogen.
Perhaps, in the temperature that is fit to, suitable solvent (as methyl alcohol, ethanol, tetrahydrofuran (THF), diox, dimethylbenzene or its mixture), the aldehyde reaction that adds or do not add under the acid (as acetate or acidic ion exchange resin) of catalytic amount the compound of general formula VII and general formula I Ia or IIIa forms imines, this imines can be by crystallization or evaporating solvent separation.In appropriate solvent (as methyl alcohol, ethanol, tetrahydrofuran (THF), water, diox or its mixture), this imines is reduced subsequently, obtain the compound of general formula VIII, wherein R with reductive agent (as sodium borohydride or sodium cyanoborohydride)
1Be hydrogen.
Optional, in order to change R
1In the solvent (as methyl alcohol, ethanol, tetrahydrofuran (THF), water, diox or its mixture) of can be under aforesaid suitable temperature, being fit to, add or do not add the acid (as acetate) of catalytic amount, with the aldehyde that is fit to and reductive agent (as sodium borohydride or sodium cyanoborohydride) compound of the general formula VIII that obtains is carried out reductive alkylation once more.This step also can be carried out with the aldehyde original position of universal architecture IIa or IIIa after first time reductive alkylation.
Perhaps, in order to change R
1In the solvent (as ethyl acetate, diox, tetrahydrofuran (THF) or ether) of can be under aforesaid suitable temperature, being fit to; add alkali (as the alcoholate of trialkylamine, salt of wormwood or lithium, sodium or potassium), use the electrophilic reagent (as acyl chlorides, acylbromide, acyl iodides, SULPHURYL CHLORIDE and halo alkyl formate) that is fit to that the compound of the general formula VIII that obtains is carried out acylation reaction.
The compound of general formula I X is under the temperature that is fit to, in the solvent (as methyl alcohol or ethanol or water/tetrahydrofuran compound) that is fit to, reducing the compound of general formula VIII with the reductive agent that is fit to (as V-Brite B, existence or do not have spirit of salt or the iron powder in the acetate or the zinc powder of organic solvent (as tetrahydrofuran (THF) or ethanol), or the hydrogen in the presence of the hydrogenation catalyst (draping over one's shoulders carbon as palladium) that is fit to) obtains.The compound that obtains is identical with the compound of general formula I of the present invention, wherein R
2And R
2 'Be hydrogen and R wherein
1, R
3, X, Y, Z and q as above define.
The compound of general formula I (R wherein
1Be not hydrogen and R
2With optional R
2 'Be not hydrogen) adopt following method by the compound of general formula I X (R wherein
1For hydrogen) reaction obtains:
R
2By under aforesaid suitable temperature, in the solvent (as methyl alcohol, ethanol, tetrahydrofuran (THF), water, diox or its mixture) that is fit to, add or do not add the catalysis metering acid (as acetate), use the aldehyde that is fit to and reductive agent (as sodium borohydride or sodium cyanoborohydride) to carry out the reductive alkylation step to introduce.
Optional R
2 'By under aforesaid suitable temperature, in the solvent (as methyl alcohol, ethanol, tetrahydrofuran (THF), water, diox or its mixture) that is fit to, add or do not add catalytic amount acid (as acetate), use the aldehyde that is fit to and reductive agent (as sodium borohydride or sodium cyanoborohydride) to carry out other reductive alkylation step once more to introduce.
Perhaps, R
2Or R
2 'By under aforesaid suitable temperature, in the solvent (as ethyl acetate, diox, tetrahydrofuran (THF) or ether) that is fit to, add alkali (as the alcoholate of trialkylamine, salt of wormwood or lithium, sodium or potassium), use the electrophilic reagent (as acyl chlorides, acylbromide, acyl iodides, SULPHURYL CHLORIDE and halo alkyl formate) that is fit to carry out acylation reaction and introduce.
In order to obtain wherein R
1Be hydrogen, and R
2With optional R
2 'Be not the compound of Formula I of hydrogen, before the reduction nitro, introduce blocking group (as tert-butoxycarbonyl) as R by this area chemical technology personnel known method
1Adopt currently known methods introducing R
2With optional R
2 'After, remove this blocking group.
The compound of general formula I Ia and IIIa is summarized as follows by the preparation of this area chemical technology personnel known method:
Go back the original carboxylic acid ester with appropriate reductant (as diisobutyl aluminium hydride), then the benzylalcohol that obtains with the oxygenant that is fit to (as crossing ruthenic acid tetrapropyl ammonium (tetrapropyl ammonium perruthenate)/N-methylmorpholine-N-oxide compound, pyridinium chlorochromate, methyl-sulphoxide/oxalyl chloride) oxidation.Perhaps, the compound of general formula I Ia and IIIa can by with the preparation of the formylation reaction of dichloromethyl metyl ether and titanium tetrachloride (people such as Gross, Org.Synth.Coll, 1973 V volume, 365; People such as Fanghaenel, J.Prakt.Chem.1997,339,277).Perhaps, the compound of general formula I I and IIIa can be by the preparation of this area chemical technology personnel known method, and for example heteroaromatics is with highly basic (as lithium alkylide) deprotonation, subsequently with N, and the dinethylformamide prepared in reaction.Perhaps, the compound of general formula I Ia and IIIa can prepare by this area chemical technology personnel known method, for example the halogen metal permutoid reaction of halo heteroaromatics (as iodide or bromide) and metallization reagent (as lithium alkylide or magnesium alkyl halide or dialkyl magnesium) reaction.Perhaps, the compound of general formula I Ia and IIIa can be by the preparation of this area chemical technology personnel known method, for example at N-methyl-N-phenyl formamide (people such as King, J.Org.Chem.1949,14,63 8) or N, dinethylformamide (Vilsmeier formylation, people such as Raimundo, J.Org.Chem.2002,67,205) there are down thiophene and thionaphthene and phosphoryl chloride reaction.
Embodiment
The LC-MS analytical data derives from the PE Sciex API 150EX instrument that ionspray source and Shimadzu LC-8A/SLC-10A LC system are housed.Post: 30 * 4.6mm WatersSymmetry C18 post, packing material size are 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 or t
R) in minute.
On identical instrument, be prepared the 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 or under Bruker AC250 instrument, 250.13MHz
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, qui=quintet, h=septet, dd=doublet of doublet, ddd=are heavy in pairs bimodal, dual three peaks of dt=, dual four peaks of dq=, triple three peaks of tt=, the m=multiplet, and b=is wide unimodal.In some cases, provide coupling constant J.Write down fusing point (M.P.) on B ü chiB-540 instrument, these data are not calibrated.
The preparation of intermediate
The preparation of (4-amino-phenyl)-urethanum
With the 4-N-methyl-p-nitroaniline (100g 0.72mol) is dissolved in ethyl acetate (800ml), add subsequently diisopropylethylamine (89.6ml, 0.936mol).(252ml 1.45mol), stirred this solution 18 hours subsequently at ambient temperature to add the Vinyl chloroformate that is dissolved in the ethyl acetate (200ml).Wash this mixture with 2M HCl (300ml) and salt solution (300ml), through dried over mgso, and vacuum concentration is to half of initial volume.Add palladium in the solution that obtains and drape over one's shoulders carbon (10g, 5%Pd, 50%H
2O), at ambient temperature with this mixture at Parr device (pH
2=3bar) in hydrogenation 12 hours.This reaction mixture filters through diatomite (Celite), and vacuum evaporating solvent obtains the title compound of 118g (90%) crystallized product form.
LC/MS(m/z)180.9(MH
+)；t
R＝0.60min.
1H NMR(CDCl
3)：1.27(t，3H)；3.42(b，，2H，NH
2)；4.19(q，2H)；6.52(b，1H NH)；6.64(m，2H)；7.14.(m，2H).
Compound below similar method preparation:
(4-amino-phenyl)-carboxylamine propyl ester
Productive rate: 98%.
1H NMR(CDCl
3)：0.96(t，3H)；1.68(m，2H)；3.51(b，2H)；4.09(t，2H)；6.46(b，1H)；6.63(d，2H)；7.14(m，2H).
(4-phthaloyl imino-phenyl)-urethanum
(118g 0.65mol) is dissolved in Glacial acetic acid (2.0L), subsequently with this mixture heating up to 90 ℃ with (4-amino-phenyl)-urethanum under nitrogen atmosphere.Added Tetra hydro Phthalic anhydride in 30 minutes (102.0g 0.69mol), is reflected at and carried out under 90 ℃ 2 hours in batches.Make this mixture be cooled to envrionment temperature, and the filtering precipitated solid.Water (2L), ether (3L) wash this solid and vacuum-drying successively on strainer.Obtain the title compound of 127g (62%) white crystal shape.
LC/MS(m/z)311.3(MH
+)；t
R＝2.57min.
1H NMR(DMSO-d
6)：1.26(t，3H)；4.15(q，2H)；7.34(dd，2H)7.58(dd，2H)；7.90(ddd，2H)；7.95(ddd，2H)；9.80(s，1H，NH).
Compound below similar method preparation:
(4-phthaloyl imino-phenyl)-carboxylamine propyl ester
Productive rate: 81%.
(2-nitro-4-phthaloyl imino-phenyl)-urethanum
(99.0g 0.32mol) is suspended in the Glacial acetic acid (1.5L) and is heated to 90 ℃ with (4-phthaloyl imino-phenyl)-urethanum.Under 90-95 ℃, in 30 minutes, drip nitrosonitric acid (17.2ml, 0.41mol).Subsequently reaction mixture was stirred 1 hour down at 100 ℃, and be cooled to envrionment temperature.Filtering crystalline solid is also washed with Glacial acetic acid (500ml), water (1L) and ether (1L) on strainer, and vacuum-drying subsequently obtains the title compound of 101g (90%) yellow solid shape.
LC/MS(m/z)355.0(MH
+)；t
R＝3.34min.
1H NMR(DMSO-d
6)：1.25(t，3H)；4.16(q，2H)；7.81(m，2H)；7.93(ddd，2H)；7.99(ddd，2H)；6.15(dd，1H)；9.99(s，1H，NH).
Compound below similar method preparation:
(2-nitro-4-phthaloyl imino-phenyl)-carboxylamine propyl ester
Productive rate: 70%.
(4-amino-2-nitro-phenyl)-urethanum
With 1,2-glycol dimethyl ether (1.0L) add (2-nitro-4-phthaloyl imino-phenyl)-urethanum (101g, 0.28mol) in, subsequently this mixture heating up is refluxed.In 10 minutes, drip a hydrazine hydrate (19.6g, 0.39mol), and with this mixture stirring and refluxing 1.5 hours.In case be cooled to envrionment temperature, this mixture is filtered, on strainer, wash solid subsequently with glycol dimethyl ether (250ml).Evaporation concentration filtrate is with red crystallization recrystallization from toluene (350ml), filtering-depositing product and vacuum-drying.Mother liquor is concentrated into half of initial volume and left standstill 16 hours.Filtering precipitate, and as above carry out recrystallization.The solid of recrystallization is merged, obtain 57.6g (90%) scarlet title compound altogether.
LC/MS(m/z)225.1(MH
+)；t
R＝2.08min.
1H NMR(CDCl
3)：1.33(t，3H)；3.77(s，2H，NH
2)；4.23(q，2H)；6.98(dd，1H)；7.45(d，1H)；8.28(d，1H)；9.39(s，1H，NH).
Compound below similar method preparation:
(4-amino-2-nitro-phenyl)-carboxylamine propyl ester
Productive rate: 91%.
1H NMR(CDCl
3)：0.98(t，3H)；1.71(m，2H)；3.78(b，2H)；4.13(t，2H)；6.98(dd，1H)；7.44(d，1H)；8.27(d，1H)；9.39(s，1H).
(4-amino-3-nitro-phenyl)-t-butyl carbamate
In 2 hours, toward the 2-nitro-1 that refluxes, (10.135g adds Boc in tetrahydrofuran (THF) 66.18mmol) (100ml) solution to the 4-diaminobenzene in batches
2O (tert-Butyl dicarbonate, 32.6g, 149mmol).With the solution impouring heptane (2L) that obtains, supersound process 15 minutes is filtered and vacuum-drying, obtains the title compound of 13.40g red solid form.Productive rate: 80%.
LC/MS(m/z)295.4([M+H+MeCN]
+)；t
R＝2.54(UV，ELSD)96％，100％.
1H NMR(DMSO-d
6)：1.47(s，9H)；6.96(d，1H)；7.24(s，2H，NH
2)，7.41(dd，1H)；8.20(s，1H)；9.28(s，1H，NH).
[4-(4-chloro-benzene sulfonyl)-3-methyl-thiophene-2-yl]-methyl alcohol
Under nitrogen atmosphere, with 4-(4-chloro-benzene sulfonyl)-3-methyl-thiophene-2-carboxylic acid methyl esters (992mg, 3.00mmol) solution in anhydrous tetrahydro furan (20ml) and anhydrous methylene chloride (10ml) is cooled to 0 ℃, adds DIBAL-H (9.0ml subsequently, 9.0mmol, the toluene solution of 1M).After 3 hours, (4.5ml 4.5mmol), and continues to stir 2 hours to add another part DIBAL-H.Add this reaction of saturated Rochelle (Rochelle) salts solution (30ml) quencher, at room temperature stirred subsequently 1 hour.Separate each phase, with ethyl acetate (2 * 50ml) aqueous phase extracted, subsequently with the organic phase that merges through dried over sodium sulfate, and vacuum-evaporation.Product is passed through the silica gel column chromatography purifying on the FlashMaster system, heptane/ethyl acetate is an elutriant (linear gradient elution 1: 0-6: 4).Merge the part that contains product, vacuum-evaporation obtains required compound (788mg, 87%).LC-MS:(m/z)=285.2 (M-H
2O+H
+), C
12H
10ClO
2S
2Calculated value: 284.9805,
t
R＝2.45min.
1H NMR(CDCl
3)：1.84(t，J＝5.7Hz，1H)，2.20(s，3H)，4.73(d，J＝5.7Hz，2H)，7.49(d，J＝8.5Hz，2H)，7.84(d，J＝8.5Hz，2H)，8.18(s，1H).
Adopt the following compound of similar method preparation:
(3-chloro-thiophene-2-yl)-methyl alcohol
Productive rate: 73%.
1H NMR(CDCl
3)：1.92(b，1H)，4.81(s，2H)，6.91(d，J＝5.2Hz，1H)，7.25(d，J＝5.2Hz，1H).
(5-dimethylamino-benzo [b] thiene-3-yl-)-methyl alcohol
Productive rate: 63%.
1H NMR(CDCl
3)：1.62(b，1H)，3.01(s，6H)，4.89(s，2H)，6.96(dd，1H)，7.11(d，1H)，7.34(s，1H)，7.68，(d，J＝9.0Hz，1H).
(5-two basic amino-3-methyl-benzo [b] thiophene-2-yl)-methyl alcohol
Productive rate: 56%.
1H NMR(CDCl
3)：1.69(t，J＝5.9Hz，1H)，2.35(s，3H)，3.00(s，6H)，4.88(d，2H)，6.90(d，1H)，6.93(dd，1H)，7.63，(d，1H).
(4-bromo-3-methoxyl group-thiophene-2-yl)-methyl alcohol
With 4-bromo-3-hydroxyl-thiophene-2-carboxylic acid methyl esters (948mg, 4.00mmol), methyl-sulfate (0.57ml, 6.0mmol) and K
2CO
3(1.11g, 8.0mmol) the suspension reflux in acetone (10ml) is 4 hours.After being cooled to room temperature, add entry (25ml).(2 * 25ml) extract this reactant, and combining extraction liquid is through dried over sodium sulfate, and vacuum-evaporation with ethyl acetate.Residue is dissolved in anhydrous tetrahydro furan (20ml), under nitrogen atmosphere, this solution is cooled to 0 ℃, add DIBAL-H (12ml, 12mmol, the toluene solution of 1M) subsequently.After 2 hours, (6ml 6mmol), continues to stir 2 hours to add another part DIBAL-H.Should react quencher by adding saturated Rochelle salt solution (30ml), at room temperature this mixture be stirred 1 hour subsequently.Separate each phase, (2 * 50ml) extracted organic phase, the organic phase of merging is through dried over sodium sulfate and vacuum-evaporation with ethyl acetate.Product is passed through the silica gel column chromatography purifying on the FlashMaster system, heptane/ethyl acetate is an elutriant (linear gradient elution 1: 0-6: 4).Merge the part that contains product, vacuum-evaporation obtains required compound (482mg, 54%).
1H NMR(CDCl
3)：1.86(b，1H)，3.90(s，3H)，4.77(s，2H)，7.15(s，1H).
Adopt the following compound of similar method preparation:
(6-chloro-3-methoxyl group-benzo [b] thiophene-2-yl)-methyl alcohol
Productive rate: 75%.
1H NMR(CDCl
3)：1.92(t，J＝5.9 Hz，1H)，3.99(s，3H)，4.90(d，J＝5.7Hz，2H)，7.33(dd，J＝1.9，8.5Hz，1H)，7.64(d，J＝8.5Hz，1H)，7.73(d，J＝1.9Hz，1H).
The preparation of the heteroaryl aldehyde of general formula I Ia and IIIa
4-(4-chloro-benzene sulfonyl)-3-methyl-thiophene-2-formaldehyde
Toward [4-(4-chloro-benzene sulfonyl)-3-methyl-thiophene-2-yl]-methyl alcohol (786mg, 2.60mmol), 4-methylmorpholine N-oxide compound (0.46g, 3.9mmol) and powdery 4 molecular sieve (1.3g, through vacuum heat-activated in short-term) added in the suspension in methylene dichloride (7ml) the ruthenic acid tetrapropyl ammonium (46mg, 0.13mmol).The mixture that obtains was stirred 1 hour,, use eluent ethyl acetate with after silica gel (approximately 25g) post filters.With the eluate vaporising under vacuum, subsequently product is passed through the silica gel column chromatography purifying on the FlashMaster system, heptane/ethyl acetate is an elutriant (linear gradient elution 1: 0-1: 1).Merge the part that contains product, vacuum-evaporation obtains title compound (644mg, 82%).
1H NMR(CDCl
3)：2.60(s，3H)，7.53(d，J＝9.0Hz，2H)，7.87(d，J＝8.5Hz，2H)，8.53(s，1H)，10.01(s，1H).
Adopt the following aldehyde of similar method preparation:
3-chloro-thiophene-2-formaldehyde
Productive rate: 94%.
1H NMR(CDCl
3)：7.07(d，J＝5.2Hz，1H)，7.72(d，J＝0.5，4.7Hz，1H)，10.07(d，J＝0.9Hz，1H).
4-bromo-3-methoxyl group-thiophene-2-formaldehyde
Productive rate: 45%.
1H NMR(CDCl
3)：4.18(s，3H)，7.60(d，J＝1.4Hz，1H)，10.08(d，J＝1.4Hz，1H).
6-chloro-3-methoxyl group-benzo [b] thiophene-2-formaldehyde
Productive rate: 86%.
1H NMR(CDCl
3)：4.34(s，3H)，7.36(dd，J＝1.7，8.7Hz，1H)，7.75(d，J＝1.4Hz，1H)，7.82(d，J＝8.5Hz，1H)，10.36(s，1H).
5-dimethylamino-benzo [b] thiophene-3-formaldehyde
Productive rate: 72%.
1H NMR(CDCl
3)：3.05(s，6H)，7.00(dd，J＝2.4，9.0Hz，1H)，7.68(d，J＝9.0Hz，1H)，7.99(d，J＝2.8Hz，1H)，8.24(s，1H)，10.11(s，1H).
5-dimethylamino-3-methyl-benzo [b] thiophene-2-formaldehyde
Productive rate: 73%.
1H NMR(CDCl
3)：2.74(s，3H)，3.03(s，6H)，7.00(d，J＝2.4Hz，1H)，7.12(dd，J＝2.4，9.0Hz，1H)，7.69(d，J＝9.0Hz，1H)，10.30(s，1H).
5-fluoro-cumarone-3-formaldehyde
Under-60 ℃ of constant temperature, will (3.27g, (2.65g be in methylene dichloride 20.9mmol) (30ml) solution, subsequently with this solution stirring 15 minutes 41.8mmol) to add oxalyl chloride at the methyl-sulphoxide in the methylene dichloride (10ml).-60 ℃ drip down 1-(5-fluorobenzene and the furans-3-yl) methyl alcohol that are dissolved in the methylene dichloride (60ml) (3.16g, 19.0mmol).This mixture was stirred 20 minutes, add subsequently triethylamine (9.61g, 0.095mmol).Stir after 10 minutes, with this reaction mixture heat temperature raising to envrionment temperature, and restir 20 minutes.Use the water of 50ml, hydrochloric acid, saturated sodium bicarbonate aqueous solution and the salt water washing of 1N successively,, obtain the title product crude product of light brown crystalline solid forms with quantitative yield through dried over mgso and vacuum concentration.
1H NMR(CDCl
3)：7.13(dt，1H)；7.50(dd，1H)；7.86(dd，1H)；8.30(s，1H)；10.15(s，1H).
5-fluoro-thiophene-2-formaldehyde
Under 0 ℃, toward thiophene (4.8ml drips positive tert-butyl lithium (70ml, 66mmol, the hexane solution of 0.95M) in anhydrous diethyl ether 60mmol) (200ml), subsequently under-5-0 ℃ with this solution stirring 1 hour.Subsequently with temperature regulation to-70 ℃, and add (PhSO
2)
2(28.4g, anhydrous tetrahydro furan 90mmol) (200ml) solution keep temperature to be lower than-50 ℃ to NF simultaneously.Make the mixture that obtains slowly rise to ambient temperature overnight subsequently, add 2N NaOH (300ml), filter this mixture, with 2N NaOH (2 * 300ml) and saturated NH
4Cl (300ml) washs organic phase, with after dried over sodium sulfate.Use the Vickers post distillation of 40cm to remove most of ether, last and heptane (50ml) condistillation, obtain 20.7mmol 2-fluorine thiophene and 4.6mmol thiophene (by
1H NMR determines that the DME that uses 200 μ l is as interior mark) solution in approximately 100ml tetrahydrofuran (THF) and heptane (boiling point 60-100 ℃).This solution is cooled to 0 ℃, and drips n-Butyl Lithium (44ml, 41mmol, the hexane solution of 0.95M).After 1 hour, (4.8ml, ether 62mmol) (15ml) solution continue to stir 1 hour down at 0 ℃ to drip DMF.Use saturated NH subsequently
4Cl (200ml) quencher should be reacted, and (2 * 200ml) extractions, extraction liquid is through dried over sodium sulfate with ether.Most of solvent is removed in distillation (40cm Vickers post) under atmospheric pressure, the residue of underpressure distillation dark color, obtain golden buttery ratio be approximately 10: 1 5-fluoro-thiophene-2-formaldehyde and thiophene-2-formaldehyde (boiling point: 78-79 ℃, mixture 25mmHg) ((1.32g, 44%).Need not to be further purified and to use this mixture.
1H NMR(CDCl
3)：6.65(d，J＝4.2，1H)，7.50(d，J＝3.8Hz，1H)，9.76(d，J＝4.2Hz，1H).
The preparation of the intermediate of general formula VII
By following preparation 4-[(5-fluoro-cumarone-3-ylmethyl)-amino]-2-nitro-phenyl-universal method of urethanum or prepare the intermediate of general formula VII by following preparation N-(4-amino-2-nitrophenyl)-2-(4-fluorophenyl) universal method of ethanamide.
4-[(5-fluoro-cumarone-3-ylmethyl)-amino]-2-nitro-phenyl }-urethanum
In three neck round-bottomed flasks of Dean-Stark device are housed with 5-fluoro-cumarone-3-formaldehyde (3.59g, 21.9mmol) and (4-amino-2-nitro-phenyl)-urethanum (4.48g, 19.9mmol) in o-Xylol (80ml), mix, add subsequently catalytic amount acidic ion exchange resin (Amberlite IRC-84,100mg).This mixture heating up was refluxed 5 hours heat filter and vacuum concentration.This crude product is dissolved in the mixture (90ml) of diox and methyl alcohol (4: 1), in 30 minutes, add subsequently in batches sodium borohydride (1.50g, 39.8mmol).At ambient temperature this reaction mixture is stirred and spend the night, (3 * 75ml) extract in the impouring water (200ml) and with ethyl acetate then.The organic moiety salt water washing that merges through dried over mgso and evaporation, obtains thick solid, and this thick solid is through silica gel column chromatography purifying (eluent: ethyl acetate: heptane 1: 2).Obtain the title compound of the red crystallized form of 4.50g (61%).
1H NMR(CDCl3)：1.33(t，3H)；4.07(t，1H)；4.23(q，2H)；4.42(d，2H)；6.99(dd，1H)；7.05(dt，1H)；7.25(dd，1H)；7.42(t，1H)；7.44(d，1H)；7.65(s，1H)；8.31(d，1H)；9.39(s，1H).
Adopt the following intermediate of similar method preparation:
4-[(5-methyl-thiophene-2-ylmethyl)-amino]-2-nitro-phenyl }-urethanum
Productive rate: 73%.LC/MS(m/z)336(MH
+)；t
R＝3.41min。
4-[(3-methyl-thiophene-2-ylmethyl)-amino]-2-nitro-phenyl }-urethanum
Productive rate: 89%.LC/MS(m/z)
4-[(thiophene-2-ylmethyl)-amino]-2-nitro-phenyl }-urethanum
Productive rate: 71%.LC/MS(m/z)321(MH
+)；t
R＝3.24min。
4-[(thiene-3-yl-methyl)-amino]-2-nitro-phenyl }-urethanum
Productive rate: 69%.LC/MS(m/z)320(MH
+)；t
R＝3.08min。
4-(benzo [b] thiene-3-yl-methyl)-amino]-2-nitro-phenyl }-urethanum
Productive rate: 87%.M.p.151-152℃。LC-MS(m/z)371.0(MH
+)，t
R＝3.59min。
N-(4-amino-2-nitrophenyl)-2-(4-fluorophenyl) ethanamide.
Past stirring 4-[2-(4-fluorophenyl)-kharophen]-3-nitro-phenyl }-(2.40g 6.16mmol) adds trifluoroacetic acid (5ml) in the suspension in methylene dichloride (5ml) to t-butyl carbamate.Methylene dichloride is removed in distillation after 15 minutes, residual solution is transferred in the saturated sodium bicarbonate aqueous solution (200ml) carries out supersound process.Filtering-depositing washes with water and vacuum-drying, obtains the title compound of 1.70g reddish-brown solid form.Productive rate: 96.3%.
LC/MS；t
R＝2.25(UV，ELSD)89％，100％.
1H NMR(DMSO-d
6)：3.59(s，2H)；5.65(b，2H，NH
2)；6.83(dd，1H)；7.08(d，1H)；7.15(t’2H)，7.21(d，1H)；7.32(dd，2H)；9.91(s，1H，NH).
Adopt the following compound of similar method preparation:
N-(4-amino-2-nitrophenyl)-3, the 3-amide dimethyl butyrate
Productive rate: 680mg, 93%.
LC/MS(m/z)293.43([M+H+MeCN]
+)；t
R＝2.29(UV，ELSD)99.5％，99.1％.
1H NMR(DMSO-d
6)：1.00(s，9H)；2.12(s，2H)；3.45(b，H
2O+NH
2)；6.84(dd，1H)；7.06(d，1H)；7.14(d，1H)；9.64(s，1H，NH).
The preparation of the intermediate of general formula VIII
N-{4-[(5-chlorothiophene-2-ylmethyl) amino]-the 2-nitrophenyl }-2-(4-fluorophenyl) ethanamide
Under 70 ℃, (306mg, 1.06mmol) dehydrated alcohol (40ml) solution with 5-chloro-2 thiophene carboxaldehyde (186mg, 1.2 equivalents) heated 30 minutes with N-(4-amino-2-nitrophenyl)-2-(4-fluorophenyl) ethanamide.With the solution concentration that obtains is small volume (approximately 3ml), and with heptane (15ml) quencher.The brown crystallized product of filtering separation obtains 350mg intermediate imines N-{4-[(5-chlorothiophene-2-methylene) amino]-the 2-nitrophenyl }-2-(4-fluorophenyl) ethanamide.Productive rate 79.2%.
1H NMR(DMSO-d
6)：3.71(s，2H)；7.17(t，2H)；7.29(d，1H)；7.36(dd，2H)；7.62(d，1H)；7.63(dd，1H)；7.71(d，1H)；8.83(s，1H)；10.44(s，1H)。This solid suspension in methyl alcohol (5ml), is added NaBH
3CN (200mg) adds acetate (2ml) subsequently.The solution that obtains becomes suspension.Water after 15 minutes (50ml) is handled, and the filtering separation product obtains the 330mg red solid after the vacuum-drying.Productive rate: 93.8%.
LC/MS(m/z)420([M+H]
+)；t
R＝3.34(UV，ELSD)97％，100％.
1H NMR(DMSO-d
6)：3.60(s，2H)；4.45(d，2H)；6.87(t，1H，NH)；6.93(dd，1H)；6.94(d，1H)；6.97(d，1H)；7.11(d，1H)；7.14(t，2H)；7.28(d，1H)；7.32(dd，2H)；9.98(s，1H).
Adopt the compound of similar method below corresponding aniline preparation:
N-{4-[(5-chlorothiophene-2-ylmethyl) amino]-the 2-nitrophenyl }-3, the 3-amide dimethyl butyrate
As mentioned above, evaporation separates thick intermediate imines and reduction.Subsequently, this reaction mixture is evaporated to small volume, handles with saturated sodium bicarbonate aqueous solution and ethyl acetate, and the evaporation organic layer.Residue is dissolved in the diisopropyl ether of heat, with heptane precipitation and filtration.
Productive rate: 880mg, 87.6%.
LC/MS(m/z)382.48([M+H]
+)；t
R＝3.46(UV，ELSD)88％，91％.
1H NMR(DMSO-d
6)：0.99(s，9H)；2.12(s，2H)；4.45(d，2H)；6.84(t，1H，NH)；6.92(dd，1H)；6.94(d，1H)；6.97(d，1H)；7.07(d，1H)；7.19(d，1H)；9.69(s，1H).
The preparation of the intermediate of general formula X II
4-[2-(4-fluorophenyl) kharophen]-the 3-nitrophenyl } t-butyl carbamate
Toward (4-amino-3-nitrophenyl)-t-butyl carbamate (1.992g, 7.87mmol) and NaHCO
3(5.4g) in the suspension of acetonitrile (20ml), add (4-fluorophenyl) Acetyl Chloride 98Min. (1.8ml, 1.3 equivalents).The suspension that obtains was carried out supersound process 5 minutes, and stirred at ambient temperature 16 hours.In this reactant impouring water (200ml), carried out supersound process 5 minutes, filter and water and heptane wash.The residue that obtains is dissolved in hot ethyl acetate (30ml), adds saturated sodium bicarbonate aqueous solution (50ml), and with mixture heptane (200ml) quencher that obtains.The suspension that obtains was carried out supersound process 5 minutes, filter then.Water and heptane wash residue, and vacuum-drying obtain the pale brown look solid of 2.48g.Productive rate: 80.9%.
LC/MS(m/z)412.54([M+Na]
+)，453.58([M+MeCN+Na]
+)；t
R＝3.33(UV，ELSD)97％，100％.
1H NMR(DMSO-d
6)：1.48(s，9H)；3.66(s，2H)；7.16(t，2H)，7.34(dd，2H)；7.54(d，1H)；7.64(dd，1H)；8.16(d，1H)；9.79(s，1H，NH)，10.29(s，1H，NH).
Adopt the compound of similar method below corresponding acyl chlorides preparation:
[4-(3-, 3-dimethyl butyrate amido)-3-nitrophenyl] t-butyl carbamate
Under the excessive situation of tertiary butyl Acetyl Chloride 98Min. (3 equivalent), reaction mixture was stirred 30 minutes down at 45 ℃.After ethyl acetate-saturated sodium bicarbonate aqueous solution is handled this crude product is separated, go up the flash chromatography purifying at silica gel (50g) subsequently, eluent is ethyl acetate-heptane of 10-15%.Productive rate: 2.20g (78.6%), yellow solid.
LC/MS(m/z)415.58([M+MeCN+Na]
+)；t
R＝3.31(UV，ELSD)99.5％，99.9％.
1H NMR(DMSO-d
6)：1.01(s，9H)；1.49(s，9H)；2.17(s，2H)；7.43(d，2H)；7.63(dd，1H)；8.11(d，1H)；9.77(s，1H，NH)；10.01(s，1H，NH).
Compound of the present invention
The acid salt of The compounds of this invention can adopt the method for well known to a person skilled in the art to prepare easily.
Embodiment 1
1a{2-amino-4-[(5-fluoro-cumarone-3-ylmethyl)-amino]-phenyl }-urethanum
Will 4-[(5-fluoro-cumarone-3-ylmethyl)-amino]-2-nitro-phenyl-urethanum (4.50g 12.1mmol) is dissolved in dehydrated alcohol (140ml), toward wherein add 6N hydrochloric acid (38ml) and iron powder (5.70g, 0.10mol).Red mixture is heated until chromatic colour disappearance (20 minutes) down at 60 ℃.Filtering solid, vacuum-evaporation are removed ethanol from filtrate.In residue, add ammoniacal liquor (saturated), use ethyl acetate (3 * 100ml) extractions subsequently.With the organic moiety of salt water washing merging, through dried over mgso and vacuum concentration.Crude product is through silica gel column chromatography purifying (eluent: ethyl acetate: heptane 1: 1), obtain the title compound of 2.70g (66%) solid form.M.p.150-151℃。C
18H
18FN
3O
3Calculated value: C 62.96; H 5.28; N12.24, measured value: C 63.00; H 5.38; N 12.13.
LC/MS(m/z)344(MH
+)；t
R＝2.00min.
1H NMR(DMSO-d
6)：1.19(t，3H)；4.03(q，2H)；4.26(d，2H)；4.55(s，2H，NH2)；5.79(t，1H)；5.91(dd，1H)；6.02(d，1H，NH)；6.72(d，1H)；7.13(dt，1H)；7.56(m，2H)；7.95(s，1H)；8.16(b，1H，NH).
Adopt below the similar approach preparation compound and with the isolated in form of its salt acid salt:
1b{2-amino-4-[(5-methyl-thiophene 2-ylmethyl)-amino]-phenyl }-the urethanum dihydrochloride
Add the spirit of salt etherate, crude product is precipitated from ethyl acetate, obtain title compound.
M.p.190 ℃ (decomposition).C
15H
19N
3O
2S.2HCl calculated value C 47.00; H 5.67; N10.97, measured value: C 46.84; H 5.86; N 11.10.
LC/MS(m/z)306(MH
+)；t
R＝1.77min.
1H NMR(DMSO-d
3)：1.22(t，3H)；2.37(s，3H)；4.08(q，2H)；4.37(s，2H)；6.64(m，1H)；6.67(dd，1H)；6.72(d，1H)；6.86(d，1H)；7.13(d，1H)；8.93(b，1H，NH).
1c{2-amino-4-[(3-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-the urethanum dihydrochloride
Add the spirit of salt etherate, crude product is precipitated from ethyl acetate, obtain title compound.
LC/MS (m/z) 306 (MH
+); t
R=1.68min.
1H NMR (CDCl
3) (free alkali): 1.25 (t, 3H); 2.23 (s, 3H); 3.78 (b, 3H); 4.13 (q, 2H); 4.32 (s, 2H); 6.05-6.10 (m, 2H+NH); 6.82 (d, 1H); 6.93 (d, 1H); 7.11 (d, 1H).
1d{2-amino-4-[(thiophene-2-ylmethyl)-amino]-phenyl }-the urethanum dihydrochloride
Add the spirit of salt etherate, crude product is precipitated from ethanol, obtain title compound.
M.p.195℃。C
14H
17N
3O
2S.2HCl calculated value: C 46.16; H 5.26; N 11.54, measured value: C 46.34; H 5.43; N 11.28.
LC/MS(m/z)292(MH
+)；t
R＝1.58min.
1H NMR(DMSO-d
6)：1.22(t，3H)；4.08(q，2H)；4.48(s，2H)；6.71(dd，1H)；6.79(d，1H)；6.97(dd，1H)；7.10(d，1H)；7.16(d，1H)；7.40(d，1H)；8.97(b，1H，NH).
1e{2-amino-4-[(thiene-3-yl-methyl)-amino]-phenyl }-the urethanum dihydrochloride
Add the spirit of salt etherate, crude product is precipitated from ethyl acetate, obtain title compound.
M.p.196-197℃。C
14H
17N
3O
2S.2HCl calculated value: C 46.16; H 5.26; N 11.54, measured value: C 46.23; H 5.47; N 11.30.
LC/MS(m/z)292(MN
+)；t
R＝1.54min.
1H NMR(DMSO-d
6)：1.21(t，3H)；4.08(q，2H；4.29(s，2H)；6.66(dd，1H)；6.73(d，1H)；7.14(dd，1H)；7.16(d，1H)；7.45(m，1H)；7.51(dd，1H)；8.86(b，1H，NH).
1f{2-amino-4-[(benzo [b] thiophene 3-ylmethyl)-amino]-phenyl }-the urethanum dihydrochloride
Add the spirit of salt etherate, crude product is precipitated from ethyl acetate, obtain title compound.
M.p.213-214℃。C
18H
21N
3C
12O
2S calculated value: C 51.68; H 4.95; N10.05, measured value: C 51.88; H 5.35; N 9.95.
LC/MS(m/z)342.2(M+H
+)；t
R＝2.08min.
1H NMR(DMSO-d
6)：1.22(t，3H)；4.08(q，2H)；4.53(s，2H)；6.81(dd，1H)；6.93(d，1H)；7.19(d，1H)；7.41(m，2H)；7.70(s，1H)；7.98(m，2H)；8.97(b，1H，NH).
Embodiment 2
2a (2-amino-4-{[4-(4-chloro-benzene sulfonyl)-3-methyl-thiophene-2-base-methyl]-amino }-phenyl)-urethanum
Under nitrogen atmosphere, with 4-(4-chloro-benzene sulfonyl)-3-methyl-thiophene-2-formaldehyde (301mg, 1.00mmol) and (4-amino-2-nitro-phenyl)-urethanum (293mg, 1.30mmol) the suspension reflux in dehydrated alcohol (10ml) is 20 hours.After the cooling, what filter to collect form is orange to the red solid imines, and vacuum-drying obtains crude product (312mg, 61%), and this crude product is suspended in methyl alcohol-acetate mixture (10ml, methyl alcohol: acetate 10: 1).Add NaBH
3(0.19g 3.0mmol), at room temperature stirs this mixture 1 hour CN subsequently.Add another part NaBH
3(0.19g, 3.0mmol), restir 1 hour adds saturated sodium bicarbonate aqueous solution (20ml) to CN.The red solid amine that filter to collect forms, and vacuum-drying obtains crude product (293mg, 94%), and this crude product is suspended in the dehydrated alcohol (10ml).Toward wherein add 6N HCl (1.1ml, 6.6mmol) and iron powder (193mg, 3.46mmol), subsequently should redness mixture heating up to 60 ℃, fading until redness is yellow approximately to need 10-20 minute.In this mixture impouring saturated sodium bicarbonate solution (50ml) and ethyl acetate (50ml), the mixture that obtains is filtered, separate each phase, water is used ethyl acetate (2 * 50ml) extractions once more.With the organic phase of dried over sodium sulfate merging, vacuum evaporating solvent subsequently.Product is through the silica gel column chromatography purifying in the FlashMaster system, and (linear gradient elution is generally 8: 2-1: 1) to use heptane/eluent ethyl acetate agent.Merge the part contain product, vacuum-evaporation obtains the title compound (213mg, 78%) of light yellow solid form.LC-MS:(m/z)=480.1 (M+H
+), C
21H
23ClN
3O
4S
2Calculated value: 480.0813, t
R=2.35min, UV purity=72.4%, ELS purity=86.5%.
1H NMR(DMSO-d
6)：1.19(b，3H)，2.16(s，3H)，4.02(q，J＝6.9Hz，2H)，4.23(d，J＝6.1Hz，2H)，4.57(s，2H)，5.81(dd，J＝2.4，8.5Hz，1H)，5.91-5.95(m，2H)，6.72(broad d，J＝6.6Hz，1H)，7.72(d，J＝8.5Hz，2H)，7.90(d，J＝8.5Hz，2H)，8.15(b，1H)，8.31(s，1H).
Adopt the following compound of similar method preparation:
2b{2-amino-4-[(3-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum
Productive rate: 76%.LC-MS:(m/z)=326.0 (M+H
+), C
14H
17ClN
3O
2The S calculated value: 326.0725, t
R=1.95min, UV purity=85.8%, ELS purity=98.1%.
1H NMR(DMSO-d
6)：1.19(b，3H)，4.03(q，J＝7.1Hz，2H)，4.30(d，J＝6.1Hz，2H)，4.57(s，2H)，5.83(dd，J＝2.4，8.5Hz，1H)，5.93-5.97(m，2H)，6.73(broad d，J＝7.1Hz，1H)，6.99(d，J＝5.2Hz，1H)，7.48(d，J＝5.2Hz，1H)，8.16(b，1H).
2c{2-amino-4-[(4-bromo-3-methoxyl group-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum
Productive rate: 66%.LC-MS:(m/z)=402.0 (M+H
+), C
15H
19BrN
3O
3The S calculated value: 400.0325 (100%), 402.0310 (97.3%), t
R=1.97min, UV purity=87.9%, ELS purity=98.2%.
1H NMR(DMSO-d
6)：1.20(b，3H)，3.83(s，3H)，4.03(q，J＝6.9Hz，2H)，4.32(d，J＝6.1Hz，2H)，4.58(s，2H)，5.84-5.89(m，2H)，5.97(d，J＝2.4Hz，1H)，6.74(b，1H)，7.46(s，1H)，8.17(b，1.H).
2d{2-amino-4-[(6-chloro-3-methoxyl group-benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum
Productive rate: 60%.LC-MS:(m/z)=405.3 (M+H
+), C
19H
21ClN
3O
3The S calculated value: 406.0987, t
R=2.39min, UV purity=95.0%, ELS purity=99.6%.
1H NMR(DMSO-d
6)：1.19(b，3H)，3.95(s，3H)，4.02(q，J＝7.1Hz，2H)，4.43(d，J＝6.1Hz，2H)，4.56(s，2H)，5.90(dd，J＝2.4，8.5Hz，1H)，5.96(t，J＝5.9Hz，1H)，6.00(d，J＝2.8Hz，1H)，6.73(broad d，J＝6.6Hz，1H)，7.39(dd，J＝1.9，8.5Hz，1H)，7.68(d，J＝8.5Hz，1H)，7.98(d，J＝1.9Hz，1H)，8.15(b，1H).
2e{2-amino-4-[(5-dimethyl-amino-benzo [b] thiene-3-yl-methyl)-amino]-phenyl }-urethanum
Productive rate: 13%.LC-MS:(m/z)=385.0 (M+H, C
20H
25N
4O
2The S calculated value: 385.1693, tR=1.29min, UV purity=87.8%, ELS purity=93.5%.
1H NMR(DMSO-d
6)：1.19(b，3H)，2.94(s，6H)，4.02(q，J＝6.9Hz，2H)，4.34(d，J＝5.7Hz，2H)，4.53(s，2H)，5.81(t，J＝5.9Hz，1H)，5.93(dd，J＝2.4，8.5Hz，1H)，6.03(d，J＝2.4Hz，1H)，6.72(b，1H)，6.95(dd，J＝2.4，9.0Hz，1H)，7.08(d，J＝2.4Hz，1H)，7.38(s，1H)，7.71(d，J＝8.5Hz，1H)，8.15(b，1H).
2f{2-amino-4-[(5-dimethyl-amino-3-methyl-benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum
Productive rate: 36%.LC-MS:(m/z)=399.2 (M+H
+), C
21H
27N
4O
2The S calculated value: 399.1849, t
R=1.31min, UV purity=98.4%, ELS purity=99.4%.
1H NMR(DMSO-d
6)：1.19(b，3H)，2.33(s，3H)，2.93(s，6H)，4.02(q，J＝6.9Hz，2H)，4.37(d，J＝5.7Hz，2H)，4.54(s，2H)，5.86(dd，J＝2.4，8.5Hz，1H)，5.89(t，J＝6.6Hz，1H)，5.96(d，J＝2.4Hz，1H)，6.71(b，1H)，6.84-6.89(m，2H)，7.58(d，J＝8.5Hz，1H)，8.16(b，1H).
Embodiment 3
3a{2-amino-4-[(5-methyl-thiophene-2-ylmethyl)-(methyl)-amino]-phenyl }-urethanum
Under argon gas atmosphere, with 5-methyl-2 thiophene carboxaldehyde (108 μ L, 1.00mmol), (4-amino-2-nitro-phenyl)-urethanum (225mg, 1.00mmol) and the mixture heating up of AmberliteIRC-84 (10mg) in o-Xylol (4ml) refluxed 5 hours.Volatile matter is removed in vacuum-evaporation, subsequently this residue is dissolved in acetonitrile (5ml).In this solution that obtains, add NaBH
3(0.25g 4.0mmol), adds HOAc (5) to CN subsequently.Stir after 5 minutes, this solution becomes scarlet.(37% the aqueous solution, 0.89ml 12mmol), and continue to stir 30 minutes, and add HOAc frequently to add formaldehyde.This mixture vacuum-evaporation to doing, is distributed residue between saturated sodium bicarbonate aqueous solution (50ml) and ethyl acetate (50ml).With ethyl acetate (50ml) aqueous phase extracted, the organic layer that merges with dried over sodium sulfate subsequently, and with solvent vacuum-evaporation.Subsequently this residue is dissolved in ethanol (10ml).Add 6N hydrochloric acid (2.0ml, 12mmol) and iron powder (0.34g 6.0mmol), heats red mixture down at 60 ℃ subsequently, and fading until this redness is yellow, about 15 minutes.In sodium bicarbonate aqueous solution that this mixture impouring is saturated (50ml) and the ethyl acetate (50ml), the mixture that obtains is filtered, separate each phase, use ethyl acetate (2 * 50ml) aqueous phase extracted subsequently.The organic layer that merges is through dried over sodium sulfate and vacuum evaporating solvent.This product is through the silica gel column chromatography purifying in the FlashMaster system, and (linear gradient elution is generally 8: 2-1: 1) to use heptane/eluent ethyl acetate agent.Merge the part contain product, vacuum-evaporation obtains the title compound (145mg amounts to 45%) of light yellow solid form.LC-MS:(m/z)=319.9 (M+H
+), C
16H
22N
3O
2The S calculated value: 320.1427, t
R=1.80min, UV purity=98.4%, ELS purity=97.2%.
1H NMR(CDCl
3)：1.29(t，J＝7.1，3H)，2.41(s，3H)，2.91(s，3H)，3.76(b，2H)，4.19(q，J＝7.1Hz，2H)，4.52(s，2H)，6.02(b，1H)，6.17(d，J＝2.8Hz，1H)，6.25(dd，J＝2.8，8.5Hz，1H)，6.53-6.58(m，1H)，6.66(d，J＝3.3Hz，1H)，6.98(d，J＝8.5Hz，1H).
Compound below preparing similarly:
3b{2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl)-amino]-phenyl }-urethanum
Productive rate: 34%.LC-MS:(m/z)=340.0 (M+H
+), C
15H
19ClN
3O
2The S calculated value: 340.0881, t
R=2.14min, UV purity=82.3%, ELS purity=90.2%.
1H NMR(CDCl
3)：1.29(t，J＝6.8，3H)，2.91(s，3H)，3.78(b，2H)，4.20(q，J＝7.2Hz，2H)，4.49(s，2H)，6.05(b，1H)，6.16(d，J＝2.4Hz，1H)，6.24(dd，J＝2.4，8.5Hz，1H)，6.73(d，J＝3.8Hz，1H)，6.99(d，J＝8.5Hz，1H).
Compound below preparing similarly, difference is to replace formaldehyde with acetaldehyde:
3c{2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-(ethyl)-amino]-phenyl }-urethanum
Productive rate: 12%.LC-MS:(m/z)=353.9 (M+H
+), C
16H
21ClN
3O
2The S calculated value: 354.1038, t
R=2.02min, UV purity=97.5%, ELS purity=99.0%.
1H NMR(CDCl
3)：1.16(t，J＝7.1，3H)，1.29(t，J＝6.8，3H)，3.36(q，J＝7.1Hz，2H)，3.76(b，2H)，4.19(q，J＝7.2Hz，2H)，4.47(s，2H)，6.05(b，1H)，6.13(d，J＝2.4Hz，1H)，6.19(dd，J＝2.4，9.0Hz，1H)，6.73(d，J＝3.8Hz，1H)，6.96(d，J＝8.0Hz，1H).
Compound below preparing similarly, difference is not carry out the formaldehyde addition.
3d{2-amino-4-[(5-fluoro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum
Productive rate: 65% (preparation LC-MS purifying is 25% after removing the by product of nonfluorinated).
LC-MS:(m/z)=310.2 (M+H
+), C
14H
17FN
3O
2The S calculated value: 310.1020, t
R=1.76min, UV purity=96.6%, ELS purity=83.4%.
1H NMR(CDCl
3)：1.29(b，3H)，3.82(b，2H)，4.19(q，J＝7.2Hz，2H)，4.31(d，J＝2.0Hz，2H)，6.05(b，1H)，6.09(d，J＝8.0Hz，1H)，6.29(dd，J＝1.5，3.8Hz，1H)，6.58(t，J＝3.5Hz，1H)，6.94(d，J＝8.0Hz，1H).
Embodiment 4
4a{2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum
With 5-chlorothiophene-2-formaldehyde (240 μ L, 111 μ mol, 463mM) 1, the 2-dichloroethane solution add 4-amino-2-nitrophenyl urethanum (240 μ L, 111 μ mol, 463mM) 1, in the 2-dichloroethane solution.Add sodium triacetoxy borohydride (118mg, 555 μ mol), under 40 ℃, the mixture that obtains was stirred 3.5 hours subsequently.Make this mixture be cooled to envrionment temperature, and add entry (100 μ L).Should mix by silica gel (500mg) and filter, and with 1,2-ethylene dichloride (3ml) washs this post.Under vacuum, be evaporated to the organic phase that merges dried.The solid that obtains is dissolved in ethanol (3ml).Iron (19mg) is added in the solution (1ml) of 1/3rd gained, add subsequently spirit of salt the aqueous solution (96 μ L, 6M).This mixture was placed ultra sonic bath 10 minutes.Subsequently, add saturated sodium bicarbonate aqueous solution (2ml).(3ml) extracts this mixture with ethyl acetate.Water (3ml) and salt solution (3ml) wash this organic phase, through dried over mgso, filter also vacuum-evaporation to doing.The product that obtains is dissolved in the methyl-sulphoxide of 190 μ L and being prepared property LC-MS purifying.The solution for vacuum that obtains is evaporated to dried.Productive rate (6.8mg, 56%).LC-MS(m/z)(M+H)
+326.1；RT＝1.90；(UV，ELSD)92％，99％。
Adopt the following compound of similar method preparation:
4b{2-amino-4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum
LC-MS(m/z)(4+H)
+371.9；RT＝1.94；(UV，ELSD)89％，98％。
4c{2-amino-4-[(4-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum
LC-MS(m/z)(M+H)
+372.0；RT＝1.96；(UV，ELSD)76％，100％。
4d{2-amino-4-[(5-ethyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum
LC-MS(m/z)(M+H)
+320.1；RT＝1.90；(UV，ELSD)72％，96％。
4e{2-amino-4-[benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum
LC-MS(m/z)(M+H)
+342.1；RT＝2.06；(UV，ELSD)75％，100％。
4f{2-amino-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum.
LC-MS(m/z)(M+H)
+368.2；RT＝2.21；(UV，ELSD)90％，99％。
Embodiment 5
5a{2-amino-4-[(benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-the carboxylamine propyl ester
(1.36g, (2.00g is in acetonitrile 8.36mmol) (10ml) solution 8.38mmol) to add (4-amino-2-nitro-phenyl)-carboxylamine propyl ester with benzo [b] thiophene-2-formaldehyde.In the microwave treatment bottle of 20ml sealing with this mixture heating up to 160 ℃ 2 minutes.In case cooling adds NaBH
3CN (1.06g, 16.7mmol) and acetate (48 μ L 0.84mmol), and stir this mixture 30 minutes under 25 ℃.(1: 1,100ml), (3 * 100ml) extracted this mixture to use ethyl acetate subsequently to add entry/salt solution.Organic phase is filtered and vacuum concentration through dried over mgso.This thick intermediate is by quick silica gel column chromatography (eluent: ethyl acetate: purifying heptane 1: 9), and be evaporated to dried.Subsequently this intermediate is dissolved in the tetrahydrofuran (THF) (20ml), and adds Na
2S
2O
4(3.67g, aqueous solution 21mmol) (50ml).Under argon gas atmosphere, the mixture that obtains was stirred 5 hours down at 40 ℃.(mixture that 3 * 100ml) extractions obtain, the organic phase of merging filter and vacuum concentration through dried over mgso with ethyl acetate.By flash chromatography purifying (eluent: ethyl acetate: heptane 1: 1), obtain the title compound of 0.3g (10%) solid state.LC/MS(m/z)356([M+H]
+)；RT＝2.45min。
1H NMR(CDCl
3)：0.95(t，3H)；1.67(m，2H)；4.08(t，2H)；4.55(s，2H)；6.08(d，1H)；6.13(dd，1H)；6.93(d，1H)；7.20(s，1H)；7.27(dt，1H)；7.32(dt，1H)；7.68(d，1H)；7.77(d，1H).
Compound below similar method preparation:
5b{2-amino-4-[(benzo [b] thiene-3-yl-methyl)-amino]-phenyl }-the carboxylamine propyl ester
Productive rate: 16%.LC/MS(m/z)356([M+H]
+)；RT＝2.24min。
1H NMR(CDCl
3)：0.96(t，3H)；1.68(m，2H)；4.10(t，2H)；4.51(s，2H)；6.12(d，1H)；6.14(dd，1H)；6.95(d，1H)；7.36(s，1H)；7.39(dt，1H)；7.40(dt，1H)；7.79(dd，1H)；7.87(dd，1H).
Embodiment 6
6aN-{2-amino-4-[(5-chlorothiophene-2-ylmethyl)-amino]-phenyl }-2-(4-fluorophenyl)-ethanamide
In 30 minutes, in batches regularly toward the N-{4-[(5-chlorothiophene-2-ylmethyl that stirs) amino]-the 2-nitrophenyl }-2-(4-fluorophenyl) ethanamide (320mg, 0.762mmol) tetrahydrofuran (THF) (25ml) and the red solution of acetate (8ml) in add zinc powder (particle diameter＜10 micron, 10g).After 5 minutes, this solution becomes colorless.The colourless suspension that obtains is filtered through silica gel (10g) filler, and with ethyl acetate as eluent, subsequently the solution for vacuum that obtains is evaporated.The solid that obtains is dissolved in ethyl acetate/acetone/trifluoroacetic acid (3ml/3ml/0.2ml), and handles with saturated sodium bicarbonate aqueous solution (50ml) and heptane (30ml), the filtering separation product obtains the 280mg light gray solid.Productive rate: 94.2%.LC/MS(m/z)390.4([M+H]
+)；RT＝2.26；(UV，ELSD)99％，100％。
1HNMR(DMSO-d
6)：3.56(s，2H)；4.28(d，2H)；4.57(s，2H，NH
2)；5.87(dd，1H)；5.98(m，2H，NH and arom.H)；6.74(d，1H)；6.86(d，1H)；6.93(d，1H)；7.13(t，2H)；7.35(dd，2H)；9.10(s，1H).
Similarly by the following compound of corresponding nitro-compound preparation:
6bN-{2-amino-4-[(5-chlorothiophene-2-ylmethyl) amino] phenyl }-3, the 3-amide dimethyl butyrate
Through SiO
2After filtering back and evaporation, product precipitates productive rate from the two-phase solution of ethyl acetate-saturated sodium bicarbonate aqueous solution (5ml/20ml) and heptane (50ml): 580mg, 71.5%.LC/MS(m/z)352.48([M+H]
+)；RT＝2.16；(UV，ELSD)96％，99％。
1HNMR(DMSO-d
6)：1.01(s，9H)，2.11(s，2H)；4.29(d，2H)；4.54(s，2H，NH
2)；5.88(dd，1H)；5.97(t，1H，NH)；5.99(d，1H)；6.72(d，1H)；6.87(d，1H)；6.93(d，1H)；8.82(s，1H).
Interior and the in vitro tests of body
Compound of the present invention has tested and has demonstrated effect in a model below a plurality of:
Relative discharge by the KCNQ2 passage
Testing the cell inoculation of the day before yesterday with the valtage-gated KCNQ2 passage of stably express, and loading [86Rb].Testing the same day, washing these cells with the damping fluid that contains HBSS.Use the medicine pre-cultured cell, and in the presence of medicine continues, use the inferior peak concentration of 15mM KCl to stimulate [
86Rb
+].Behind one section suitable incubation time, remove the upper strata stillness of night, and in liquid scintillation counter (Tricarb), count.With 2mM NaOH dissolved cell, and counting
86The amount of Rb+.Calculate relative flow:
((CPM
suoer/CPM
super+CPM
cell)C
mpd/(CPM
suoer/CPM
super+CPM
cell)
15mMKCl)*100-100。
The EC of compound of the present invention
50Less than 20000nM, in most of the cases less than 2000nM, as a rule 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.
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 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 Behavior1993,45,321-325)
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, and the amygdala of surveying outside the back of the body are implanted into three utmost point electrodes.After the operation, allow these animals recover, 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).This compound of wireless remote control sensor determination of implantation that maybe can measure temperature by rectal thermometer is to the cooling behavior of animal subject temperature.(people such as Keeney, Physiology and Behaviour2001,74,177-184).
Pharmacokinetics
By measuring pharmacokinetic properties for Spraque Dawley rat intravenous injection and oral administration of compound, after 20 hours, take a blood sample then.
Plasma concentration is measured with LC/MS/MS.
Claims (25)
1. 1,2 of a formula I, 4-triaminobenzene derivative or its pharmacy acceptable salt:
Wherein:
R
1Be 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, acyl group, hydroxyl-C
1-6-alkane (alkene/alkynes) base and hydroxyl-C
3-8-cycloalkanes (alkene) base;
R
2And R
2 'Be independently selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, 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, acyl group, hydroxyl-C
1-6-alkane (alkene/alkynes) base and hydroxyl-C
3-8-cycloalkanes (alkene) base;
R
3Be selected from hydrogen, C
1-6-alkane (alkene/alkynes) base, 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, hydroxyl-C
1-6-alkane (alkene/alkynes) base, aryl-C
3-8-cycloalkanes (alkene) base, NR
10R
10 '-C
1-6-alkane (alkene/alkynes) base, NR
10R
10 '-C
3-8-cycloalkanes (alkene) base and hydroxyl-C
3-8-cycloalkanes (alkene) 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 'The nitrogen-atoms that connects with them forms optional 1,2 or 3 other the saturated or unsaturated ring of heteroatomic 4-8 unit that comprises;
X is CO or SO
2
Z is O or NR
4, wherein:
R
4Be 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 and hydroxyl-C
3-8-cycloalkanes (alkene) base; Or
R
3And R
4The nitrogen-atoms that connects with them forms optional 1,2 or 3 other the saturated or unsaturated ring of heteroatomic 4-8 unit that comprises, and is described by R
3And R
4And the ring that nitrogen-atoms forms is optional by one or more C that are independently selected from
1-6-alkane (alkene/alkynes) base, aryl and aryl-C
1-6The substituting group of-alkane (alkene/alkynes) base replaces;
Q is 0 or 1;
And
Y represents the heteroaryl of formula II or III:
Wherein:
W is O or S;
M is 0,1,2 or 3;
N is 0,1,2,3 or 4;
P is 0 or 1; And
R
5Independently be selected from C separately
1-6-alkane (alkene/alkynes) base, 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, acyl group, halogen, halo-C
1-6-alkane (alkene/alkynes) base, C
1-6The basic oxygen base of-alkane (alkene/alkynes) ,-CO-NR
6R
6 ', cyano group, nitro ,-NR
7R
7 ',-S-R
8,-SO
2R
8And SO
2OR
8
Wherein:
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; And
R
8Be 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, 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.
2. the compound of claim 1, wherein R
1Be selected from hydrogen and C
1-6-alkane (alkene/alkynes) base.
3. each compound, wherein substituent R in the claim 1 and 2
2And R
2 'In at least one is a hydrogen atom.
4. each compound, wherein R among the claim 1-3
2And R
2 'Be hydrogen atom.
5. each compound among the claim 1-4, wherein X is CO.
6. each compound among the claim 1-5, wherein q is 0.
7. each compound among the claim 1-5, wherein q be 1 and Z be Sauerstoffatom.
8. each compound, wherein R among the claim 1-7
3Be selected from C
1-6-alkane (alkene/alkynes) base and aryl-C
1-6-alkane (alkene/alkynes) base.
9. the compound of claim 8, wherein R
3Be C
1-6-alkane (alkene/alkynes) base.
10. the compound of claim 8, wherein R
3Be aryl-C
1-6-alkane (alkene/alkynes) base.
11. each compound among the claim 1-10, wherein W is a Sauerstoffatom.
12. each compound among the claim 1-11, wherein W is a sulphur atom.
13. each compound among the claim 1-12, wherein Y is formula II.
14. each compound among the claim 1-12, wherein Y is a formula III.
15. each compound among the claim 1-14, wherein Y is formula IIb or IIIb:
Wherein W, m, n, p and R
5As above definition.
16. each compound among the claim 1-14, wherein Y is formula IIc or IIIc:
Wherein W, m, n, p and R
5As above definition.
17. each compound, wherein R among the claim 1-16
5Independently be selected from C separately
1-6-alkane (alkene/alkynes) base, aryl, halogen, C
1-6The basic oxygen base of-alkane (alkene/alkynes) ,-NR
7R
7 ',-SO
2R
8
18. each compound among the claim 1-17, described compound are selected from following compound or its pharmacy acceptable salt:
2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-methyl-amino]-phenyl }-urethanum;
2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(5-methyl-thiophene-2-ylmethyl)-methyl-amino]-phenyl }-urethanum;
2-amino-4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(6-chloro-3-methoxyl group-benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(5-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(4-bromo-3-methoxyl group-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(3-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
(2-amino-4-{[4-(4-chloro-benzene sulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-phenyl)-urethanum;
2-amino-4-[(3-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(5-fluoro-cumarone-3-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(4-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(5-ethyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(thiene-3-yl-methyl)-amino]-phenyl }-urethanum;
2-amino-4-[(5-chloro-thiophene-2-ylmethyl)-ethyl-amino]-phenyl }-urethanum;
2-amino-4-[(benzo [b] thiene-3-yl-methyl)-amino]-phenyl }-urethanum;
2-amino-4-[(5-dimethyl-amino-benzo [b] thiene-3-yl-methyl)-amino]-phenyl }-urethanum;
2-amino-4-[(5-dimethyl-amino-3-methyl-benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(5-fluoro-thiophene-2-ylmethyl)-amino]-phenyl }-urethanum;
2-amino-4-[(benzo [b] thiophene-2-ylmethyl)-amino]-phenyl }-the carboxylamine propyl ester;
2-amino-4-[(benzo [b] thiene-3-yl-methyl)-amino]-phenyl }-the carboxylamine propyl ester;
N-{2-amino-4-[(5-chloro-thiophene-2-ylmethyl) amino]-phenyl }-2-(4-fluoro-phenyl)-ethanamide; With
N-{2-amino-4-[(5-chloro-thiophene-2-ylmethyl) amino]-phenyl }-3,3-dimethyl-butyramide.
19. a medicinal compositions, described medicinal compositions comprise among the claim 1-18 that treats significant quantity each compound and one or more pharmaceutically acceptable carrier or thinner.
20. each compound is used for preventing, treating and/or suppress the purposes of the medicinal preparations of central nervous system disease among the claim 1-19 in preparation.
21. the purposes of claim 20 is characterized in that described central nervous system disease is selected from the epileptic seizures disease, as convulsions, epilepsy and epileptic state.
22. the purposes of claim 21 is characterized in that described central nervous system disease is selected from neurodynia and migraine, as allodynia, hyperpathia pain, phantom pain, the neurodynia relevant with diabetic neuropathy and the neurodynia of being correlated with migraine.
23. the purposes of claim 21, it is characterized in that described central nervous system 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.
24. the purposes of claim 21, it is characterized in that described central nervous system 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 other unknown pathogenic infections cause.
25. the purposes of claim 21 is characterized in that described central nervous system 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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|---|---|---|---|
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| DKPA200202012 | 2002-12-27 |
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| DE19539861A1 (en) * | 1995-10-26 | 1997-04-30 | Asta Medica Ag | Use of 4-amino-4- (4-fluorobenzylamino) -1-ethoxy-carbonylaminobenzen for the prophylaxis and treatment of the consequences of acute and chronic cerebral low blood circulation and neurodegenerative diseases |
| GB9915414D0 (en) * | 1999-07-01 | 1999-09-01 | Glaxo Group Ltd | Medical use |
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