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CN1350539A - Imidazo-containing heterocyclic compounds, their compositions and uses - Google Patents

Imidazo-containing heterocyclic compounds, their compositions and uses Download PDF

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Publication number
CN1350539A
CN1350539A CN00807636A CN00807636A CN1350539A CN 1350539 A CN1350539 A CN 1350539A CN 00807636 A CN00807636 A CN 00807636A CN 00807636 A CN00807636 A CN 00807636A CN 1350539 A CN1350539 A CN 1350539A
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alkyl
hydrogen
aryl
hydrocarbon
acid amides
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S·刘
D·E·波特洛克
S·F·彭
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Procter and Gamble Ltd
Procter and Gamble Co
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The subject invention involves compounds having structure (I), wherein each R1 is independently alkyl, aryl, or heterocycle; each R2 - R7 is independently hydrogen or other substituent; B is nil and n is 0-3, or B is ethenyl and n is 0-1; and pharmaceutically acceptable forms thereof. The subject invention also involves pharmaceutical compositions containing such compounds, and methods for treating or preventing diseases or disorders using such compounds.

Description

The heterogeneous ring compound that contains imidazo, their composition and application
Invention field
The present invention relates to contain the novel heterogeneous ring compound that contains imidazoles, contain medicinal compositions and their treatment or prophylactic applications in cardiovascular, oncology, infection and inflammatory disease of described compound.
Background
United States Patent (USP) 3,917,610 (1975,11,4 promulgations) have disclosed certain imidazo isoquinoline compound; It is reported that they have some cardiac vascular activity.Borchard, Fox and Greeff be at Achives ofPharmacology, the 312nd volume (1980), the 187-192 page or leaf, " isoquinilone derivatives, BILA, positive variable force, anti-arrhythmia and Na +, K +-ATP enzyme retarding effect " in the literary composition, further reported the compound of this type.
Summary of the invention
The present invention includes compound and optical isomer, diastereomer or its enantiomorph with following formula structure; But the ester of its pharmacy acceptable salt, hydrate or biological hydrolysis, acid amides or inferior acid amides: Wherein
(a) each R1 is independently selected from alkyl (alkyl), aryl and heterocycle;
(b) R2 is selected from hydrogen atom, alkyl, hydrocarbon acyl group, aroyl, hydrocarbon alkylsulfonyl and arylsulfonyl;
(c) each R3 is independently selected from hydrogen, halogen, alkyl, aryl, heterocycle, nitro, cyano group and unsubstituted or by alkyl-or aryl-or hydroxyl, sulfenyl, amino, acid amides, formyl radical (acyl group), carboxyl and the methane amide (carboxamide) of heterocycle-replacement; Two R3 on the adjacent carbons of phenyl can randomly be all alkylidene group or assorted alkylidene group, thereby form fused rings with the phenyl that links to each other with them;
(d) R4 is selected from hydrogen, halogen, alkyl, aryl, heterocycle and carboxyl and its hydrocarbon ester and aromatic ester and acid amides;
(e) each R5 is independently selected from hydrogen, alkyl and aryl;
(f) each R6 is independently selected from hydrogen, halogen, alkyl, aryl, heterocycle, nitro, cyano group and unsubstituted or alkyl-or aryl-or hydroxyl, sulfenyl, amino, acid amides, sulphonamide, formyl radical (acyl group), carboxyl and the methane amide (carboxamide) of heterocycle-replacement; Or two R6 can randomly be all alkylidene group or assorted alkylidene group, thereby form fused rings with the phenyl that is connected with them;
(g) B does not have, or B be-C (R7)=C (R7)-;
(h) if B does not have, n is 0 to about 3 integer, otherwise n is 0 to about 1 integer;
(j) each R7 is independently selected from hydrogen, alkyl and aryl.
The present invention also comprises the composition that contains described compound and pharmaceutically acceptable vehicle; Treat with the The compounds of this invention that gives safe and effective amount by people or lower animal or the method for preventing disease or dysfunction needs.
Detailed Description Of The Invention
Unless otherwise indicated, " alkyl (alkyl) " used herein expression side chain, straight chain or cyclic saturated or unsaturated (but not being aromatics), replacement or unsubstituted hydrocarbon chain.Term " alkyl " can use separately or as the hydrocarbon part of other term (as-oxyl, hydrocarbon acyl group).Preferred straight-chain alkyl has 1 to about 20 carbon atoms, and more preferably 1 to about 10 carbon atoms, further is 1 to about 6 carbon atoms, further is 1 to about 4 carbon atoms; Optimum is methyl or ethyl.Preferred cyclic hydrocarbon group and branched hydrocarbyl have 3 to about 20 carbon atoms, and more preferably 3 to about 10 carbon atoms, and further preferably 3 to about 7 carbon atoms, further preferably 3 arrive about 5 carbon atoms.Preferred cyclic hydrocarbon group has 1 hydrocarbon ring, but two, the three or more hydrocarbon ring that condenses also can be arranged.Preferred alkyl is to have a unsaturated alkyl to about three two keys or triple bond (preferably two key); More preferably, they are monounsaturated that two keys are arranged.Preferred alkyl is saturated.Saturated alkyl is called as " alkyl (alkanyl) ".The unsaturated alkyl that has one or more pairs of keys (not having triple bond) is called as " thiazolinyl " in this article.Preferred hydrocarbyl substituent comprises halogen, alkyl, aryl, heterocycle, hydroxyl,-oxyl, aryloxy, sulfenyl, alkylthio, arylthio, amino, alkylamino, virtue amino, acid amides, hydrocarbon acid amides, fragrant acid amides, formyl radical, hydrocarbon acyl group, aroyl, carboxyl and its hydrocarbon ester and aromatic ester and acid amides, nitro and cyano group.Preferably undersaturated alkyl.Equally, undersaturated alkyl also is preferred.
" heteroatoms " used herein expression nitrogen, oxygen or sulphur atom.
The alkyl that " alkylidene group " used herein expression is connected with two other parts, " assorted alkylidene group " is illustrated in one or more heteroatomic alkylidene groups is arranged in the connection chain.
Unless otherwise indicated, " aryl " expression replaces or unsubstituted aromatic hydrocarbon ring (or fused rings).Term " aryl " can use separately or as the part of other term (as aryloxy, aroyl).Have 6 in the aromatic ring of preferred aryl groups to about 14 carbon atoms, preferably arrive about 10 carbon atoms, total carbonatoms is about 6-20, preferably arrives about 6-12 carbon atom.Preferred aryl groups is a phenyl or naphthyl; Best is phenyl.The aryl preferred substituted comprises halogen, alkyl, aryl, heterocycle, hydroxyl,-oxyl, aryloxy, sulfenyl, sulfenyl, arylthio, amino, hydrocarbon amino, virtue amino, acid amides, hydrocarbon acid amides, fragrant acid amides, formyl radical, hydrocarbon acyl group, aroyl, carboxyl and its hydrocarbon ester and aromatic ester and acid amides, nitro and cyano group.Equally, unsubstituted aryl is preferred.
Unless otherwise indicated, this paper " heterocycle " is illustrated in and has one or more heteroatomic saturated, unsaturated or aromatic ring hydrocarbon rings (or fused rings) in the hydrocarbon ring.Have 1 to about 6 heteroatomss in the preferred heterocyclic ring, more preferably in the ring 1 or 2 or 3 heteroatomss are arranged.Preferred heterocycle nuclear carbon adds heteroatoms, has 3 preferably to arrive about 10 atoms to about 14 atoms, and carbon adds heteroatoms in more preferably encircling has 3 to about 7 atoms, more preferably 5 or 6 atoms.Carbon atom adds heteroatomic sum about from 3 to 20, can be preferably about from 3 to 10, and what more optimize is that carbon atom adds that the heteroatoms sum is 5 or 6.Preferred heterocycle has a ring, but two, three or more fused rings also can be arranged.Preferred heterocycle comprises has 5 or 6 carbon to add heteroatoms in the ring, and heteroatoms in no more than three rings, and wherein no more than two heteroatomss are oxygen and sulphur.It is oxygen or sulphur that 5 Yuans or 6 Yuans rings of more preferred this class contain 1 or 2 annular atomses, and other then are carbon, and perhaps wherein 1,2 or 3 annular atomses are nitrogen-atoms, and other then are carbon atoms.This class 5-or 6-unit annular atoms heterocycle preferably saturated, undersaturated (one or two pair key is arranged), or aromatics.Preferred 5-of this class or 6-unit annular atoms heterocycle be monocycle preferably; Or condense with the 3-hydrocarbon ring of atom in the 6-unit ring that has of saturated, as to have two keys undersaturated or aromatics (phenyl); Or with another this class 5-or 6-ring in atom heterocyclic fused.Heterocycle is unsubstituted or replaces.Preferred heterocyclic substituent is identical with the substituting group of alkyl.
Compound of the present invention
The present invention relates to have the compound of following formula structure:
Figure A0080763600081
In the structure 1, each R1 is independently selected from alkyl, aryl and heterocycle.Preferred R1 includes the straight chained alkyl of 1 to 6 left and right sides carbon atom, has 2 to arrive the straight-chain alkenyl of about 6 carbon atoms and 3 side chain and cyclic alkyl and thiazolinyls to about 6 carbon atoms are arranged, and this class thiazolinyl preferably has 1 two key.Preferred alkyl of this class and thiazolinyl are preferably unsubstituted, or by phenyl, the heterocycle that atom in 5 or 6 rings is arranged, carboxyl and its C 1-C 6Alkane ester and phenyl ester or cyano group replace.Preferred this class alkyl and thiazolinyl have about 5 carbon atoms at most, more preferably maximum 4 carbon atoms.Better R1 is methyl, ethyl and sec.-propyl.Best R1 is unsubstituted methyl.Two R1 are that identical part is preferred.
In structure 1, R2 is selected from hydrogen, alkyl, hydrocarbon acyl group, aroyl, hydrocarbon alkylsulfonyl and aryl sulfonyl.Preferred R2 is selected from hydrogen; C 1-C 6Alkyl, this class alkyl be saturated or have the undersaturated alkyl of two keys, and be unsubstituted, or replaced by phenyl; C 1-C 6Alkyl acyl group, alkyl are saturated or have the unsaturated alkyl of two keys; With the phenyl acyl group.More preferably the hydrocarbyl portion of aforementioned group is C 1-C 4, and be saturated.Preferred R2 is a methyl, and best R2 is a hydrogen.
In structure 1, each R3 is independently selected from hydrogen, halogen, alkyl, aryl, heterocycle, nitro and cyano group; Also can be selected from hydroxyl, sulfenyl, amino, acid amides, formyl radical (acyl group), carboxyl and do not replace or replace, preferably by the methane amide (carboxamide) of alkyl or aryl or heterocyclic substituted; Or two R3 are all alkylidene group or assorted alkylidene group, and they are connected with adjacent carbon atoms on a benzene ring, thereby have formed and phenyl ring condensed cyclic hydrocarbon radical or aryl or heterocycle.Preferred R3 is independently selected from hydrogen, halogen, alkyl, aryl, heterocycle, hydroxyl, alkoxyl group, aryloxy, sulfenyl, sulfenyl, arylthio, amino, alkylamino, virtue amino, acid amides, hydrocarbon acid amides, fragrant acid amides, methane amide, hydrocarbon acyl group, aroyl, carboxyl and its hydrocarbon ester or aromatic ester and acid amides; More preferably be selected from hydrogen, halogen, C 1-C 4Alkyl, sulfenyl, C 1-C 4Alkyl sulfenyl, C 1-C 4Single-or dialkyl amino and C 1-C 4The alkyl acyl group.More preferably, one to three R3 is a halogen, and other is a hydrogen.Perhaps, preferably, one to three R3 is methyl or ethyl, and other R3 is a hydrogen.Equally preferably, a R3 is that the dialkyl hydrocarbyl amino has 1 to 6 left and right sides carbon atom, and 1 to 4 left and right sides carbon atom is preferably arranged), other R3 is a hydrogen, such R3 preferably links to each other with 4 ' carbon.More preferably, one to three R3 is independently selected from F, Cl and Br, and other R3 is a hydrogen; Same preferred when two or three R3 are F, Cl or Br, they are identical.Perhaps more preferably, 1-3 R3 is substituent methyl not, and other R3 is a hydrogen.More preferably 1 or 2 R3 are trifluoromethyls, other be hydrogen.
Perhaps, preferably, two R3 that adjacent carbon atom connects on phenyl ring be saturated or undersaturated have 1 to about 6 carbon atoms and 0 to about 3 heteroatomic alkylidene groups or assorted alkylidene group, formed and phenyl condensed ring atom during this class ring is had an appointment 5-8 and encircled like this.This class and phenyl condensed ring preferably have atom in about 5-6 the ring, and wherein 0 to 2, preferably 0 or 1 is heteroatoms.Preferred fused rings (comprising the phenyl that is connected with R3) comprises naphthyl, indyl, benzimidazolyl-, benzofuryl, benzopyranyl.When two R3 formation and phenyl condensed ring, other R3 is H preferably.
In structure 1, R4 is selected from hydrogen, halogen, alkyl, aryl, heterocycle, carboxyl and its hydrocarbon ester and acid amides.Preferred R4 is selected from hydrogen, halogen, C 1-C 4Alkyl, phenyl.The phenyl that preferred R4 is selected from hydrogen and does not replace and replace; Substituting group on this class phenyl is selected from hydroxyl,-oxyl, sulfenyl and sulfenyl.Most preferred R4 is a hydrogen.
In structure 1,, each R5 is independently selected from hydrogen, alkyl and aryl.Preferred R5 is selected from hydrogen and 1 to 4 alkyl about carbon atom, particularly unsubstituted methyl or ethyl is arranged.Best is that two R5 are hydrogen entirely.
In structure 1, each R6 is independently selected from hydrogen, halogen, alkyl, aryl, heterocycle, cyano group and nitro; Also can be selected from hydroxyl, sulfenyl, amino, acid amides, formyl radical (acyl group) carboxyl, methane amide and sulphonamide, they are unsubstituted or replace, and are preferably replaced by alkyl or aryl or heterocycle.Preferred R6 is selected from hydrogen, halogen, alkyl, aryl, heterocycle, hydroxyl,-oxyl, aryloxy, sulfenyl, sulfenyl, arylthio, amino, hydrocarbon amino, virtue amino, acid amides, hydrocarbon acid amides, fragrant acid amides, sulphonamide, alkyl sulphonamide, aryl sulfonic acid amides, formyl radical, hydrocarbon acyl group, aroyl, carboxyl and its hydrocarbon ester and aromatic ester and acid amides; More preferably be selected from hydrogen, halogen, hydroxyl, C 1-C 4-oxyl, sulfenyl, C 1-C 4The C of alkyl sulfenyl, carboxyl 1-C 4Hydrocarbon ester and acid amides and the heterocycle of atom in 5 or 6 rings is arranged.More preferably select one or two R6 like this, at least one heteroatoms directly is connected with phenyl ring.When the heteroatoms that all has as two R6 directly linked to each other with the carbon atom of adjacent phenyl ring, two R6 can form the alkylene moiety that links to each other with two heteroatomss, and alkylene moiety preferably has 1 to about 4 carbon atoms, and 1 or 2 carbon atoms are more preferably arranged.Preferably, a R6 or two R6 are non-hydrogen groups; More preferably two R6 are non-hydrogen groups.Be more preferably, two R6 are-oxyl or alkyl sulfenyl; Preferably two R6 are identical.The preferred hydrocarbyl portion of R6 has 1 to about 4 carbon atoms, and 1 or 2 carbon atoms are more preferably arranged; Methyl preferably.This class hydrocarbyl portion is preferably unsubstituted.This class hydrocarbyl portion is preferably saturated.Preferably, two R6 are methoxy or ethoxies, particularly methoxyl group.
Preferably, R5 that is connected with the adjacent carbons of phenyl ring and R6 have been both 1 and have arrived about 6 carbon atoms and 0 to about 3 heteroatomic saturated or undersaturated alkylidene groups or assorted alkylidene group, formed like this and phenyl condensed ring, this class ring have an appointment 5 in about 8 rings atom.This class and phenyl condensed ring preferably have an appointment 5 in about 6 rings atom, wherein 0 to 2, preferably 0 or 1 is heteroatoms.The preferred ring that is formed by this class R5 and R6 comprises phenyl, furyl, pyrryl, alkyl dioxin, imidazolyl, pyridyl, pyrrolidyl, piperidyl.When this class R5 and R6 formation fused rings, other R5 and R6 preferably are hydrogen.
In structure 1, B do not have or-C (R7)=C (R7)-.When B did not have, n was an integer about 0 to 3, preferably 1 or 2.When B be-C (R7)=C (R7)-time, n is an integer 0 to about 1, preferably 0.Preferably there is not B.
In structure 1 and B, each R7 is independently selected from hydrogen, alkyl and aryl.Non-hydrogen R7 is phenyl or about 1 to 4 carbon atoms are arranged preferably, is more preferably the alkyl of 1 or 2 carbon atom.The non-hydrogen R7 of this class is preferably unsubstituted.Alkyl R7 is preferably saturated.Be preferably that more than one R7 is a hydrogen among all R7.Being more preferably all R7 is hydrogen.
The present invention includes the optical isomer of structure 1 compound, diastereomer and enantiomorph.The present invention includes pharmacy acceptable salt, hydrate and biological hydrolyzable ester, acid amides and the inferior acid amides of this compounds.
" pharmacy acceptable salt " is to go up the cationic salts that forms at any acidic-group (as hydroxy-acid group) on structure 1 compound, or goes up the anion salt that forms at any basic group (as amino).Many pharmacy acceptable salts are known.Preferred cation salt comprises an alkali metal salt, as sodium salt and sylvite, and alkaline earth salt, as magnesium salts and calcium salt, and organic salt, as ammonium salt.Preferred anionic surfactants salt comprises halogenide, sulfonate, carboxylate salt, phosphoric acid salt etc.Can be behind the salify to the optical center of giving that does not originally have optical center.
The compounds of this invention and its salt can have one or more chiral centres.The present invention includes all optical isomers of structural formula 1 compound and its salt, comprise diastereomer and diastereomer.The present invention includes the pure product of their each optical isomer, diastereomer or enantiomorph, purified form and mixture basically, comprise racemic mixture.
The preferred compound of the present invention comprises the compound of structural formula 2.
In structural formula 2, the description of R1, R3 and R6 is the same, and x is 0 or 1.
In structural formula 2, each R1 preferably is selected from the straight chained alkyl of 1-4 carbon atom, and the straight-chain alkenyl of 1 two key and 2-4 carbon atom is arranged, and the side chain and the cyclic alkyl of 3-5 carbon atom is arranged and the side chain and the ring-type thiazolinyl of 1 pair of keys, a 3-5 carbon atom are arranged.The preferred R1 of this class is unsubstituted or is replaced by phenyl, and is more preferably unsubstituted.R1 is selected from methyl, ethyl, vinyl, n-propyl, sec.-propyl, positive propenyl, pseudoallyl, sec-butyl, cyclopropyl, cyclobutyl and cyclopentyl preferably.Better R1 is selected from methyl, ethyl, vinyl, sec.-propyl and positive propenyl.Best R1 is a methyl.Preferably two R1 are identical.
In structural formula 2, one or two R6, preferably two R6 are alkylthios, or alkoxyl group more preferably, wherein alkyl has 1-4 carbon atom.If a R6 is not alkylthio or alkoxyl group, it is hydrogen preferably.More preferably, two R6 are methoxy or ethoxies; Preferably two R6 are methoxyl groups.
In structural formula 2, R3 preferably is selected from the hydrogen of doing; Preferably the list of 2 ', 3 ', 4 ' and 5 ' a place or many places-, two-or three-halo, preferably be selected from the halo of fluorine, chlorine and bromine; Preferably the list of 2 ', 3 ', 4 ' and 6 ' a place or many places-, two-or trimethylammoniumization; Preferably in the list at 3 ' and 5 ' a place or two places-or di-trifluoromethylization.A R3 is a dialkyl amino, and preferably on 4 ', preferably two alkyl are identical, and 1-4 carbon atom arranged, and other R3 is a hydrogen.The preferred combination of R3 is selected from 4 '-fluorine, 4 '-chlorine, 4 '-bromine, 2 ', 4 '-difluoro, 2 ', 4 '-dichloro, 2 ', 4 '-dibromo, 2 ', 4 ', 5 '-trifluoro, 2 ', 4 ', 5 '-trichlorine, 3 ', 4 '-difluoro, 3 ', 4 '-dichloro, 3 ', 4 '-dibromo, 4 '-methyl, 2 ', 4 '-dimethyl, 2 ', 4 ', 6 '-trimethylammonium, 3 '-trifluoromethyl, 3 ', 5 '-di-trifluoromethyl and 4 '-dibutylamino; In each case, all other R3 ' is a hydrogen.Preferred R3 combination is selected from 2 ', 4 '-dihalo and 3 ', 4 '-dihalo, and one of them halogen atom is selected from fluorine, chlorine and bromine, and other halogen atom is to be different from this halogen atom of three; One that is more preferably in this class halogen atom is fluorine, and all other R3 is a hydrogen.Best R3 combination is selected from 4 '-chlorine, 4 '-bromine and 2 ', 4 '-dichloro, and all other R3 is a hydrogen.
The The compounds of this invention non-limiting example comprises the compound of structural formula 2, and wherein two R6 are methoxyl groups, R1 and R3 (R3 that does not point out is a hydrogen) as shown below:
Embodiment ????x ????R1 ????R3
????1 ????0 Methyl, methyl Hydrogen
????2 ????0 Methyl, methyl 4 ' fluorine
????3 ????1 Methyl, methyl 4 '-chlorine
????4 ????0 Methyl, methyl 4 '-bromine
????5 ????0 Methyl, methyl 2 ', 4 '-difluoro
????6 ????1 Methyl, methyl 2 ', 4 '-dichloro
????7 ????0 Methyl, methyl 2 '-fluorine, 4 '-chlorine
????8 ????1 Methyl, methyl 2 '-fluorine, 4 '-bromine
????9 ????0 Methyl, methyl 2 '-chlorine, 4 '-fluorine
????10 ????1 Methyl, methyl 2 '-bromine, 4 '-fluorine
????11 ????1 Methyl, methyl 3 ', 4 '-difluoro
????12 ????0 Methyl, methyl 3 ', 4 '-dichloro
????13 ????0 Methyl, methyl 3 '-fluorine, 4 '-chlorine
????14 ????1 Methyl, methyl 3 '-fluorine, 4 '-bromine
????15 ????0 Methyl, methyl 3 '-chlorine, 4 '-fluorine
????16 ????1 Methyl, methyl 3 '-bromine, 4 '-fluorine
????17 ????0 Methyl, methyl 2 ', 4 ', 5 '-trifluoro
????18 ????0 Methyl, methyl 4 '-methyl
????19 ????1 Methyl, methyl 2 ', 4 '-dimethyl
????20 ????0 Methyl, methyl 3 ', 4 '-dimethyl
????21 ????1 Methyl, methyl 2 ', 4 ', 6 '-trimethylammonium
????22 ????1 Methyl, methyl 3 '-trifluoromethyl
????23 ????0 Methyl, methyl 3 ', 5 '-two trifluoromethyls
????24 ????0 Methyl, methyl 4 '-fluorine, 3 '-trifluoromethyl
????25 ????1 Ethyl, ethyl 4 '-fluorine
????26 ????0 Ethyl, methyl 4 '-chlorine
????27 ????0 Ethyl, ethyl 4 '-bromine
????28 ????1 Ethyl, methyl 2 ', 4 '-dichloro
????29 ????1 Ethyl, ethyl 3 '-fluorine, 4 '-chlorine
????30 ????1 Vinyl, vinyl 4 '-chlorine
????31 ????0 Vinyl, methyl 2 ', 4 '-dichloro
????32 ????0 Sec.-propyl, sec.-propyl 4 '-fluorine
????33 ????0 Sec.-propyl, methyl 4 '-chlorine
????34 ????1 Sec.-propyl, sec.-propyl 4 '-bromine
????35 ????1 Sec.-propyl, methyl 2 ', 4 '-dichloro
????36 ????0 Sec.-propyl, sec.-propyl 3 '-fluorine, 4 '-chlorine
????37 ????0 -CH 2-CH＝CH 2, methyl 4 '-fluorine
????38 ????1 -CH 2-CH＝CH 2，-CH 2-CH＝CH 2 4 '-chlorine
????39 ????1 -CH 2-CH＝CH 2, ethyl 2 ', 4 '-dichloro
????40 ????0 Sec-butyl, sec-butyl 4 '-chlorine
????41 ????1 Cyclopentyl, methyl 4 '-chlorine
????42 ????1 Methyl, methyl 2 ', 4 ', 5 '-trifluoro
????43 ????0 Methyl, methyl 2 ', 3 ', 4 '-trifluoro
????44 ????0 Ethyl, ethyl 2 ', 4 ', 5 '-trifluoro
????45 ????1 Ethyl, ethyl 2 ', 3 ', 4 '-trifluoro
????46 ????1 Sec.-propyl, sec.-propyl 2 ', 4 ', 5 '-trifluoro
????47 ????0 Sec.-propyl, sec.-propyl 2 ', 3 ', 4 '-trifluoro
????48 ????0 Methyl, methyl 4 '-dibutylamino
????49 ????1 Ethyl, ethyl 4 '-dimethylamino
????50 ????0 Sec.-propyl, sec.-propyl 4 '-diethylamino
In addition, can recognize that for purifying, administration etc. can be used the salt of above-claimed cpd and other derivative.Like this, the ester of their pharmacy acceptable salt, hydrate or hydrolyzable biology, acid amides or inferior acid amides are regarded as a part of the present invention.
The method for preparing compound
In the preparation The compounds of this invention,, can change the order of synthesis step in order to improve the yield of desired product.The present technique field personnel will appreciate that, selective reagents, solvent and temperature are important for successfully synthesizing advisably.The parent material that is used to prepare The compounds of this invention is known, maybe can be buied from commerce by known method preparation.
Can know that present technique field personnel can implement the standard operation of organic compounds at an easy rate and need not further guidance.These include, but not limited to reduction, oxidation, acidylate, replacement, etherificate, esterification, sulfonylation etc.The example of these operations all has discussion in received text.
It is described to prepare the method for some imidazo-isoquinoline compounds such as United States Patent (USP) 3,917,610 (1975,11,4 promulgation) and United States Patent (USP) 4,143,143 (1979,3,6 issue), and it is for reference to incorporate this paper at this.
Following general flow can be used to synthetic compound of the present invention.In these flow processs, the definition of R1, R2, R3, R4, R5, R6, R7, B and n is the same.For skilled chemist, may defined as among the following embodiment with abbreviation by unclear unconventional property symbol in other group and the chemical.General flow I
Figure A0080763600141
Figure A0080763600151
General flow II
Figure A0080763600152
The following example provides the further information of synthetic The compounds of this invention.
Precursor embodiment 1
Figure A0080763600162
With the aaerosol solution of NaH (6.5 grams, are used twice of hexane wash by 0.162 mole) in anhydrous dimethyl formamide (300 milliliters).Cooling adds solid imidazoles (10 grams, 0.145 mole) on a small quantity in batches in ice/acetone bath (bathing-15 ℃ of temperature), and mixture was at room temperature stirred 0.5 hour; The solution becomes clarification.At room temperature in 1 hour, be added dropwise to ESM-Cl (25 grams, 0.150 mole) by syringe pump; NaCl is precipitated out during adding.Make mixture stir about 1 hour at room temperature.By thin-layer chromatography (CH 2Cl 2/ MeOH, 9: 1) the monitoring reaction process.The careful H that adds 2O comes the cancellation reaction.Vacuum evaporating solvent.Residue is dissolved in Et 2O (200 milliliters) uses H 2O (4 * 50 milliliters), salt solution (50 milliliters) washing, dry (MgSO 4), to filter, vacuum-evaporation obtains the orange liquid of compd A.Precursor embodiment 2 Under-78 ℃ argon gas; to the imidazoles A of SEM-protection (1.48 grams; 7.50 mmole) in the solution of anhydrous tetrahydro furan (75 milliliters), be added dropwise to n-Butyl Lithium (1.6M is in hexane) (6 milliliters, 9.60 mmoles), mixture stirred 30 minutes down at-78 ℃.Be added dropwise to the curing benzene (2.1 grams, 9.60 mmoles) that is dissolved in (2ml) THF then.After reinforced, replace dry ice/acetone batch with ice bath.Mixture was stirred 1 hour down at 0 ℃, at room temperature stirred then 1 hour, by TLC (CH 2Cl 2/ methyl alcohol, 9: 1) the monitoring reaction process.Add entry (5 milliliters) and come the cancellation reaction.Vacuum evaporating solvent, residue is dissolved in ether, uses 5%NaHCO 3The washing of (3 * 20 milliliters), salt solution (20 milliliters), dry (MgSO 4), vacuum-evaporation obtains the yellow oil of B through chromatography purification (silica gel, hexane/ethyl acetate 3: 1).
Precursor embodiment 3
Figure A0080763600172
(MCPBA, 80-85%) (17.03 grams, 78.9 moles) are added to the 2-phenyl sulfide imidazoles B (9.71 grams, 31.6 mmoles) of SEM-protection at anhydrous CH with the 3-chloro peroxide acid 2Cl 2Solution (160ml) makes to be reflected under the argon gas and carries out, stirred 15 hours under the room temperature.By TLC (hexane/ethyl acetate, 3: 1) monitoring reaction process.Add Sulfothiorine (3.9 gram) and remove excessive MCPBA.Filtering mixt.Filtrate is used 5%Na 2CO 3(3 * 150ml), salt solution (150 milliliters) washing, dry (MgSO 4), to filter, vacuum-evaporation by chromatography (silica gel, hexane/ethyl acetate EtOAc 3: 1) purifying, obtains the light yellow oil of C.
Precursor embodiment 4
Figure A0080763600181
Under argon gas ,-78 ℃, in the solution of the 2-phenylsulfone imidazoles C of SEM-protection (8.61 grams, 25.4 mmoles) in anhydrous THF (250 milliliters), be added dropwise to n-Butyl Lithium (1.6M is in hexane) (19.0 milliliters, 30.0 mmoles) by the device pump; Solution was stirred 30 minutes down at-78 ℃.Be added dropwise to tributyltin chloride (6.9 milliliters, 25.4 mmoles) by syringe pump.Mixture was at room temperature stirred 1 hour.By TLC (hexane/EtOAc, 9: 1) monitoring reaction process.Add H 2O (30 milliliters) comes the cancellation reaction.Vacuum evaporating solvent.Residue is dissolved in ether (550 milliliters), uses saturated NH 4Cl (3 * 150 milliliters), salt solution (150 milliliters) washing, dry (MgSO 4), to filter, vacuum-evaporation is by chromatography purification (silica gel.Gradient: hexane (500 milliliters), hexane/EtOac, 50: 1; Hexane/EtOAc, 12: 1), obtain the clean oil of D.
Precursor embodiment 5 At room temperature with Pd (PPh 3) 4(0.0177 gram, 0.015 mmole) be added to stannyl imidazoles D (0.51 gram, 0.80 mmole), 4,5-dimethoxy-2-(2-hydroxyethyl) phenyl-bromide E (0.33 gram, 1.1 mmole) and the solution of LiCl (0.087 gram, 2.1 mmoles) in no Shui diox (4.0 milliliters).Add the crystal (about 2 milligrams) of some radical scavenger 2.6-di-tert-butyl-4-methy phenols, the heating reflux reaction thing reaches 5 hours under argon gas.To react cool to room temperature, with 1: 1 ether and the saturated KF aqueous solution (10 milliliters) mixture process 15 hours.By TLC (hexane/EtOAc, 3: 1) monitoring reaction process.Mixture helps filtering layer to filter by diatomite, uses ether drip washing.Filtrate water (3 * 12 milliliters), salt solution (3 * 12 milliliters) washing, dry (MgSO 4), to filter, vacuum-evaporation obtains the orange oil of F by chromatography purification (silica gel, hexane/EtOAc, 2: 3).
Precursor embodiment 6
Figure A0080763600191
Under argon gas, 0 ℃, in 0.5 hour to F (2.2 grams, 4.24 mmoles) and Et 3Add Methanesulfonyl chloride (MsCl, 492 microlitres) in methylene dichloride (200 milliliters) solution of N (886 microlitre).Make reactant be warming to room temperature then, and stirred 1 hour.Be used for monitoring reaction with TLC (EtOAc: hexane, 1: 1); Its expression has formed the MsO-ester, after the ring closure, splits SWM in reactor then.Use CH 2Cl 2(25 milliliters) diluted mixture thing is with the cold HCl aqueous solution (0.5N), NaHCO 3The aqueous solution, H 2MgSO is used in O, salt water washing 4Dry.Filtering also, evaporating solvent obtains yellow solid.HPLC purifying (EtOAc: hexane, the gradient from 1: 1 to 1: 0) with preparation obtains product G (1.3 gram).
Invention compound example I In 25 milliliters of single neck round-bottomed flasks that magnetic stirring bar, argon gas inlet and diaphragm of rubber are housed, the solution of 1-methyl isophthalic acid-phenyl-ethamine (H) (164 milligrams, 1.2 mmoles) in anhydrous THF is cooled to 0 ℃ under argon atmospher.In solution, slowly add solution in the hexane of n-Butyl Lithium (0.5 milliliter, 2.4M).Reactant becomes faint yellow.Stir after 45 minutes, add the compound G (150 milligrams, 0.405 mmole) that is dissolved among the THF (1 milliliter).Make solution be warming to room temperature, reheat refluxed 12 hours.With TLC (CH 2Cl 2: CH 3OH, 99: 1) the finishing of Indicator Reaction.Solution MeOH cancellation, evaporation obtains residue, and it is dissolved in CH again 2Cl 2, use NaHCO 3(5%), H 2Na is used in O, salt water washing 2SO 4Dry.Filter and high vacuum evaporation to remove the residue that obtains behind any excess amine H through chromatography purification (CH 2Cl 2: CH 3OH, 99: 1) obtain compound J of the present invention.
Invention compound example II In 25 milliliters of single neck round-bottomed flasks, the solution of compound J (181 milligrams, 0.5 mmole) in anhydrous THF is cooled to 0 ℃ under argon atmospher, will join in the solution with the hexane supernatant liquid among the NaH (18 milligrams) of hexane pre-wash then.Stir after 15 minutes, add the methyl-iodide (71 milligrams, 0.5 mmole) that is dissolved among the THF (0.5 milliliter) and exist.Make solution be warming to room temperature, reheat refluxes 2 hours to finish reaction.Solution MeOH cancellation, evaporation obtains residue, and it is dissolved in CH once more 2Cl 2, use NaHCO 3(5%), H 2Na is used in O, salt water washing 2SO 4Dry.Residue is through chromatography purification (CH 2Cl 2: CH 3OH, 99: 1 to 95: 5) obtain Compound P of the present invention.
Precursor embodiment 7
N-bromination succinimide (NBS) solid (98 milligrams, 0.26 mmole) adds compound G (0.5 mmole) at 15 milliliters of CCl 4Solution in.Add radical initiator benzoyl peroxide (2 moles of %) subsequently.Flask is placed in 90 ℃ the oil bath.After stirring in 10 minutes, finish reaction.Mixture helps the filtering layer pad to filter by diatomite, and evaporated filtrate obtains residue.By chromatography (EtOAc: hexane, 1: 3 to 1: 1) purifying, obtain compound K.
Precursor embodiment 8 To K (0.22 mmole) and Pd (PPh 3) 4(13 milligrams, 0.056 mmole) are dissolved in and add phenyl tributyl tin (0.26 mmole) and some 2, the crystal of 6-two-tertiary butyl-4-methylphenol (about 2 milligrams) in the solution of 7 milliliters of dry toluenes.Allow reaction mixture 110 ℃, refluxed under nitrogen 6 hours to finish reaction.Reaction mixture, dilute with 1-2 milliliter ethyl acetate (EtOAc) back.The mixture of gained washes with water, uses the salt water washing then, uses CH 2Cl 2Na is used in extraction 2SO 4Drying is filtered.Filtrate was at room temperature handled 2 hours with 3 milliliters of 30%KF aqueous solution.The elimination solid.Filtrate is used CH 2Cl 2Dilution, water, 30%NH 4OH (3 *), salt water washing, with the EtOAc extraction, dry (Na 2SO 4), vacuum concentration obtains crude product.Chromatography purification (silica gel, EtOAc: hexane, 1: 1 to 1: 0) obtains compound L.
Inventive embodiments III
Figure A0080763600221
In 25 milliliters of single neck round-bottomed flasks that magnetic stirring bar, argon gas inlet and diaphragm of rubber are housed, make (1-methyl isophthalic acid-phenyl-ethamine) (M) anhydrous THF solution of (1.2 mmole) under argon atmospher, be cooled to 0 ℃.In solution, slowly add n-Butyl Lithium hexane solution (0.5 milliliter, 2.4M).Reactant becomes faint yellow.Stir after 45 minutes, add THF (1 milliliter) solution of compound L (180 milligrams, 0.405 mmole).Make solution be warming to room temperature, reheat refluxes 12 hours to finish reaction.Solution MeOH cancellation, evaporation obtains residue, and it is dissolved in CH again 2Cl 2, use NaHCO 3(5%), H 2Na is used in O, salt water washing 2SO 4Dry.Filtration and high vacuum evaporation obtain compound N of the present invention to remove the residue that obtains behind any excess amine M through chromatography purification.
Composition of the present invention
The present composition comprises:
A) The compounds of this invention of safe and effective amount; With
B) acceptable accessories.
Be typically, this based composition comprises several auxiliary materials, and it also can randomly comprise does not disturb active other active compound of The compounds of this invention.
That the present composition can be is suitable (as) various forms of oral, rectal administration, local topical administration or parenteral administration.The present composition is preferably unit dosage." unit dosage " used herein is meant according to practising medicine experience, contains the composition with single agent administration of human or zootic The compounds of this invention amount.
" the safe and effective amount " of invention compound used herein is to be enough to greatly to the symptom and/or the amelioration of disease that can obviously cause the host who is treated, to be small enough to avoid the amount of host's serious adverse reaction (as toxicity, stimulation or anaphylaxis), has rational income/risk ratio.Safe and effective amount can change with this class factor, as by the specified disease of being treated, patient's age and physical condition, the time length of treatment, character, the particular dosage form of use and the used formulation scheme of treatment simultaneously (if the words that have).
Term used herein " acceptable accessories " comprises on the physiology compatible with the physico-chemical property of The compounds of this invention the material of non-activity on inert, the pharmacology, their purity is enough high, toxicity is enough low, is suitable for human body or lower animal administration.The conflicting mode of auxiliary material meeting of no use under normally used situation obviously minimizing compound medicine effect of term used herein " compatible " the expression present composition mixes with The compounds of this invention.
According to the particular approach of required administration, can use various acceptable accessories well-known in the art.Auxiliary material includes, but are not limited to, heteropolymer, resin, plastics, weighting agent, tackiness agent, lubricant, glidant, disintegrating agent, solvent, solubility promoter, buffering system, tensio-active agent, sanitas, sweeting agent, correctives and pigment or dyestuff.The amount of the vehicle that is used with The compounds of this invention is enough to provide usage quantity to the per unit formulation of The compounds of this invention.
Some examples that can be used as the material of pharmaceutically acceptable auxiliary material are, as lactose, dextrose, dextrose plus saccharose; Starch; As W-Gum and potato starch; Mierocrystalline cellulose and its derivative are as methylcellulose gum, Xylo-Mucine, ethyl cellulose, hydroxypropylcellulose and rhodia; Polymkeric substance is as polyvinylpyrrolidone (povidone) and carbomer; The tragacanth gum of powdered; Colloid is as xanthan gum, guar gum and gum arabic; Fructus Hordei Germinatus; Solid lubricant is as stearic acid, Magnesium Stearate and talcum powder; Inorganic filler is as calcium phosphate and calcium sulfate; Disintegrating agent is as sodium starch glycol, polyvinylpolypyrrolidone, croscarmelose sodium and Microcrystalline Cellulose; Sealing capsule and coating substance are as gelatin, wax class and derivatived cellulose; Vegetables oil is as peanut oil, Oleum Gossypii semen, sesame oil, sweet oil, Semen Maydis oil and obroma oil; Polyvalent alcohol is as propylene glycol, glycerine, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; Alginic acid; Tensio-active agent is as tween , alkyl-sulphate, soap, sucrose ester; Ethyl oleate; Tinting material; Seasonings; Tablet agent; Stablizer; Oxidation inhibitor; Sanitas; Solvent is as ethanol, pyrogen-free water; Isotonic saline solution; With buffering solution, as sulfuric acid, tartrate, citric acid and acetate and their sodium salt, sylvite and ammonium salt.
Preferred compositions of the present invention is an oral dosage form.Term used herein " oral dosage form " expression oral cavity or the gi tract release composition by individuality come any pharmaceutical composition to individual whole body administration.Oral unit dosage form preferably is as dressing or not tablet and the hard capsule or the soft capsule of dressing.The oral unit dosage form composition comprises at least about 4 milligrams, more preferably at least about 20 milligrams, is more preferably at least 100 milligrams, preferably maximum 1000 milligrams, more preferably maximum about 500 milligrams, is more preferably about 250 milligrams of The compounds of this invention at most.Oral dosage form composition of the present invention preferably comprises at least about 1%, more preferably at least about 10% and preferably at most about 70%, and about 40% The compounds of this invention at most more preferably; And comprise preferably at least about 30%, more preferably at least about 60% and preferably about at most 99%, about 90% pharmaceutically acceptable vehicle at most more preferably.
Parenteral formulations also is a preferred compositions of the present invention.Term used herein " parenteral formulations " expression comes human body or the administration of lower animal whole body by solution or the emulsion that the skin infusion that thrusts individuality contains active ingredient, so that by intravenous injection, intramuscular injection, intraperitoneal injection or subcutaneous injection recycle system release solution or the emulsion to individuality.The unit dosage composition of parenteral route of the present invention comprises at least about 1 milligram, preferably at least about 6 milligrams, and preferably at least about 30 milligrams with contain 400 milligrams at most, preferably at most about 100 milligrams, preferably maximum 40 milligrams The compounds of this invention.Parenteral formulations composition of the present invention preferably comprises at least about 1%, more preferably at least about 5% and preferably comprise at most about 20%, about 80% The compounds of this invention at most more preferably; And comprise at least about 80%, more preferably at least about 90% with comprise at most approximately 99%, be more preferably about 95% pharmaceutically acceptable vehicle at most.In addition, injectable dosage forms can be prepared into dried forms or lyophilized form.But this class formulation dosage form water, salt brine solution or buffered soln dissolve again.This class formulation can be packaged into single agent or multi-agent so that handle.When using freeze-drying or dry formulation, solvent-borne type is preferably isoosmotic again, has the compatible pH of physiology, and it comprises The compounds of this invention and vehicle, and its consumption and percentage ratio are as previously mentioned.
Method with compounds for treating
The compounds of this invention demonstrates pharmacologically active known the transfer in the relevant process with the protein of one or more cardiac vascular activities, inflammatory mechanisms, oncology and adjusting cell.The present invention includes and use above-claimed cpd treatment of the present invention or prevent and treat one or more following diseases: knurl, psoriasis, migraine, nasal congestion, transformation reactions, rheumatoid arthritis and osteoporosis in congestive heart failure, irregular pulse, hypertension, heart reperfusion injury, arteriosclerosis, restenosis, vasotonia, infectation of bacteria, cancer, the Kaposi.These class methods comprise to this class treatment of needs or need the human body of this class prevention or the The compounds of this invention that lower animal gives safe and effective amount.
For effective oral The compounds of this invention and/or composition, preferably with at least about 0.1mg/kg, be more preferably at least about 0.5mg/kg, preferably at least about 2mg/kg, with maximum about 20mg/kg, more preferably about at most 5mg/kg, the dosage of preferably about 2mg/kg The compounds of this invention give human body or lower animal about 1 time of every day at least, preferably about 2 times of every day, with every day about 4 times at most, about 2 times of every day preferably.Time length with the treatment of this class oral every day of formulation decides according to the disease of being treated, preferably at least about 1 day, and more preferably at least about 3 days, preferably at least 7 days, and about 5 days at most, preferably maximum about 60 days, preferably at least about 15 days.
Give The compounds of this invention and/or composition for preferred parenteral route, its dosage is at least about 0.04mg/kg, preferably, be more preferably at least about 1mg/kg and about at most 10mg/kg at least about 0.2mg/kg, preferably about at most 4mg/kg, be more preferably maximum about 1mg/kg The compounds of this invention, give human body or lower animal every day, preferably at least about 2 times at least about 1 time, with every day about 4 times at most, preferably at most about 2 times.Time length with this class parenteral route formulation every day treatment decides according to the disease of being treated; Preferably about 1 day, more preferably at least about 3 days, preferably at least 7 days and preferably maximum 60 days, more preferably maximum about 20 days, preferably maximum about 5 days.
Though set forth concrete technical scheme of the present invention already, obviously, present technique field personnel can make various changes and improvement to the present invention and not deviate from the spirit and scope of the present invention.This all class that appending claims is intended to cover in the scope of the invention is improved.

Claims (10)

1. compound and its optically active isomer with following formula structure, diastereomer or enantiomorph; Its pharmacy acceptable salt, hydrate or biological hydrolyzable ester, acid amides or inferior acid amides: Wherein:
(a) each R1 is independently selected from hydrogen, alkyl, aryl and heterocycle; Preferred each R1 is independently selected from hydrogen; Straight chain, side chain and cycloalkyl and thiazolinyl; And phenyl;
(b) R2 is selected from hydrogen, alkyl, hydrocarbon acyl group, aroyl, alkylsulfonyl and arylsulfonyl; Preferably, each R2 is selected from hydrogen; Straight chain, side chain and cycloalkyl and thiazolinyl; Hydrocarbon acyl group and phenyl acyl group;
(c) each R3 is independently selected from hydrogen, halogen, alkyl, aryl, heterocycle, nitro, cyano group and unsubstituted or by alkyl-or aryl-or hydroxyl, sulfenyl, amino, acid amides, formyl radical (acyl group), carboxyl and the methane amide of heterocycle-replacement; Or two R3 on the phenyl adjacent carbons can randomly be all alkylidene group or assorted alkylidene group; Preferably, each R3 is independently selected from hydrogen, halogen, alkyl, aryl, heterocycle, hydroxyl,-oxyl, aryloxy, sulfenyl, sulfenyl, amino, hydrocarbon amino, virtue amino, acid amides, hydrocarbon acid amides, fragrant acid amides, formyl radical, hydrocarbon acyl group, carboxyl and its hydrocarbon ester and aromatic ester and its acid amides; Or preferably two R3 are both alkylidene group or assorted alkyl, and the carbon that links to each other with them forms cyclic hydrocarbon radical, aryl or heterocycle;
(d) R4 is selected from hydrogen, halogen, alkyl, aryl, heterocycle and carboxyl and its hydrocarbon ester and aromatic ester and acid amides;
(e) each R5 is independently selected from hydrogen, alkyl and aryl;
(f) each R6 is independently selected from hydrogen, halogen, alkyl, aryl, heterocycle, nitro, cyano group and unsubstituted or alkyl-or aryl-or hydroxyl, sulfenyl, amino, acid amides, sulphonamide, formyl radical, carboxyl and the methane amide of heterocycle-replacement; Or two R6 can randomly be both alkylidene group or assorted alkylidene group, or the R5 that links to each other with adjacent carbons and R6 are both alkylidene group or assorted alkylidene group; Preferably, each R6 is independently selected from hydrogen, halogen, alkyl, aryl, heterocycle, hydroxyl,-oxyl, aryloxy, sulfenyl, sulfenyl, arylthio, amino, alkyl amino, arylamino, acid amides, hydrocarbyl amide, fragrant acid amides, sulphonamide, hydrocarbon sulphonamide, aromatic sulfuryl amine, formyl radical, hydrocarbon acyl group, aryl-acyl, carboxyl and its hydrocarbon ester and aromatic ester and acid amides; Or preferably two R6 are both alkylidene group or assorted alkylidene group, form cycloalkyl, aryl or heterocycle with the carbon that is connected with them;
(g) B does not have, or B be-C (R7)=C (R7)-;
(h) if B does not have, n is about 0 to 3 integer, otherwise n is about 0 to 1 integer;
(j) each R7 is independently selected from hydrogen, alkyl and aryl; Preferably each R7 is hydrogen or the alkyl that 1 to 4 left and right sides carbon atom is arranged;
Wherein preferred R2, R4 and two R5 are hydrogen.
2. compound according to claim 1, wherein:
(a) each R1 is C independently 1-C 5Straight chained alkyl, or C 3-C 5Side chain or cycloalkyl; Or contain the unsubstituted C of two keys 2-C 5Straight-chain alkenyl or C 3-C 5Branched-chain alkenyl or cycloalkenyl group;
(b) R2 is selected from hydrogen; Unsubstituted C 1-C 5Straight chained alkyl, or C 3-C 5Side chain or cycloalkyl; Or contain the unsubstituted C of two keys 2-C 5Straight-chain alkenyl or C 3-C 5Branched-chain alkenyl or cycloalkenyl group;
(c) each R3 is independently selected from hydrogen, halogen, C 1-C 4Alkyl, sulfenyl, C 1-C 4Sulfenyl, C 1-C 4Single-or dialkyl amino, C 1-C 4The alkyl acyl group;
(d) R4 is selected from hydrogen, halogen, C 1-C 4Alkyl and phenyl;
(e) two R5 are hydrogen;
(f) R6 is selected from hydrocarbon alkyl, alkyl sulfenyl, single alkyl amino, dialkyl amino, and its hydrocarbyl portion is saturated, unsubstituted, has 1 to about 4 carbon atoms; Or the hydrocarbyl portion of two R6 is connected to form 1 to the alkylene moiety of about 4 carbon atoms, and wherein preferred two R6 are C 1-C 4-oxyl or C 1-C 4Sulfenyl; With
(g) be hydrogen more than one R7; Preferably all R7 are hydrogen.
3. compound according to claim 1 and 2, wherein two R6 are methoxyl groups.
4. compound according to claim 2 does not wherein have B, and n is 1 or 2.
5. compound according to claim 2, wherein B is-C (R﹠amp; )=C (R7)-, n is 0.
6. compound according to claim 1 and 2, wherein 1-3 R3 is independently selected from F, Cl and Br, other be hydrogen; Or 1-3 R3 be unsubstituted methyl, other be hydrogen; Or one or two R3 is trifluoromethyl, other be hydrogen.
7. compound according to claim 2, wherein two R1 are methyl.
8. composition, it comprises:
(a) compound as claimed in claim 1 or 2 of safe and effective amount; With
(b) pharmaceutically acceptable vehicle.
9. the application of compound as claimed in claim 1 or 2 in damage, congestive heart failure or hypertensive medicine that preparation treatment or prevention people or zootic nose hyperemia, migraine, irregular pulse, heart are irritated again comprises the compound as claimed in claim 1 or 2 that described object is given safe and effective amount.
10. compound as claimed in claim 1 or 2 make a kind of treatment or prevention people or than lower animal in the disease or the disorder that cause because of the cell protein transposition, comprise, but be not limited to that osteoporosis, rheumatoid arthritis, anaphylaxis, restenosis, blood vessel follow the string, the application in the medicine of cancer, Kaposi sarcoma, psoriasis and infectation of bacteria, comprise the compound as claimed in claim 1 or 2 that described object is given safe and effective amount.
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