CN1849301A - Substituted arylthiourea derivatives useful as inhibitors of viral replication - Google Patents
Substituted arylthiourea derivatives useful as inhibitors of viral replication Download PDFInfo
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Abstract
Substituted arylthiourea compounds of Formula I, and the pharmaceutically acceptable salts of such compounds, useful as antiviral agents, are provided herein. Certain substituted arylthioureas disclosed herein are potent and/ or selective inhibitors of viral replication, particularly Hepatitis C virus replication. Pharmaceutical compositions containing one or more substituted arylthiourea compounds and one or more pharmaceutically acceptable carriers, excipients, or diluents are provided herein. Such pharmaceutical compositions may contain a substituted arylthiourea as the only active agent or may contain a combination of a substituted arylthiourea derivative and one or more other pharmaceutically active agents. Methods of treating Hepatitis C viral infections in mammals are also provided herein.
Description
Technical field
The invention discloses substituted aryl thiourea compound with antiviral activity.Some substituted aryl thiocarbamide disclosed by the invention is effectively and/or is selected from the inhibitor of inhibitor, particularly hepatitis C virus as virus replication.The invention also discloses pharmaceutical composition, said composition contains one or more substituted aryl thiourea compounds, and pharmaceutically acceptable carrier, vehicle or thinner.These pharmaceutical compositions can contain the substituted aryl thiocarbamide as unique active agent, also can contain composition and one or more pharmaceutically active agents of substituted aryl thiourea derivative.The present invention further discloses the method that treatment Mammals hepatitis C virus infects.
Background technology
The forties in 20th century, the viral hepatitis disease begins to be divided into two classes, promptly infectious hepatitis (A type hepatitis, HAV) and homologous serum hepatitis (viral hepatitis type b, HBV).The input blood products is the common route of infection of viral hepatitis.Because sick labour is learned and the not normal symptom and the HAV of Clinical symptoms do not meet, and therefore thinks originally that HBV was the pathogenic agent of blood transfusion type hepatitis.
With the method for radioimmunoassay the patient's of infection HBV viral hepatitis type b surface antigen (HBsAg) is analyzed subsequently, clearly, the patient of most of blood transfusion type hepatitis is negative to HBsAg.Therefore, blood transfusion type hepatitis is not A type hepatitis, neither viral hepatitis type b, confirm as non-a non-b hepatitis subsequently.
1989, infected the document that the cDNA of RNA, DNA of the chimpanzee of non-a non-b hepatitis serum expresses by analysis, found non-a non-b hepatitis (C C-type virus C hepatitis, pathogenic agent HCV).For the genome of identifier number viral protein, document analysis infect non-a non-b hepatitis patient's antibody.Research shows that further these viruses that identify have caused most non-a non-b hepatitis.
C C-type virus C hepatitis is one of main chronic hepatopathy in the U.S..It has accounted for the chronic hepatopathy of 15% acute viral hepatitis, 60-70% greatly, and up to 50% liver cirrhosis, hepatopathy late period and liver cancer.Almost 4,000,000 American, or 1.8% American has carried HCV antibody (whose anti-HCV), and this shows that a lot of people or have infected hepatopathy virus.Cause about 8000 to 10000 people's death every year in U.S. C type hepatopathy.C type hepatitis (HCV) all will take place all over the world.The seroprevalence (seroprevalence) of whose anti-HCV accounts for 0.02-1.23% in donating blood in the world.HCV also is a common factor of accepting the individuality infection hepatitis of blood products.In the past ten years, the newly-increased case of the annual HCV infection of the U.S. estimates at about 150000 people.
The infective stage of HCV is attended by gentle symptom usually.But, evidence shows only has the infection of 15%-20% colony can remove HCV.In these chronic infection colonies, the colony of 10-20% can develop into liver cirrhosis, and the colony of 1-5% can develop into liver cancer in addition.Unfortunately, owing to can not predict the situation of individual development, so the life of all infection colonies will be on the hazard.
HCV is that yellow fever virus section (Flaviviridae family) is medium and small, armouring with strand male RNA viruses.Genome has 10000 nucleosides approximately, and the polymeric protein of about 3000 nucleic acid of encoding.This polymeric protein is processed into necessary three the main structural proteins of virus replication and several nonstructural proteins with host cell and virus protease.Thereby, identified the different genotype of the HCV relevant with the treatment of alpha-interferon, that genome sequence is slightly different.
HCV duplicates in the tenuigenin of cells infected, and closely related with endoplasmic reticulum.Discharge the positive sense RNA of introducing, and translate by playing initialize in the body and translate mechanism (internal initiation mechanism) beginning.Initialize is led by genome 5 ' terminal cis acting RNA element in the body; Some reports show that whole activity in the insertion site (IRES) of this body internal ribosome and 700 first nucleosides show that together above-mentioned nucleosides is crossed over 123 initial amino acid of 5 ' non-coding region (UTR) and open reading frame (ORF).The all proteinaceous product of HCV obtains by the hydrolysis of big polymeric protein (about 3000 amino acid), and by a kind of realization in three kinds of proteolytic enzyme: host signal peptase, viral self cracked metalloprotein, NS2, or virus serine protease NS3/4A.The combined reaction of these enzymes produces structural protein (C, E1 and E2) and Nonstructural Protein (NS2, NS3, NS4A, NS4B, NS5A and NS5B), and these albumen are used to duplicate and the packaging virus geneome RNA.NS5B is the viral RNA polymerase (RDRP, RNA-dependent RNAPolymerase) that depends on RNA, and the geneome RNA of control input is converted into minus strand replica (complementary RNA or cRNA); CRNA transcribes template as the NS5B of more positive sense genome/messenger RNA(mRNA) then.
Need a large amount of effective vaccines, but can not get along with current, this be because: i) lack the effective cell culture system small animal model of unifying; Ii) Ruo body fluid neutralization reaction and protective immunological reaction; The iii) hereditary variability of virus signature; And iv) lack viral correction mechanism.
Research institution of a few family and laboratory attempt to differentiate and exploitation whose anti-HCV medicine.At present unique is alpha-interferon to the effective medicine of HCV, and alpha-interferon only can reduce the viral load (viral load) in sub-fraction infected patient liver and the blood.The alpha-interferon approval is used for the treatment of HCV before more than ten years.Alpha-interferon is the host protein of response virus infection, has the nature antiviral activity.But, the standard form of these Interferon, rabbit is just substituted (peginterferons) by long-acting interferon now.Long-acting interferon is to carry out the alpha-interferon of chemical modification by adding macromolecular inertia polyoxyethylene glycol.At present, best drug regimen was 24 or 48 course of treatment Monday, long-acting alpha-interferon and nucleosides ribavirin (Ribavarin) and usefulness, and the nucleosides ribavirin is a kind of oral Anti-virus agent, and large-scale virus is had activity.Ribavirin itself is very little to the effect of HCV, has increased by 2 to 3 times but continue response rate (sustained response rate) after joining it in Interferon, rabbit.Even so, although the response rate of the selection genotype of HCV (particularly genotype 2 and 3) is generally all higher, the response rate of Interferon, rabbit/ribavirin and usefulness is medium, in the scope of 50-60%.During the treatment, among the negative patient of the RNA of HCV, when treatment stopped, patient was recurred again greatly.
In addition, these reagent all have very big side effect usually.Accept the symptom of the frequent similar influenza of patient of Interferon, rabbit.Long-acting interferon is attended by the bone marrow depression effect.Extended treatment can cause significant violent rage, anxiety, personality change, depression, even suicide or acute mental disorder.For the historical people that takes drugs or be addicted to drink is arranged, interferon therapy also can recur.
The side effect of ribavirin therapy comprises anaemia and the similar side effect of histamine that the side effect (rhiocnesmus, the gas of having a stuffed up nose) of similar histamine, relevant erythrocyte hemolysis cause.
In sum, the aforesaid fact shows needs a kind of above-mentioned shortcoming that do not have in the reality, and can effectively suppress the micromolecular inhibitor that hepatitis C virus duplicates.Compound provided by the invention can satisfy above-mentioned requirements, and has tangible advantage.
Summary of the invention
The invention provides the compound shown in the formula I (as follows).Formula I comprises substituted aryl thiourea derivative and relevant compound, and these compounds have antiviral activity.Compound shown in the formula I that other some embodiment provide is a selective depressant effective and/or that hepatitis C virus duplicates.In addition, pharmaceutical composition contains one or more formulas I compound, or salt, solvate, or the acidylate precursor of these compounds, and one or more pharmaceutically acceptable carriers provided by the invention, vehicle or thinner.
The present invention also provides a kind of treatment to suffer the patient's of specified disease infection method, and this method comprises a certain amount of formula I compounds effective that doses a patient with, to reduce disease and not normal symptom and sign.These infectious diseases comprise virus infection, and particularly HCV infects.Method of the present invention comprises that not only treatment suffers the patient of infectious diseases, also comprises other Mammals of treatment, as suffers the livestock and the domestic animal of infectious diseases.
The invention provides a kind of method that HCV duplicates that suppresses in vivo, this method comprises that the patient to HCV infection takes formula I compound or salt certain density, q.s, to suppress HCV replicon duplicating in vivo.
Methods of treatment comprises that the compound of taking formula I is as the single-activity agent or take a kind of compound of formula I together and one or more other pharmaceutical agent.
Thereby, comprise compound shown in the formula I and pharmacy acceptable salt in the first embodiment of the present invention.
Formula I
In formula I:
Z is 0,1 or 2.
R is hydrogen, methyl or ethyl.
A
1Be nitrogen or CR
1A
2Be nitrogen or CR
2A
3Be nitrogen or CR
3A
4Be nitrogen or CR
4And A
5Be nitrogen or CR
5The A of one of them
1, A
2, A
3, A
4Or A
5Be nitrogen, or do not have.
R
1, R
4And R
5Be respectively hydrogen, hydroxyl, amino, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group.
R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And R
2And R
3In another be:
(i) C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino replaces;
(ii) C
4-C
8Carbalkoxy, C
5-C
8Alkyl, C
5-C
8Alkene, C
5-C
8Alkynyl; Or C
4-C
8Alkoxyl group;
(iii) (phenyl) L-or (pyridyl) L-, each group be condensed ring to 6 yuan carbocyclic ring or contain 1 or 2 heteroatoms such as 5 or 6 yuan of heterocycles of N, O, S optionally; Wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group ,-C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl-; Or
(iv) (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, the bridge joint of each group selectivity and the condensed ring to 6 of each group selectivity yuan carbocyclic ring or contain 1 or 2 heteroatoms such as 6 yuan of heterocycles of N, O, S; Wherein (i), (ii), (iii) and (iv) each is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
When there being R
6And R
7The time, they are selected from hydrogen, halogen, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group and phenyl; Or R
6And R
7Add and form 3-7 unit alkyl ring.
Accordingly, another embodiment provides formula I compound and pharmacy acceptable salt, wherein:
R is hydrogen, methyl or ethyl.
Z is 2.
A
1Be nitrogen or CR
1A
2Be nitrogen or CR
2A
3Be nitrogen or CR
3A
4Be nitrogen or CR
4And A
5Be CR
5The A of one of them
1, A
2, A
3Or A
4Be nitrogen, or do not have.
R
1And R
4Be respectively hydrogen, hydroxyl, amino, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group.
R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And R
2And R
3In another be:
(i) hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group;
(ii) C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino replaces;
(iii) C
4-C
8Carbalkoxy, C
5-C
8Alkyl, C
5-C
8Alkene, C
5-C
8Alkynyl; Or C
4-C
8Alkoxyl group;
(iv) (phenyl) L-or (pyridyl) L-, each group be condensed ring to 6 yuan carbocyclic ring or contain 1 or 2 heteroatoms such as 5 or 6 yuan of heterocycles of N, O, S optionally; Wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group ,-C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl-; Or
(v) (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, the bridge joint of each group selectivity and the condensed ring to 6 of each group selectivity yuan carbocyclic ring or contain 1 or 2 heteroatoms such as 6 yuan of heterocycles of N, O, S; Wherein (ii), (iii), (iv) and (each v) is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
R
5With a R
6Form the 5-7 unit alkyl ring of condensed ring together; And
Another R
6With with two R
7Be selected from hydrogen, halogen, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group and phenyl.
The invention discloses some and in the HCV replicated test, have fine active substituted aryl thiocarbamide, the HCV replicon test shown in following example 9.Preferred substituted aryl thiocarbamide demonstrates about 10 micromoles or EC still less
50, particularly preferred is about 1 micromole or EC still less
50Perhaps about 500 nmoles (nanomolar) or EC still less in HCV replicon test
50
Embodiment
The description of chemical products and term
Before being described in detail the present invention, earlier the term of using is defined.The compound that the present invention uses is normally narrated with standardized denomination.
Formula I of the present invention comprises various derivatives.For example, formula I comprises compound and the pharmacy acceptable salt of formula IA-IC and formula 2-19.
In some cases, the compound of formula I can comprise one or more asymmetric parts such as chiral centre, chiral axis, and as unsymmetrical carbon, thereby compound can have different steric isomers.For example, these compounds can be racemoid or optically active form compound.For the compound that 2 or more a plurality of asymmetric parts are arranged, these compounds can form the mixture of diastereomer.For compound, should comprise these optical isomers and its mixture with asymmetric center.In addition, the compound with the two keys of carbon can appear in Z-and the E-forms form, comprises the isomerism form that compound is all among the present invention.In these situations, single enantiomorph, promptly the optically active form form can obtain by the asymmetric synthesis of pure optically active form precursor, perhaps obtains by decomposing racemoid.For example, the decomposition of racemoid can perhaps be used the chromatography of chirality HPLC post by the crystallization under conventional method such as the decomposition agent existence.
When a kind of compound has multiple tautomerism volume morphing, the invention is not restricted to any specific tautomer, but comprise all tautomerism volume morphings.
Compound among the present invention comprises all isotropic substances of atom.The coordination of these atoms have identical ordination number, but the nucleidic mass difference.For example, the isotropic substance of hydrogen comprises tritium and deuterium, and the isotropic substance of carbon comprises
11C,
13C and
14C.
What the compound among the present invention used is general formula, comprises variable, as R, A
1-A
5And R
1-R
7Unless special the qualification, the every kind of variable and other the variable of these molecular formula are independently of one another.Therefore, if certain group by as 0-2R
*Replace, this group can be by maximum two R
*Group replaces, each R
*Substituting group is independent of respectively R
*The middle selection.Simultaneously, as long as the combination of substituting group and/or variable is stable compound, then this combination allows.
The term of using among the present invention " replacement " meaning is that any one or a plurality of hydrogen atom on specified atom or the group replaced by described group, were it not for the valency above specified atom.When substituting group is that oxygen (promptly=O) time, just has 2 hydrogen atoms to be substituted.When aromatic portion was replaced by oxygen groups, aromatic nucleus was replaced by the unsaturated ring of corresponding part.For example, the pyridine group that is replaced by oxygen is a pyridone.If the combination of substituting group and/or variable is stable compound or useful synthetic mesophase thing, this combination is exactly passable.Stable compound or stable structure mean that compound is stable for reaction mixture, and can be used as a kind of effective medicinal reagent.
The dash ("-") between two letters or symbol is not used to represent substituent tie point.For example ,-COOH connects by carbon atom.
" alkyl " among the present invention comprises straight or branched, has the saturated fatty hydrocarbyl group of the carbon atom of given number.Therefore, the phrase C among the present invention
1-C
6Alkyl comprises that carbon atom is the alkyl group of 1-6.Work as C
0-C
nWhen alkyl is connected with other group, such as, phenyl C
0-C
4Alkyl, this moment phenyl or directly with covalent linkage (C
0) connect, or connect by the alkyl chain with particular carbon atom number, wherein carbon atom number is 1-2.The example of alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl and the second month in a season-amyl group.
" thiazolinyl " among the present invention comprises the hydrocarbon chain of side chain or linear chain structure, has one or more unsaturated carbon bonds, and unsaturated carbon bond can be on the stable point of chain, as vinyl and propenyl.
" alkynyl " among the present invention comprises the hydrocarbon chain of side chain or linear chain structure, has one or more carbon carbon triple bonds, and carbon carbon triple bond can be on the stable point of chain, as ethynyl and proyl.
What " alkoxyl group " among the present invention represented is the group that abovementioned alkyl is connected with carbon atom by oxo bridge.Some examples of alkoxy base include but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentyloxy, 2-pentyloxy, 3-pentyloxy, isopentyloxy, neopentyl oxygen, positive hexyloxy, 2-hexyloxy, 3-hexyloxy and 3-methyl hexyloxy.
The abovementioned alkyl of " alkyloyl " expression connects by ketone bridge ((C=O)-).Alkyloyl has the carbon atom of certain number, in wherein the carbon atom of ketone group is also included within.For example, C
2Alkyloyl is an ethanoyl, and molecular formula is CH
3(C=O)-.
What term " carbalkoxy " was represented is that above-mentioned certain carbonatoms purpose alkoxyl group connects by ketone group.The carbon atom that connects ketone group is not included in the above-mentioned carbon atom number, thereby C
2The molecular formula of carbalkoxy is CH
3CH
2O (C=O)-.
What term " alkyl carboxylic acid amides " was represented is that above-mentioned certain carbonatoms purpose alkyl connects by the carboxylic acid amides connecting key, promptly-and CONH
2Connecting key, one of them and two hydrogen atoms are replaced by alkyl.The alkyl carboxylacyl amine group can be singly-and two-alkyl carboxylacyl amine group, as ethyl carboxylic acid amides or dimethyl carboxylic acid amides.
Term among the present invention " single-or two-alkylamino " what represent is secondary or three grades of alkylamino groups, wherein alkyl has the carbon atom of certain number as mentioned above.The tie point of alkylamino group is a nitrogen-atoms.Single-as to comprise ethylamino-, dimethylin and first-Propylamino with two-alkylamino examples of groups.
What the term among the present invention " aryl " was represented is the aromatic group of carbon atom in aromatic nucleus.This aryl can be further by carbon or non-carbon atom or group replacement.Typical aryl contains the ring of 1 to 3 that separate, condensed ring or 6 to 18 atom, and does not have heteroatoms in the ring.This aryl can be substituted.This replacement can comprise condensed ring 5-7 unit saturated rings, and saturated rings optionally contains 1 or 2 heteroatoms, and heteroatoms is selected from N, O and S respectively, thereby forms one 3,4-methylene radical dioxy base-phenyl.Aryl comprises phenyl, naphthyl, as 1-naphthyl, 2-naphthyl and biphenyl.
In term " (aryl) alkyl ", aryl and alkyl as mentioned above, tie point is on alkyl.This term includes but not limited to phenyl, styroyl and piperonyl.Equally, in term (aryl) alkyl, aryl and alkyl as mentioned above, tie point is on alkyl, as vinylbenzene-1-base.
" alkyl " among the present invention comprises the alkyl of side chain and straight chain, and this group is saturated or undersaturated, has the carbon atom of certain number.
The saturated alkyl ring of " cycloalkyl " among the present invention expression has the carbon atom of certain number, normally 3-8 ring carbon atom, or 3-7 carbon atom.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the saturated rings of ethyl bridge-type or cage such as norcamphane or tristane.
" alkylhalide group " expression be the aliphatic saturated hydrocarbon of certain carbonatoms purpose side chain and straight chain, by 1 or a plurality of halogen atom replace, can allow maximum halogen atoms usually.The example of alkylhalide group includes but not limited to trifluoromethyl, difluoromethyl, 2-fluoro ethyl and pentafluoroethyl group.
What " halogen alkoxyl group " represented is that above-mentioned alkylhalide group connects by oxo bridge.
" halogen " or " halogen " among the present invention refer to fluorine, chlorine, bromine or iodine.
" heteroaryl " that use among the present invention expression be stable 5-7 unit's monocycle or two heterocycles of 7-10 unit, contain at least one aromatic nucleus, and contain 1-4 heteroatoms that is selected from N, O, S, it is individual to be preferably 1-3, remaining atom is a carbon atom in the ring.When S whole in the heteroaryl and O atom number surpassed 1, these heteroatomss were not adjacent to each other.Preferably, whole S and O atomicities is no more than 2 in the heteroaryl.The example of heteroaryl includes but not limited to pyridyl, indyl, pyrimidyl, pyridizin base, pyrazinyl, imidazolyl, oh azoles base, furyl, thiophenyl, thiazolyl, triazolyl, tetrazyl, different azoles base, quinolyl, pyrryl, pyrazolyl and 5,6,7, the 8-tetrahydroisoquinoline.In term " heteroaralkyl ", heteroaryl and alkyl as mentioned above, tie point wherein is on alkyl.This term includes but not limited to picolyl, benzene thiomethyl and pyrroles (1-ethyl).
Term " Heterocyclylalkyl " is used to represent to contain 1 to 3 heteroatomic saturated rings that is selected from N, O, S, and remaining annular atoms is a carbon atom.Heterocyclylalkyl has 3 to 8 annular atomses, normally 5 to 7 annular atomses.C
2-C
7Heterocyclylalkyl contain 2 to 7 carbon atoms and at least one and be selected from the heteroatoms of N, O, S.The example of Heterocyclylalkyl comprises morpholinyl, piperazinyl, piperidyl and pyrrolidyl.
" heterocycle of 6-unit carbocyclic ring or 5-or 6-unit " of condensed ring is saturated, and part is unsaturated or the aromatic nucleus of certain annular atoms number is arranged, and annular atoms and condensed ring group form dicyclo.6-unit carbocyclic ring comprises phenyl, cyclohexyl and cycloalkenyl group.5-and 6-unit heterocycle contain 1,2 and 3 heteroatoms, are selected from N, O, S respectively, as pyridyl, piperidyl, pyrrolidyl and morpholinyl.
" (benzene oxygen) alkyl " is the phenoxy group that connects by certain carbonatoms purpose alkyl.When the alkyl that connects is C
0During alkyl, phenoxy group is connected with substituting group by Sauerstoffatom, as benzene-O-.Same, " (benzene) alcoxyl " is the phenyl that connects by certain carbonatoms purpose alkoxyl group, as benzyloxy substituting group, benzene-CH
2-O.And the phenyl that connects by amido when " (benzene) alkylamino radical ", the secondary amine of certain carbonatoms is normally arranged.
" pharmacy acceptable salt " comprises the derivative of disclosed compound, and wherein parent compound is by nontoxic bronsted lowry acids and bases bronsted lowry salt modification, and this pharmacy acceptable salt further refers to the pharmaceutically acceptable solvate of these compounds and salt.The example of pharmacy acceptable salt includes but not limited to the alkaline residue such as the amine of mineral or organic acid salt; The acid residue of alkali or organic salt such as carboxylic acid; And analogue.Pharmacy acceptable salt comprises common non-toxic salt and passes through the quaternary ammonium salt of the parent compound of nontoxic inorganic or organic acid formation.For example, common nontoxic hydrochlorate comprises the salt that obtains from mineral acid, example hydrochloric acid salt, hydrobromate, vitriol, sulfanilamide (SN) salt, phosphoric acid salt, nitrate; The salt that obtains from organic acid comprises acetate, propionic salt, succinate, oxalate, stearate, lactic acid salt, malate, tartrate, Citrate trianion, vitamins C salt, the piperazine hydrochlorate, maleate, hydroxymaleic acid salt, phenylacetate, glutaminate, benzoate, salicylate, methylsulfonyl salt, ethyl sulfonic acid, Phenylsulfonic acid, sulfanilate, 2-acetoxy-benzoic acid salt, fumarate, tosylate, methane sulfonates, ethane disulfonate, Herba Oxalidis Corniculatae salt, isethionate, HOOC-(CH
2)
n-COOH, wherein n is 0-4.Acceptable salt can obtain by the parent compound that contains alkalescence or acidic moiety is synthetic by the conventional chemical method on the Chinese materia medica of the present invention.Usually, these salt can be by these compounds the form of acid and suitable stoichiometric alkali (as the oxyhydroxide of Na, Ca, Mg or K, carbonate, hydrocarbonate) carry out prepared in reaction, perhaps prepared in reaction is carried out in the form of the alkali by these compounds and suitable stoichiometric acid.These reactions are carried out in water or in the organic acid solvent usually, or carry out in water and the organic acid mixture.Usually, non-aqueous media such as ether, ethyl acetate, ethanol, Virahol or second cyanogen are preferred.All suitable salt of listing can find in the 1418th page of the 17th edition the pharmaceutical science (1985) of the Lei Mingdun that fraternal publishing company publishes.
Term " precursor " comprises any compound that becomes formula I compound when taking to Mammals by metabolism.The example of precursor includes but not limited to the derivative of acetate, formate and the benzoate of the functional group's (as alcohol radical or amido) in the formula I compound.
" the treatment significant quantity " of the term compound among the present invention refers to when patient or other sick body are taken significant quantity can improve illness, can reduce the symptom of virus infection as significant quantity, and preferred significant quantity is enough to reduce the symptom that HCV infects.In some cases, the patient of the virus infection symptom that can not occur infecting.Thereby the treatment significant quantity of compound also is the q.s that prevents to roll up or extremely reduce virus in sick body blood, serum or the tissue or antiviral antibody.Virus or antiviral antibody are the variations that can survey surveying rolling up or reducing on the horizontality, and this variation is significant in the T-test of canonical parameter test as Student ' s of statistical significance, wherein p＜0.05.
" replicon " among the present invention comprises any gene element, as plasmid, clay, shuttle vectors (bacmid), antibiotic or virus, this gene element can oneself control condition under massive duplication.Replicon can be RNA or DNA, can be strand or two strands.
" nucleic acid " among the present invention or " nucleic acid molecule " refer to any DNA or RNA molecule, strand or two strands, if strand, the complementary sequence of this molecule is linearity or annular.In nucleic acid molecule was discussed, according to the convention that sequence is provided in 5 ' to 3 ' direction, the present invention was illustrated the sequence or the structure of specific nucleic acid molecule.
{。##.##1},
Except formula I compound, the compound and the pharmacy acceptable salt formula IA of " summary of the invention " part narration have identical chemical formula with formula I compound, but wherein z, A
1-A
5, R and R
1-R
7Different, as described below.
Formula I
In formula IA,
Z is 0,1 or 2.
R is hydrogen, methyl or ethyl.
A
1Be nitrogen or CR
1A
2Be nitrogen or CR
2A
3Be nitrogen or CR
3A
4Be nitrogen or CR
4And A
5Be CR
5The A of one of them
1, A
2, A
3Or A
4Be nitrogen, or do not have.
R
1, R
4And R
5Be respectively hydrogen, hydroxyl, amino, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group.
When z is zero, R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And R
2And R
3In another be:
(a) C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino replaces;
(b) C
4-C
8Carbalkoxy;
(c) (phenyl) C
1-C
2Alkoxyl group, (phenyl) C
1-C
2Alkylamino radical, (aniline) C
1-C
2Alkyl, (phenoxy group) C
1-C
2Alkyl and (pyridyl) L-, wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group ,-C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl-;
(d) (cyclopentyl) L-or (pyrrolidyl) L-,
(e) (cyclohexyl) C
0-C
2Alkyl, (cyclopentyl) C
0-C
2Alkyl, (piperidyl) C
0-C
2Alkyl or (pyrrolidyl) C
0-C
2Alkyl, each group condensed ring is to 6-unit's carbocyclic ring or contain 1-2 the first heterocycle of heteroatomic 6-that is selected from N, O, S; Or
(f) (benzene) C
1-C
2Alkyl or (pyridine) C
1-C
2Alkyl, each group condensed ring are to containing 1-2 heteroatomic 5-or 6-unit heterocycle.
Wherein (a) and (b), (c), (d) and (e) in each be selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
4Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
Perhaps other R
2And R
3Be (g) cyclohexyl, piperidyl, bridge-type cyclohexyl or bridge-type piperidyl, each group is selected from C at least
2-C
6Carbalkoxy, phenyl, pyridyl, C
4-C
8Alkyl and C
4-C
8Alkoxyl group replaces; And further be selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group and C
1-C
2The substituting group of halogen alkoxyl group replaces.
Perhaps R
2And R
3In a kind of be halogen, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group, another is cyclohexyl, piperidyl, C
5-C
8Alkyl, C
5-C
8Thiazolinyl, C
5-C
8Alkynyl or C
4-C
8Alkoxyl group.
Z is 1 or 2 o'clock; Work as R
3When being methoxyl group, suppose R
2Not benzyloxy or cyclopentyloxy; R
2And R
3Or one of them is hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another is:
(i) C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino replaces;
(ii) C
4-C
8Carbalkoxy, C
5-C
8Alkene or C
5-C
8Alkynyl;
(iii) (phenyl) L-or (pyridyl) L-, each group be condensed ring to 6 yuan carbocyclic ring or contain on 1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from as N, O, S optionally;
(iv) (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, the bridge joint of each group selectivity and the condensed ring to 6 of each group selectivity yuan carbocyclic ring or contain 1 or 2 heteroatoms such as 6 yuan of heterocycles of N, O, S on;
Wherein (i), (ii), (iii) and (iv) each is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
Perhaps R
2And R
3In one be halogen, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group, another is C
5-C
8Alkyl or C
4-C
8Alkoxyl group.
When R occurring
6And R
7The time, they are selected from hydrogen, halogen, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group and phenyl; Or R
6And R
7Add and form 3-7 unit alkyl ring.
The present invention also provides compound and pharmacy acceptable salt formula IB, has identical chemical formula with formula I compound, but wherein z, A
1-A
5, R and R
1-R
7Different, as described below.
In formula IB, z is 0,1 or 2.
R is hydrogen, methyl or ethyl.
A
1Be nitrogen or CR
1A
2Be nitrogen or CR
2A
3Be nitrogen or CR
3A
4Be nitrogen or CR
4And A
5Be CR
5The A of one of them
1, A
2, A
3Or A
4Be nitrogen, or do not have.
R
1, R
4And R
5Be respectively hydrogen, hydroxyl, amino, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group.
When z is zero, R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And R
2And R
3In another be:
(a) C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino replaces;
(b) C
4-C
8Carbalkoxy;
(c) (phenyl) ethyl, (phenyl) C
1-C
2Alkoxyl group, (phenyl) C
1-C
2Alkylamino radical, (aniline) C
1-C
2Alkyl, (phenoxy group) C
1-C
2Alkyl, or (pyridyl) L-, wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group ,-C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl-;
(d) (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, the bridge joint of each group selectivity and the condensed ring to 6 of each group selectivity yuan carbocyclic ring or contain 1 or 2 heteroatoms such as 6 yuan of heterocycles of N, O, S on;
(e) (phenyl) L-or (pyridyl) L-, each group condensed ring to 6 yuan carbocyclic ring or contain on 5 or 6 yuan of heterocycles of 1 or 2 Sauerstoffatom.
Wherein (a) and (b), (c), (d) and (e) in each be selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
Perhaps R
2And R
3In one be halogen, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group, another is cyclohexyl, piperidyl, C
5-C
8Alkyl, C
5-C
8Thiazolinyl, C
5-C
8Alkynyl or C
4-C
8Alkoxyl group.
Z is 1 or 2 o'clock; Work as R
3When being methoxyl group, suppose R
2Not benzyloxy or cyclopentyloxy; R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another is:
(i) C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino replaces;
(ii) C
4-C
8Carbalkoxy, C
5-C
8Alkene or C
5-C
8Alkynyl;
(iii) (phenyl) L-or (pyridyl) L-, each group be condensed ring to 6 yuan carbocyclic ring or contain on 1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from as N, O, S optionally;
(iv) (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, the bridge joint of each group selectivity and the condensed ring to 6 of each group selectivity yuan carbocyclic ring or contain 1 or 2 heteroatoms such as 6 yuan of heterocycles of N, O, S on;
Wherein (i), (ii), (iii) and (iv) each is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces;
Perhaps R
2And R
3In a kind of be halogen, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group, another is C
5-C
8Alkyl or C
4-C
8Alkoxyl group.
When R occurring
6And R
7The time, they are selected from hydrogen, halogen, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group and phenyl; R
6And R
7Can add and form 3-7 unit alkyl ring.
The present invention further provides compound and the pharmacy acceptable salt of formula I, formula IA and formula IB, and satisfied following a kind of or a plurality of condition:
(1) R is a hydrogen.
(2) R
1, R
4And R
5Be respectively hydrogen, chlorine, fluorine, cyano group, methyl or ethyl.
(3) R
1, R
4And R
5All be hydrogen.
(4) A
1Be CR
1A
2Be CR
2A
3Be CR
3A
4Be CR
4And A
5Be CR
5The present invention also provides the compound and the salt of formula 2.
Formula 2
(5) A
1Be nitrogen; A
2Be CR
2A
3Be CR
3A
4Be CR
4And A
5Be CR
5The present invention also provides the compound and the salt of formula 3.
Formula 3
(6) A
1Be CR
1A
2Be nitrogen; A
3Be CR
3A
4Be CR
4And A
5Be CR
5The present invention also provides the compound and the salt of formula 4.
Formula 4
(7) A
1Be CR
1A
2Be CR
2A
3Be nitrogen; A
4Be CR
4And A
5Be CR
5The present invention also provides the compound and the salt of formula 5.
Formula 5
(8) A
1Be CR
1A
2Be CR
2A
3Be CR
3A
4Be nitrogen; And A
5Be CR
5The present invention also provides the compound and the salt of formula 6.
Formula 6
(9) variable z is zero.R
2And R
3One of them be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino replaces.
(10) variable z is zero.R
2And R
3One of them be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be C
4-C
8Carbalkoxy.
(11) variable z is zero.R
2And R
3One of them be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be (benzene) C
1-C
2Alkoxyl group, (benzene) C
1-C
2Alkylamino, (aniline) C
1-C
2Alkyl, (phenoxy group) C
1-C
2Alkyl and (pyridine) L-; Each is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
4Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces;
Wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group ,-C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl-.
(12) variable z is zero.R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be (benzene) C
1-C
2Alkoxyl group, (benzene) C
1-C
2Alkylamino, (aniline) C
1-C
2Alkyl, (phenoxy group) C
1-C
2Alkyl and (pyridine) L-; Each is selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Cycloalkyl, list-and two-(C
1-C
4Alkyl) amino, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces;
Wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl-.
(13) variable z is zero.R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be (benzene) C
1-C
2Alkoxyl group, (benzene) C
1-C
2Alkylamino, (aniline) C
1-C
2Alkyl, (phenoxy group) C
1-C
2Alkyl and (pyridine) L-; Each is selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Cycloalkyl, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces;
Wherein L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
(14) variable z is zero.R
2And R
3One of them be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be (cyclopentyl) L-or (pyrrolidyl) L-; Each is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
4Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces;
Wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl.
(15) variable z is zero.R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be (cyclopentyl) L-or (pyrrolidyl) L-; Each is selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces;
Wherein L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino.
(16) variable z is zero; R
2And R
3One of them be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be (cyclohexyl) C
0-C
2Alkyl, (cyclopentyl) C
0-C
2Alkyl, (piperidyl) C
0-C
2Alkyl or (pyrrolidyl) C
0-C
2Alkyl, each group condensed ring is to 6-unit's carbocyclic ring or contain 1-2 the first heterocycle of heteroatomic 6-that is selected from N, O, S; Each is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
4Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
(17) variable z is zero; R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be (cyclohexyl) C
0-C
2Alkyl, (cyclopentyl) C
0-C
2Alkyl, (piperidyl) C
0-C
2Alkyl or (pyrrolidyl) C
0-C
2Alkyl, each group condensed ring is to phenyl, cyclohexenyl, cyclohexyl piperidyl or pyridyl ring; Each is selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
(18) variable z is zero; R
2And R
3One of them be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be (phenyl) C
0-C
2Alkyl or (pyridyl) C
0-C
2Alkyl, each group condensed ring is to 5-that contains 1 or 2 Sauerstoffatom or 6-unit heterocycle; Each is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
4Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.In some preferred compounds and salt of formula I, 5-or 6-unit heterocycle contain 2 Sauerstoffatoms.
(19) variable z is zero; R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be
Wherein, R
8That represent is individual halogen, the C of being selected from respectively of 0-2
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl, C
1-C
2The substituting group of trifluoromethyl and phenyl.
(20) variable z is zero; R
2And R
3One of them be hydrogen, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be cyclohexyl, piperidyl, bridge-type cyclohexyl or bridge-type piperidyl, each group is at least by a kind of C that is selected from
2-C
6Carbalkoxy, phenyl, pyridyl, C
4-C
8Alkyl and C
4-C
8Alkoxyl group; And further be selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group and C
1-C
2The substituting group of halogen alkoxyl group replaces.
(21) R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be cyclohexyl, piperidyl, bridge-type cyclohexyl or bridge-type piperidyl, each group is selected from C respectively by the 1-2 kind
2-C
6Carbalkoxy, phenyl, pyridyl, C
4-C
8Alkyl and C
4-C
8The substituting group of alkoxyl group replaces.
(22) R
2And R
3One of them be halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be cyclohexyl, piperidyl, C
5-C
8Alkyl, C
5-C
8Thiazolinyl, C
5-C
8Alkynyl or C
4-C
8Alkoxyl group.
(23) R
2And R
3One of them be chlorine, fluorine, methoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be cyclohexyl, piperidyl, C
5-C
8Alkyl or C
4-C
8Alkoxyl group.
(24) variable z is 1.
(25) variable z is 2.
(26) variable z is 1 or 2, R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be C
3-C
6Alkyl or C
3-C
6Alkoxyl group, and by a C
1-C
4Alkoxyl group or list-or two-C
1-C
4Alkylamino replaces.
(27) variable z is 1 or 2, R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be C
4-C
8Carbalkoxy, C
5-C
8Thiazolinyl or C
5-C
8Alkynyl.
(28) variable z is 1 or 2, R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be (benzene) L-or (pyridine) L-, each group optionally condensed ring to 6-unit carbocyclic ring or condensed ring to containing respectively on 1 or 2 heteroatomic 5-or 6-unit heterocycle that is selected from N, O, S.Every kind of (benzene) L-or (pyridine) L-are selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces;
Wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl.
(29) variable z is 1 or 2, R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be (benzene) L-or (pyridine) L-, every kind of (benzene) L-or (pyridine) L-are selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces;
Wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl.In some preferred compound and salt of formula I, L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
(30) variable z is 1 or 2, R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be (benzene) L-or (pyridine) L-, each group condensed ring to 6-unit carbocyclic ring or condensed ring to containing respectively on 1 or 2 heteroatomic 5-or 6-unit heterocycle that is selected from N, O, S.Every kind of (benzene) L-or (pyridine) L-are selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
Wherein, L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl.In some preferred compound and salt of formula I, L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
(31) variable z is 1 or 2, R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, the bridge joint of each group selectivity, and the condensed ring of each group selectivity to 6-unit carbocyclic ring or condensed ring to containing on 1 or 2 heteroatomic 6-unit heterocycle that is selected from N, O, S respectively.
Every kind of (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-are selected from hydroxyl, amino, cyano group, halogen, C respectively by 0-3
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, list-and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
Wherein, L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl.In some preferred compound and salt of formula I, L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
(32) variable z is 1 or 2, R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be (cyclohexyl) L-or (cyclopentyl) L-, the bridge joint of each group selectivity, and each group is selected from cyano group, halogen, C respectively by 0-3
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
Wherein, L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl.In some preferred compound and salt of formula I, L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
(33) variable z is 1 or 2, R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; R
2And R
3In another be (cyclohexyl) L-, (cyclopentyl) L-or (piperidyl) L-, each group selectivity condensed ring is to phenyl, pyridine, cyclohexyl, cyclohexenyl or piperidines basic ring.
Every kind of (cyclohexyl) L-, (cyclopentyl) L-or (piperidyl) L-are selected from cyano group, halogen, C respectively by 0-3
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
Wherein, L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl.In some preferred compound and salt of formula I, L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
(34) variable z is 1 or 2, R
2And R
3One of them be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy;
R
2And R
3In another be (cyclohexyl) L-, (cyclopentyl) L-or (piperidyl) L-, each group is selected from cyano group, halogen, C respectively by 0-3
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
Wherein, L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl.In some preferred compound and salt of formula I, L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
(35) variable z is 1 or 2, R
2And R
3One of them be halogen, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another be C
5-C
8Alkyl or C
4-C
8Alkoxyl group.
(36) R appears
6And R
7The time, R
6And R
7Be respectively hydrogen, halogen, methyl or ethyl.
For example, the compound of formula 7-20 and its salt are as follows.
Formula 7
Formula 9
Formula 10
Formula 11
Formula 14
Formula 15
Formula 18
Formula 19
In formula 7-20, z, R, R
1, R
4, R
5, R
6And R
7Can definition according to the present invention change.R in formula I for example
1Be to define R like this
1Be hydrogen, hydroxyl, amino, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group.Perhaps R
1Can be definition in the condition (2), be hydrogen, chlorine, fluorine, cyano group, methyl or ethyl.
G in the formula 7 is NH, CH
2Or O.
R
8And R
9Respectively representative be 0-3 be selected from hydroxyl, amino ,-COOH ,-CONH
2, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, list-and two-C
1-C
6Alkylamino, C
1-C
6The substituting group of alkane carboxylic acid amides and benzene.
R in formula 10, formula 11 or the formula 15
3" alkane-O-" on the position, " alkane-C ≡ C " or " alkyl " substituting group are respectively the saturated straight or branched alkyl of 3-9 unit, optionally are selected from hydroxyl, amino, halogen, C by 0-3
1-C
4Alkoxyl group, trifluoromethyl, trifluoromethoxy and list-and two-C
1-C
4The substituting group of alkylamino replaces.
R
11Be hydrogen or methyl.
In formula 18 and formula 19, one among J and the L is Sauerstoffatom, and another is NH, CH
2, S or O.In some preferred embodiment, R
2Be selected from halogen, methoxyl group, trifluoromethyl and trifluoromethoxy.In some preferred embodiments, the R in the formula 17
3Be halogen, methoxyl group, trifluoromethyl and trifluoromethoxy.
In the compound and salt of this present invention formula I, variable R, R
1, R
4And R
5As above-mentioned definition, R
2And R
3Be connected on the 5-6 unit ring that contains 1 or 2 Sauerstoffatom, and be selected from chlorine, fluorine, C by 0-2 respectively
1-C
2Alkyl, C
1-C
2The substituting group of alkoxyl group, trifluoromethyl, trifluoromethoxy replaces.
Any variable or any variable of deriving that can form the stable compound of formula I is as R, R
1-R
7, z or A
1-A
5All included.
The structural formula of compound shown in the formula IC among another embodiment and pharmacy acceptable salt is consistent with the compound of formula I, but variable wherein such as A
1-A
5, z and R
1-R
7Value and its pharmacy acceptable salt as described below.
Formula I
In formula IC, z, R, A
1, A
2, A
3, A
4, A
5, R
6And R
7Be defined as follows.
Variable Z is 0,1,2,3 or 4.
A
1Be nitrogen or CR
1A
2Be nitrogen or CR
2A
3Be nitrogen or CR
3A
4Be nitrogen or CR
4And A
5Be CR
5The A of one of them
1, A
2, A
3, A
4Or A
5Be nitrogen, or do not have.
R
1And R
4Be respectively hydrogen, hydroxyl, amino, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group.
R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group;
R
2And R
3In another be selected from (a) and (b) and (c).
(a) C in
3-C
10Cycloalkyl optionally condensed ring to phenyl ring, C
2-C
7Heterocyclylalkyl optionally condensed ring to phenyl or C
3-C
8On the cycloalkyl ring, each group (a) is selected from following substituting group respectively and is replaced: (i) hydroxyl, cyano group, amino ,-COOH ,-CONH
2, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, list-and two-C
1-C
6Alkylamino, C
2-C
6Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
6Alkyl amido; And (ii) benzene (C
0-C
4Alkyl) and pyridine (C
0-C
4Alkyl), and respectively be selected from hydroxyl, amino, halogen, C by 0-3
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group and C
1-C
2The substituting group of halogen alkoxyl group replaces.
(b) be X-R
a, X wherein is-(CH
2)
nNH-,-(CH
2)
nNR
10-,-(CH
2)
nO-,-CH=CH-or-C ≡ C-; N wherein is 0,1 or 2, R
aBe C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
10Cycloalkyl (C
0-C
4Alkyl), C
2-C
7Heterocyclylalkyl, aryl (C
0-C
6Alkyl), heteroaryl (C
0-C
6Alkyl), indanyl or tetralyl, each group respectively by 0-3 be selected from hydroxyl, amino ,-COOH ,-CONH
2, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, list-and two-C
1-C
6Alkylamino, C
1-C
6Carbalkoxy, C
1-C
6Alkyl amido and phenyl substituent replace.
R
10Be C
1-C
6Alkyl, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
7Cycloalkyl, C
3-C
7Cycloalkyl (C
1-C
4Alkyl) or aryl, each group respectively by 0-3 be selected from hydroxyl, amino ,-COOH ,-CONH
2, halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group and list-and two-C
1-C
4The alkylamino substituting group replaces.
(c) be Y-R
b, Y wherein is 0-3 and is selected from halogen, amino, C respectively
1-C
2Alkyl, C
1-C
2The C that alkoxyl group replaces
1-C
4Alkyl, R
bBe selected from C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
1-C
6Alkoxyl group, list-and two-C
1-C
6Alkylamino, C
3-C
10Cycloalkyl (C
0-C
4Alkyl), C
2-C
7Heterocyclylalkyl, aryl (C
0-C
6Alkyl), heteroaryl (C
0-C
6Alkyl), indanyl or tetralyl, each group respectively by 0-3 be selected from hydroxyl, amino ,-COOH ,-CONH
2, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, list-and two-C
1-C
6Alkylamino, C
2-C
6Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
6Alkyl amido and phenyl substituent replace.
R
2And R
3One of add to form and to contain 0,1 or 2 heteroatomic 5-7 unit ring that is selected from nitrogen, sulphur and oxygen respectively, and be selected from hydroxyl, amino, halogen, C by 0-3
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2Halogen alkoxyl group, phenyl and xenyl substituting group replace.
When there being R
6And R
7The time, it is selected from hydrogen, halogen, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group or phenyl.R
6And R
7Preferably all be hydrogen.
Some compounds of formula I and its derive formula IA, formula IB, formula IC and formula 2-20 have antiviral activity, particularly the whose anti-HCV activity.The specific compound of formula I disclosed by the invention is the inhibitor that the inhibitor of virus replication, particularly HCV duplicate.Formula I compound disclosed by the invention is the inhibitor of disclosed good HCV replicon during the standard HCV replicon in the example 9 is tested.What can be sure of is that the whose anti-HCV activity of formula I compound is because they have suppressed duplicating of HCV replicon.The EC of the preferred substituted aryl thiocarbamide shown in the formula I
50Be about 10 micromoles or still less, the EC that is more preferably
50Be about 1 micromole or still less; EC during perhaps the HCV replicon is tested
50Be about 500 nmoles or still less.
The preferred compound of formula I has some specific pharmacology performances.These performances include but not limited to oral administration biaavailability, hypotoxicity, low serum protein combination, and are fit to the transformation period in external and the body.
Medication preparation
Compound of the present invention and salt can be taken with pure compound, but preferably take in the mode of pharmaceutical composition or preparation.Accordingly, pharmaceutical preparation provided by the invention comprises compound or the pharmacy acceptable salt of formula I, and one or more pharmaceutically acceptable carriers, vehicle, assistant agent, thinner or other component.
One embodiment of the present of invention are about pharmaceutical composition, said composition contains compound or its pharmacy acceptable salt of formula I, and at least a pharmaceutically acceptable carrier, thinner or vehicle, wherein the preparation of composition is that injecting fluid, aerosol, colloid, tablet, pill, capsule, syrup, eye drop or skin paste.
Except one or more compounds among the present invention, pharmaceutical composition of the present invention also contains pharmaceutically acceptable carrier, one or more compatible solids or liquid filling agent or forms capsular material, and these compositions are fit to patient and take.The purity that is used for the carrier that treatment of animals takes is wanted enough height, and toxicity is enough low.Carrier can be inert or have pharmaceutically advantage.The practicality amount that provides every dosage compound to take will be provided the amount of the carrier that is used in combination with compound.
The example of pharmaceutically acceptable carrier or its component can be: sugar, as lactose, dextrose plus saccharose; Starch is as W-Gum and potato starch; Mierocrystalline cellulose and its derivative are as Xylo-Mucine, ethyl cellulose and methylcellulose gum; Pulverous tragacanth; Fructus Hordei Germinatus; Gelatinum; Mica; Dry-film lubricant is as stearic acid and Magnesium Stearate; Calcium sulfate; Vegetables oil, as peanut oil, cottonseed oil, sesame oil, sweet oil and Semen Maydis oil; Polyol is as propylene glycol, glycerol, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; Alginic acid; Emulsifying agent is as tween; The bioavailability toughener as the big glyceryl ester of lauroyl (lauroyl macroglycerides), comprises glyceryl monostearate (Gelucire); Wetting agent is as sodium laurylsulfate; Tinting material; Seasonings; Tablet agent; Stablizer; Antioxidant; Sanitas; The pyrogen-free pure water; Deng a normal saline solution; And phosphoric acid buffer.
Selectable active agent can be included in the pharmaceutical composition, and this active agent is to the not influence of activity of The compounds of this invention.
One or more compounds of effective concentration among the present invention comprise pharmacy acceptable salt, ester or derivatives thereof and suitable pharmaceutical carrier, vehicle, assistant agent or vehicle mixing.In some instances, the solubleness of compound is not enough, use the method that is used for dissolved compound.Method well known in the art includes but not limited to use solubility promoter such as methyl-sulphoxide, uses tensio-active agent such as tween, or dissolves in sodium bicarbonate aqueous solution.The derivative of compound can use in the preparation of active drug composition as the salt of compound or the precursor of compound.
When mixing or adding compound of the present invention, the mixture that obtains can be solution, suspension, emulsion or analogue.The form of the mixture that obtains depends on many factors, comprises that the mode of taking and compound are in carrier of selecting or the solvability in the sanitas.The effective concentration that is used to improve the symptom under disease, the not normal or therapeutic state determines by experience.
Compound general among the present invention can take with unit formulation oral dose, external application, injection, suction or injection, hypogloeeis, through Leatherwear with, by orally administer, rectum take, eye takes with liquid or for his mode.
Be suitable for oral preparation, for example, comprise tablet, lozenge, the aqueous solution or oily suspension, dispersible powder or particle, milk sap, hard or soft capsule or syrup or elixir.Being used for composition for oral use can be prepared by preparation of drug combination method well known in the art.In order to make taste of medicine and drug effect better, this pharmaceutical composition can contain one or more reagent, as sweeting agent, seasonings, tinting material and sanitas.Oral preparations contains the The compounds of this invention of 0.1-99%, usually at least about the The compounds of this invention of 5% (wt%).Among some embodiment, contain the The compounds of this invention of have an appointment 25%-50% or 5%-75% usually.
Oral compositions also comprises liquor, emulsion, suspension, powder, particle, elixir, tincture, syrup and analogue.The pharmaceutically acceptable carrier that is suitable for the said composition preparation also is well known in the art.Oral preparations can contain sanitas, seasonings, sweeting agent such as lactose or asccharin, the reagent of covering up the sense of taste and tinting material.
The typical component that is used for syrup, elixir, emulsion and suspension comprises ethanol, glycerol, propylene glycol, polyoxyethylene glycol, liquid sugar, sorbose and water.Syrup and elixir can be prepared together with sweeting agent such as glycerol, propylene glycol, sorbose or sucrose.Also can contain softener in these preparations.
Oral liquid preparation
Compound of the present invention can join in oral liquid such as the aqueous solution or oral suspension, solution, emulsion, syrup or the elixir.And the preparation that contains these compounds can be the form that exsiccant solid and water or other suitable vehicle constitute together before use.This liquid preparation can contain conventional additive as suspension agent (as sorbitol syrups, methylcellulose gum, glucose/sugar, syrup, gelatinum, Natvosol, carboxymethyl cellulose, aluminium stearate gel and hydrogenation edible fat); Emulsifying agent (as Yelkin TTS, sorbitanic (sorbitan monsoleate) or Sudan Gum-arabic); Can contain edible oil (non-water vehicle such as Prunus amygdalus oil, fractionated Oleum Cocois, silyl ester, propylene glycol and ethylene glycol); And sanitas (as methyl or propyl group p-Para Hydroxy Benzoic Acid salt and Sorbic Acid).
Suspension
The typical case of the suspension reagent that suspends comprises methylcellulose gum, Xylo-Mucine, AVICEL RC-591, tragacanth and sodiun alginate; Typical case's wetting agent comprises Yelkin TTS and polysorbate80; And typical preservatives comprises methyl para (paraben) and sodium benzoate.
Aqeous suspension contains the active substance of the mixed with excipients of producing with suitable aqeous suspension.These vehicle are: suspension agent, as Xylo-Mucine, methylcellulose gum, Vltra tears, sodiun alginate, polyvinylpyrrolidone, tragacanth gum and Sudan Gum-arabic; Disperse or wetting agent; Vehicle can be phosphatide such as the Yelkin TTS that nature generates, or the condensation product of lipid acid alkylene such as stearic acid polyoxyethylene, the perhaps condensation product of long chain aliphatic alcohol vinylene such as heptadecane oxidation of ethylene hexadecanol (heptadecaethyleneoxycetanol), or have the vinylene condensation product of the partial ester that lipid acid and hexitol such as the reaction of polyoxyethylene sorbitol substituent obtain, or has the vinylene condensation product of the partial ester that lipid acid and hexitan such as the reaction of polyethylene sorbitanic substituent obtains.Aqeous suspension can contain one or more sanitass, as ethyl or n-propyl p-Para Hydroxy Benzoic Acid salt.
Oil suspension can be prepared by active ingredient is suspended in the vegetables oil, vegetables oil such as peanut oil, sweet oil, sesame oil or Oleum Cocois, or prepare as whiteruss in the mineral oil.Oil suspension can contain thickening material such as beeswax, paraffinum durum or hexadecanol.Aforesaid sweeting agent and seasonings can add the taste that wherein improves oral preparations.These compositions can be undertaken anticorrosion by antioxidant such as the xitix that adds.
Emulsion
Pharmaceutical composition of the present invention also can be the form of O/w emulsion.Oil phase can be vegetables oil such as sweet oil or peanut oil or mineral oil such as whiteruss or above-claimed cpd.Suitable emulsifying agent can be resin such as the tragacanth gum that nature generates, naturally phosphatide of Sheng Chenging such as soybean, Yelkin TTS, and the reaction of lipid acid and the hexitol ester or the partial ester that obtain, acid anhydride such as sorbitanic monoleate, and the condensation product of described ethylene oxide,1,2-epoxyethane partial ester such as polyoxyethylene sorbitanic monoleate.
Dispersible powder
Be suitable for dispersion or wetting agent, suspension agent and one or more sanitass being mixed with active ingredient by adding dispersible powder and the particle that entry prepares aqeous suspension.Suitable dispersion or wetting agent and suspension agent are as mentioned above.
Tablet and capsule
Tablet contains the assistant agent of common pharmaceutically compatible usually: inert diluent such as calcium sulfate, sodium sulfate, N.F,USP MANNITOL, lactose and Mierocrystalline cellulose; Binding agent such as starch, gelatinum and sucrose; Disintegrant such as starch, alginic acid and croscarmellose (
Croscarmelose)Slipping agent such as Magnesium Stearate, stearic acid and mica.Glidant such as silicon-dioxide can be used to improve the flowability of powdered mixture.Tinting material such as FD﹠amp; The C staining agent can add and improves outward appearance.Sweeting agent and seasonings such as aspartame sugar, asccharin, menthol, spearmint oil and fruity agent are useful assistant agents to the tablet of chewing.Capsule (comprising sustained release preparation) generally includes one or more above-mentioned solid diluents.Second factor such as the sense of taste, cost and preservation term are depended in the selection of carrier component usually.
These compositions also can apply with the method for routine, usually with pH or time-delay dressing (time-dependent coatings), thereby main material are discharged near the treatment part time, perhaps repeatedly discharge, thus the expansion curative effect.These batching forms generally include but are not limited to one or more cellulose acetate phthalates, polyethylene acetate phthalate, HYDROXY PROPYL METHYLCELLULOSE phthalate, ethyl cellulose, Ou Waji (Eudragit) dressing, wax and lac.
Oral preparations can be hard gelatinum capsule, and wherein active ingredient and inert solid diluent such as lime carbonate, calcium phosphate or kaolin mix; Oral preparations or soft gelatinum capsule, wherein active ingredient and water or oily medium such as peanut oil, liquid wax or mixed with olive oil.
Injectable and parenteral preparation
Pharmaceutical composition can be the injection water liquid or the oleagenous suspension of sterilization.This suspension can be according to using the above-mentioned suitable dispersion or the prior art of wetting agent and suspension agent to prepare.The preparation of sterile solution for injection also can be the suspension in sterile solution for injection or nontoxic thinner or solvent such as the 1,3 butylene glycol.These operable acceptable vehicle things and solvent are water, Run Shi (Ringer ' s) solution and wait a sodium chloride solution.In addition, the expressed oil of sterilization is usually as solvent or suspension medium.Therefore, any bland expressed oil can use, and comprises synthetic list-or two-glyceryl ester.In addition, lipid acid such as oleic acid also are useful in the preparation of injection liquid.
Compound of the present invention can be taken without stomach in sterile medium.Take without stomach and to comprise subcutaneous injection, intravenous injection, intramuscular injection, stndon sheath injection or other injection technique.Compound of the present invention according to vehicle and employed concentration can be suspend or be dissolved in vehicle.Advantageously, assistant agent such as narcotic, sanitas and sustained release dosage can be dissolved in the vehicle.For the composition of many parenteral admistration, carrier accounts for the 90wt% of whole approximately compositions at least.Be used for the preferred carrier of parenteral admistration and comprise propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil.
Suppository
Compound of the present invention also can suppository formulation use at rectum.These compositions can be by preparing medicine and suitable non--pungency mixed with excipients, and this vehicle is a solid when normal temperature, is liquid under the temperature of rectum, thereby can melt and discharge medicine in rectum.This material is theobroma oil and polyoxyethylene glycol.
The local preparation that uses
Compound of the present invention can be the preparation of topical application, and as the topical application at skin and mucous membrane, such as in eyes, its form is that the form of gelinite, paste and lotion is used for eyes, or is used in the brain pond or in the backbone.The local composition that uses of the present invention can be to comprise that solution, paste, ointment, gelinite, lotion, milk sap, sanitising agent, wetting agent, sprays, skin paste or other similar form.
This solution can be the isotonic solution of 0.01%-10%, and pH is about 5-7, contains suitable salt simultaneously.Compound of the present invention also can be the form that the skin that uses on the skin pastes.
The active compound that the composition that topical preparation uses contains can mix with many carrier substance well known in the art, as water, ethanol, aloe ointment, wallantoin, glycerol, Vitamin A and E oil, mineral oil, propylene glycol, PPG-2, tetradecane propionic ester and analogue thereof.
The carrier substance of other suitable topical preparation comprises softener, solvent, wetting Agent for Printing Inks, thickening material and powder.These materials can be used alone or as a mixture.The typical material of these materials is as follows:
Softener, as stearyl alcohol, the glyceryl ricinoleate, the glyceryl stearic acid, propyl group-1, the 2-glycol, butyl-1, the 3-glycol, ermine oil, hexadecanol, the sec.-propyl stearate, stearic acid, the isobutyl-palmitate, the hexadecyl stearate, oleyl alcohol, the sec.-propyl laurate, the hexyl laurate, decyl oleate salt, octadecane-2-alcohol, isocetyl alcohol, spermaceti, the dimethyl poly(silicon aether), two-n-butyl sebate, sec.-propyl 14 esters, isopropyl cetylate, the sec.-propyl stearate, the butyl stearate, polyoxyethylene glycol, triethylene glycol, lanolin, sesame oil, Oleum Cocois, peanut oil, the Viscotrol C acetyl lanolin alcohol, oil, mineral oil, the butyl myristinate, Unimac 5680, palmitinic acid, the sec.-propyl linoleate, the lauryl alcohol lactic acid salt, the tetradecyl lactic acid salt, decyl oleate salt and tetradecyl myristinate; Volatilizer is as propane, butane, Trimethylmethane, dimethylether, carbonic acid gas and nitrous oxide; Solvent is as ethanol, methylene dichloride, different propane, Viscotrol C, ethyl glycol monoethyl ether, diethylene glycol monobutyl ether, glycol ether monoethyl ether, dimethyl sulfoxide (DMSO), dimethyl formamide, tetrahydrofuran (THF); Wetting Agent for Printing Inks is as glycerine, sorbyl alcohol, 2-Pyrrolidone-5-carboxylic acid sodium, soluble collagen matter, dibutyl phthalate and gelatinum; And powder, as the neusilin of chalk, mica, Fuller's earth, kaolin, starch, resin, silica colloidal, sodium acrylate, tetraalkyl ammonia montmorillonite, trialkyl aryl ammonia montmorillonite, chemical modification, organically-modified illiteracy unsticking soil, hydrated aluminium silicate, fumed silica, carboxyl ethyl polymer, Xylo-Mucine and ethyl glycol Monostearate.
Described compound of the present invention also can the liposome delivery system form local application, as little thin slice capsule, big thin slice capsule and composite wafer capsule.Liposome can be multiple phosphatide, as cholesterol, stearylamine or Yelkin TTS.
Other formulation
Other is used to carry described compound compositions to comprise the hypogloeeis, the oral cavity and formulation nasal cavity.These compositions generally include one or more solvable weighting materials such as sucrose, sorbyl alcohol and N.F,USP MANNITOL, and binding agent such as Sudan Gum-arabic, Microcrystalline Cellulose, carboxymethyl cellulose and Vltra tears.In glidant disclosed by the invention, lubricant, sweeting agent, tinting material, oxidation inhibitor and seasonings are also included within.
The form of the composition that sucks is the suspension or the emulsion of solution, powder formation in volatilizer (as Refrigerant 12 or chlorofluoromethane) commonly used normally.
Other component
Composition disclosed by the invention optionally comprises active reinforcing agent.Active reinforcing agent can never be selected in the molecule of same-action mode on a large scale, thereby strengthens the antibacterial effect of The compounds of this invention.Concrete active reinforcing agent comprises skin penetration enhancer and absorption enhancer.
Pharmaceutical composition also can contain from the additional activity reagent of Molecular Selection on a large scale, and these reagent strengthen the antibiotic or result of treatment of The compounds of this invention in a different manner.When containing these optionally during other active agent, these active agents content range in described pharmaceutical composition usually are about 0.01%-15%.In certain embodiments, the content of these active agents per-cent that accounts for composition weight is about 0.1%-10%.In further embodiments, the content of these active agents per-cent that accounts for composition weight is about 0.5%-5%.
The formulation of packing
The invention discloses the formulation of drug packages.Comprise the pharmaceutical composition that contains one or more formulas I compound or its salt in the box of the formulation of these packings, and optionally containing the specification sheets that uses said composition, said composition is used for the treatment of the infected by microbes that suffers infected by microbes or not normal animal (normally patient) or prevent sick body.
Comprise the pharmaceutical composition that contains one or more formulas I compound or its salt in the box among the embodiment relevant, and further comprise the specification sheets that uses said composition to treat the patient who suffers C type virus infection with the pharmaceutical composition packing.
The present invention includes the information that regulation is provided to patient or health care supplier, perhaps adhesive label on the pharmaceutical preparation of packing.The information of regulation comprises effect, dosage and instructions about how to take medicine, contraindication and the side effect of pharmaceutical preparation.
All aforesaid The compounds of this invention can be taken separately, take or take with other promoting agent combination as mixture.
Methods of treatment
The present invention includes the method that infects with treatment virus infection, particularly HCV by the formula I compound of taking one or more significant quantities for the patient who suffers virus infection.The significant quantity of formula I compound is meant that this amount is enough to reduce the symptom of virus infection.Selectable, the significant quantity of formula I compound is meant that this amount can be reduced in the sick body tissue or the human body greatly can detected antiviral antibody or the amount of virus.
This methods of treatment comprises the compound of taking enough formula I, thereby reduces or alleviate that HCV infects that the jaundice, fatigue, the urine that cause are red, abdominal pain, do not have appetite and feel sick.
Formula I compound be owing to can suppress duplicating of hepatitis C virus, thereby is considered to improve the process of HCV disease.Compound among the present invention can be viricidal, therefore except independent inhibition virus replication, and virus that can also killing living.The mechanism of action of The compounds of this invention is the combination that viricidal activity and inhibition are duplicated.
Methods of treatment of the present invention comprises takes formula I compound separately as unique active substance, and formula I compound and other one or more active agents are taken, these active agents such as Anti-virus agent, effective Anti-virus agent that particularly anti-HCV infects.The present invention includes and Peg-Intron (PEG-interferon), glycol interferon alpha 2b, virazole (Ribavarin), natural interferon, A Fulong (Albuferon), interferon beta-1a, IL-10, gamma interferon 1-b, tristane or ZADAXIM take one or more formulas I compound together.
Methods of treatment also comprises and suppresses HCV duplicating in vivo, and to the patient of HCV infection, the formula I compound by taking enough concentration is to suppress duplicating of HCV replicon.The formula I compound of " enough concentration " of dosing a patient with is meant that available compound concentration can be anti-infective in the patient body.This concentration is definite by testing, for example test of compound concentration in the blood; Or carry out theory by the calculating of bioavailability and determine.
Every day per kilogram of body weight dosage range to be about 0.1mg-140mg be useful (each patient's every day of about 0.5mg-7g) at above-mentioned symptom at least.With carrier substance in conjunction with the amount of the active ingredient of the medicament that generates according to the treatment main body with the mode of taking and different.The amount of the active ingredient that general unit dose contains is about 1mg to 500mg.
The frequency that medicament uses is different and different according to the compound that uses and the disease of specifically treating also.But, not normal in order to treat most of infectivities, the dosage of one day 4 times or less number of times is preferred, and it is particularly preferred taking 1-2 every day.
But, be understandable that, concrete patient's concrete dosage level will depend on several factors, these factors comprise activity, the patient of employed particular compound age, body weight, healthy state, sex, diet, the time of taking, the approach of taking and discharge rate, make up a prescription and treat the concrete severity of disease.
Synthesizing of compound
The preparation of The compounds of this invention is shown in scheme 1, and scheme 1 has been described the general method of preparation The compounds of this invention.It will be appreciated by those skilled in the art that initial substance can be different, other reactions steps also can be included in the present invention.In scheme 1 and example 1, variable R, R
1, R
2, R
3, R
4And R
5As above-mentioned definition.
Scheme 1: the preparation of substituting thioureido
Aniline 1 formula I
In scheme 1, the compound that any suitable substituted aniline (aniline 1) and suitable reactant reaction obtain formula I.Aniline 1 can synthesize by the method for organic synthesis well known in the art.The reactant that is used for the aniline functional group is converted into thiocarbamide includes but not limited to alkaline thiocyanic ester, thiocarbonyl two-imidazoles and the alkali of crossing with ammonia treatment, or thiophosgene and the alkali crossed with ammonia treatment.
Example
The preparation of example 1:1-(3-benzyloxy) phenylthiourea (compound 1)
Be converted into ether (Y) after a series of processing of 3-nitrophenols (X) by sodium hydride and bromotoluene.Aniline obtains aniline (z) after reducing with tin chloride.In some cases, when the substituting group on the aryl did not comprise aryl, reduction also can be finished by hydrogen/Pd catalyzer.
Final product compound 1 obtains with ammonia treatment after z is handled with sulfo-hydroxyl two-imidazoles again.3-benzyloxy-aniline (5g, 25 mmoles) dropwise joins in one minute in methylene dichloride (150ml) solution of sulfo-hydroxyl two-imidazoles of 4.94g (27.6 mmole).The mixture that obtains at room temperature stirs and spends the night.The sulfo-hydroxyl two-imidazoles (TCDI) that adds 400mg again, reaction carried out 2 hours or the longer time.Reaction weakens with hexane, and passes through diatomite filtration.Concentrate the 3-benzyl oxy phenyl lsothiocyanates that obtains 5.1g.
2M ammoniacal liquor in this lsothiocyanates of a part in the 1ml methylene dichloride (50mg, 0.21 micromole) and the 0.5ml methyl alcohol mixes.After 30 minutes, reaction obtains quantitative compound 1.
Selectable, (1.1 mmoles, (1 mmole is in methylene dichloride 199mg) (5ml) solution 196mg) to join the 3-benzyloxy-aniline for sulfo-hydroxyl two-imidazoles.Reaction is at room temperature stirred, and is intact until aniline reaction, about 1 hour.(2M 2ml), continues to stir 2 hours to add methanol aqueous ammonia solution.After the solvent evaporation, residue is purified, obtain (3-benzyloxy benzene) thiocarbamide of 150mg with silica gel chromatography.
1NMR(CDCl
3)D：5.08(s，2H)，6.03(brs，2H)，6.8(m，2H)，6.93(m，1H)，7.3-7.47(m，6H)，7.82(brs，1H)。MS(APCI)：M
++1＝259。
Example 2: other compound of the present invention
The method of the following compound of scheme 1 disclosed preparation, and further be illustrated by example 1.Those of ordinary skill in the art can understand the difference according to compound, and reactant and reaction conditions can be done corresponding slight the adjustment.
1-(4-cyclohexyl-phenyl)-thiocarbamide (compound 2)
1H NMR (300MHz, CDCl
3) δ 8.04 (br s, 1H, NH), 7.28-7.25 (m, 2H, aryl H) 717-714 (m, 2H, aryl H), 6.11 (br s, 2H, NH
2), 2.51 (m, 1H, CH), 1.88-1.74 (m, 5H cyclohexyl) 1.48-1.22 (m, 5H, cyclohexyl).MS(APCI)m/z 235[M+H]+。
1-(3-phenoxy group-phenyl)-thiocarbamide (compound 3)
1H NMR (300MHz, CDCl
3) δ 8.46 (br s, 1H, NH), 7.41-6.84 (m, 9H, aryl H), 6.34 (br s, 2H, NH
2).MS(APCI)m/z245[M+H]+。
1-(4-butoxy carbonyl-phenyl)-thiocarbamide (compound 4)
1H NMR (300MHz, CDCl
3) δ 9.14 (s, 1H, NH), 8.07 (d, J=7.5Hz, 2H, aryl H), 7.34 (d, J=7.5Hz, 2H, aryl H), 6.65 (br s, 2H, NH
2), 4.30 (t, J=6.3Hz, 2H, COCH
2), 1.74 (m, 2H, CH
2), 1.46 (m, 2H, CH
2), 0.97 (t, J=6.0Hz, 3H, CH
3).MS(APCI)m/z 253[M+H]+。
1-(3-benzyl-phenyl)-thiocarbamide (compound 5)
MS(APCI)m/z 243[M+H]+。
1-(4-pentyloxy-phenyl)-thiocarbamide (compound 6)
1H NMR (300MHz, CDCJ
3) δ 7.92 (s, 1H, NH), 7.15 (d, J=8.4Hz, 2H, aryl H), 6.92 (d, J=8.4Hz, 2H, aryl H), 3.95 (t, J=6.6Hz, 2H, OCH
2), 1.82-1.77 (m, 2H, CH
2), 1.44-1.38 (m, 4H, (CH
2)
2), 0.94 (t, J=7.2Hz, 3H, CH
3).MS(APCI)m/z239[M+H]+。
1-(4-amyl group-phenyl)-thiocarbamide (compound 7)
1H NMR(300MHz，CDCl
3)δ7.99(br s，1H，NH)，7.24(d，J＝8.4Hz，2H)，7.13(d，J＝8.4Hz，2H)，6.09(br s，2H，NH2)，2.61(t，J＝7.8Hz，2H，CH
2)，1.66-1.56(m，2H，CH
2)，1.38-1.28(m，4H，(CH
2)
2)，0.90(t，J＝6.9Hz，3H，CH
3)。MS (APCI)m/z 223[M+H]+。
1-(4-cyclohexyl methoxyl group-phenyl)-thiocarbamide (compound 8)
MS(APCI)m/z 265[M+H]+。
1-(3-butoxy-phenyl)-thiocarbamide (compound 9)
1H NMR (acetone-d6): 9.10 (s, 1H), 7.25 (t, J=8Hz, 1H), 7.11 (s, 1H), 7.04 (s, broad peaks, 1H), 6.92 (m, 1H), 6.74 (m, 1H), 4.02 (q, J=9Hz, 2H), 2.05 (m, 1H), 1.76 (m, 2H), 1.50 (m is 2H) with 0.99 (t, J=8Hz, 3H) MS:225.10 (M+1).
1-(4-(3-(dimethylamino) propoxy-) phenyl) thiocarbamide (compound 10)
1H NMR (dimethyl sulfoxide (DMSO)-d6): 9.48 (s, 1H), 7.38 (s, broad peak, 1H), 7.22 (d, J=6Hz, 2H), 6.88 (d, J=6Hz, 2H), 3.99 (t, J=7.5Hz, 2H), 2.54 (t, J=9Hz, 2H), 2.21 (s, 6H) and 1.85 (m, 2H).
1-[3-fluoro-(4-(3-dimethylamino propoxy-) phenyl)] thiocarbamide (compound 11)
1H NMR (MeOD-d4): 7.12 (m, 3H), 4.12 (t, J=9Hz, 2H), 2.59 (m, 2H), 2.32 (s, 6H) and 2.02 (m, 2H) MS:272.4 (M+1).
1-(3-fluoro-(4-pentyloxy)-phenyl)-thiocarbamide (compound 12)
1H NMR (CDCl
3): 8.51 (s, 1H), 6.95 (m, 3H), 6.27 (s, broad peak, 1H), 4.04 (t, J=8Hz, 2H), 1.82 (m, 2H), 1.43 (m, 4H) and 0.93 (t, J=9Hz, 3H) MS:257.0 (M+1).
Example 4:N-(4-benzene oxygen styroyl) thiocarbamide (compound 78)
The preparation method of the preparation of this compound and N-(3-benzyl oxy phenyl) thiocarbamide is similar, is reactant with 4-benzene oxygen phenylethylamine.
1H NMR(CDCl
3，δ)：2.92(t，J＝6.9Hz，2H)，3.31-3.90(m，2H)，5.65(s，2H)，5.85-6.16(m，1H)，6.97-7.04(m，4H)，7.11-7.15(m，1H)，7.19(d，J＝7.4Hz，2H)，7.36(t，J＝7.8Hz，2H)；LCMS(M+1)：273。
Example 5:(3-benzyl-phenyl)-thiocarbamide (compound 79)
3-benzylaniline (183mg, 1 mmole) solution and 1,1 '-thio-carbonyldiimidazole (197mg, 1.1 mmoles) stirred 1.5 hours under the room temperature in methylene dichloride (5ml).The ammoniacal liquor methyl alcohol (2.5ml) of 2M joins in the solution, and mixture at room temperature stirs and spends the night.Solution dilutes with ethyl then, organic layer 5%HCl, saturated NaHCO
3Clean with salt solution, and dry (anhydrous Na
2CO
3).Thick product recrystallization in ethylhexoate and sherwood oil obtains the product of white powder.
1H NMR (300Hz, CDCl
3) δ 7.93 (br s, 1H, NH), 7.73-7.02 (m, 9H, aryl H), 6.06 (br s, 2H, NH
2), 3.98 (s, 2H, CH
2).MS(APCI)m/z 243[M+H]+。
Example 6:(4-pentyloxy-phenyl)-synthetic (compound 80) of thiocarbamide
4-pentyloxy aniline in the methylene dichloride (3ml) (370ml, 2 mmoles) at room temperature joins 1, and in methylene dichloride (5ml) solution of 1 '-thio-carbonyldiimidazole (537mg, 3 mmoles), this mixture at room temperature stirred 30 minutes.The ammoniacal liquor methyl alcohol (30ml) of 2N joins in the solution, and this solution is restir 1 hour at room temperature.Remove and desolvate, product extracts with who and ethylhexoate.Thick product recrystallization in methylene dichloride and hexane obtains the white solid thiocarbamide.
1H NMR (300Hz, CDCl
3) δ 7.92 (s, 1H, NH), 7.15 (d, J=8.4Hz, 2H, aryl H), 6.92 (d, J=8.4Hz, 2H, aryl H), 6.0 (br s, 2H, NH
2), 3.95 (t, J=6.6Hz, 2H, CH
2), 1.79 (m, 2H, CH
2), 1.44-1.38 (m, 4H, (CH
2)
2), 0.94 (t, J=7.2Hz, 3H, CH
3).MS(APCI)m/z 239[M+H]+。
Synthetic (compound 81) of example 7:1-(4-(N-benzyl-N-methylamino-) 3-fluorophenyl) thiocarbamide
1,2-two fluoro-4-oil of mirbane (0.96g, 6.0 mmoles) and benzyl methylamine (0.79g, 6.6 mmoles) heated 16 hours in 80 ℃ together with K2CO3 in the anhydrous DMF solution of 4ml.Remove desolvate after, purify on the sharp separation chromatogram of residue with ethyl acetate/hexane (0-15%), obtain the yellow oil 1.05g (4.0 mmole) of benzyl-(2-fluoro-4 oil of mirbane)-methylamine of 67%.
1.7g the tin chloride (II) of (7.4 mmole) joins in benzyl-(2-fluoro-4 oil of mirbane)-methylamine (0.60g, 2.3 mmoles) ethanolic soln of 30 milliliters, reaction mixture refluxed 3 hours.After the cooling, add the NaOH solution of 2N under condition of stirring, the pH value that makes reaction mixture is 8.The mixture that obtains filters with diatomaceous stopper, the filtrate ethyl acetate extraction.Organic layer cleans with salt solution, and dry on Na2SO4, concentrates the yellow oil N that obtains 0.52g (2.2 mmoles, 95%) at last
1-benzyl-2-fluoro-N
1-methyl-benzene-1, the 4-diamines.MS：231(M+1)。
N
1-benzyl-2-fluoro-N
1-methyl-benzene-1,4-diamines (23mg, 0.1 mmole) and thio-carbonyldiimidazole (21mg, 0.12 mmole) stirred 2 hours under the room temperature in the dichloroethane solution of 0.8ml; The NH that adds the 2M in the methyl alcohol (0.4ml, 0.4 mmole) then
3Reaction mixture is agitation and filtration at room temperature.Except that after desolvating, residue is purified on LC/MS, obtains canescence oily product [4-(benzyl-methylamine) 3-fluorophenyl] thiocarbamide of 6.3mg.MS：290(M+1)。
Example 8:(4-pentyloxy-3-trifluoromethyl-phenyl)-synthetic (compound 82) of thiocarbamide
NaH (0.24g, 6.0 mmoles) joins in the time of 0 ℃ in Pentyl alcohol (1.5ml, the excessive) solution of 5mlTHF.After at room temperature stirring 30 minutes, add 1-fluoro-4-nitro-2-trifluoromethyl-benzene of 1.0g (5.0 mmole), reaction mixture at room temperature stirs and spends the night.After removing reagent, the resistates up in ethyl acetate.Organic layer is with NaOH solution and the salt water washing of 1N, at Na
2SO
4After the last drying, concentrate and obtain xanchromatic oil.After purifying with DCM/ normal hexane (1/2) sharp separation chromatogram, product obtains the oily product 4-nitro-1-phenoxy group-2-trifluoromethyl-benzene of yellow-gray.
On 4-nitro-1-phenoxy group-2-trifluoromethyl-benzene and the gac 40ml ethanolic soln of the palladium of 0.1g10% under room temperature at atmosphere of hydrogen (hydrogen balloon) following one night of hydrogenation.Obtain the pink oily 1.2g (100%) of 4-pentyloxy-3-trifluoromethyl-aniline after filtering and concentrating.MS：248(M+1)。
4-pentyloxy-3-trifluoromethyl-aniline (25mg, 0.1 mmole) solution and thio-carbonyldiimidazole (21mg, 0.1 mmole) stirred 2 hours under room temperature in the methylene dichloride of 1ml.The NH that adds 2M then
3Methyl alcohol (0.4ml, 0.4 mmole), reaction mixture at room temperature stirs and spends the night.Except that after desolvating, residue cleans with the first alcohol and water, obtains pale solid product (4-pentyloxy-3-trifluoromethyl-phenyl) thiocarbamide.MS：307(M+1)。
Example 9: the telling test of the compound that inhibition HCV duplicates
On the culturing cell that is combined with the HCV replicon constructs, the ability of the inhibition of the compound among the present invention C type hepatitis replicon virus replication is tested.People such as Bartenschlager have carried out open (Science, 285, pp.110-113 (1999)) to HCV replicon system.The replicon system is the active omen of whose anti-HCV in the body; Activated compound has also shown same activity in the replicon test in human body.
The cell that contains the HCV replicon is handled with the alpha-interferon of different concns, and alpha-interferon is a kind of known HCV replication inhibitors, as the positive control of the test compounds of different concns.The replicated test system comprises self component of Xin Meisu transphosphorylase (NPT) as replicon, thereby detect transcribing of replicon gene prod in host cell.Cell among the HCV is active replication in high-caliber NPT.NPT level and HCV are copied into ratio.HCV replicon cell does not duplicate in low-level NPT yet, thereby can not stock when handling with Xin Meisu.The NPT level of each sample is tested with the enzyme linked immunological absorption (ELISA) of catching.
The following discloses the source recording of C type hepatitis replicon virus replication ability that test compounds suppresses to be combined with the culturing cell of replicon constructs.
9A.HCV replicon and replicon are expressed
The HCV genome comprises the single ORF of 3000 the amino acid polymeric protein of encoding.ORF by as inner entry site (internal ribosome entry site, IRES) unsaturated regional side and 5 ' side are joined, and 3 ' side by to virus replication (3 '-NTR) necessity height reservation queue side join.To the structural protein of virus infection necessity 5 ' end near ORF.Specified NS2 to NS5B nonstructural proteins comprises the residue of ORF.
IRES and the 3 ' NTR of the encephalomyocarditis virus that the HCV replicon contains 5 '-3 ', the NS3 sequence of HCV-IRES, Xin Meisu transphosphorylase (neo) gene, guiding HCV is translated to the NS5B sequence.The sequence of HCV replicon is GenBank preservation (number of landing is AJ242652).
Replicon can be converted into the Hub-7 cell with standard method such as electroporation effect.
9B: cell is kept
Equipment and material include but not limited to contain the Hub-7 cell (Huh-7HCV replicon-containing cells) of HCV replicon, safeguard that medium (DMEM (Dulbecco ' smodified Eagle media) comprises 10% FBS, the L-glutaminate, non-essential amino acid, penicillin (100 units per ml), the Geneticin G418 of Streptomycin sulphate (100 mcg/ml) and 100 mcg/ml), the tissue culture substrate (flat) in 96 holes, 96 orifice plates (at the bottom of the U-shaped of drug dilution), the alpha-interferon that is used for positive control, fixating reagent is (as methyl alcohol: acetone), antibody (rabbit anti--NPTH), secondary antibodies Eu-N11 and enhancing liquid.
When the density of the cell that contains the HCV replicon was suitable, the cell that contains the HCV replicon was supported duplicating of high-caliber viral RNA replicon.Excessive fusion can cause the minimizing that viral RNA duplicates.Therefore, cell must keep growth in the propagation phase in the G148 of 500 mcg/ml.Usually, cell should pass 1 twice weekly: the diluent of 4-6.Carrying out cell in the following manner keeps.
The cell that contains the HCV replicon is examined under a microscope, thereby guarantees the cell well-grown.Cell cleans once with PBS, and adds the Regular Insulin of 2ml.Cell/Regular Insulin mixture under 37 ℃ in CO
2Cultivated 3-5 minute in the incubator.After the cultivation, the perfect dielectric that adds 10ml stops the trypsinized reaction.Gently blow cell, put in the test tube of 15ml, and rotation 4 minutes under 1200rpm.Remove Regular Insulin/medium solution.Add medium (5ml), careful cell mixing.Write down the number of cell.
Then cell is bred on 96 orifice plates, density is 6000-7500 cell/(6-7.5 * 10,100ul/ hole
5Cell/10ml/ plate).Then culture dish under 37 ℃ in 5% CO
2Cultivate in the incubator.
Before the breeding back added medicine, cell was examined under a microscope nearly 24 hours.If counting and dilution operation are accurately, cell 60-70% merges, and nearly all cell is average the adhesion and expansion in the hole.
9C: substances is to the treatment of the cell that contains the HCV replicon
The cell that contains the HCV replicon cleans once with PBS, and adds the Regular Insulin of 2ml.Cell under 37 ℃ in 5% CO
2Cultivated 3-5 minute in the incubator.The perfect dielectric that adds 10ml stops reaction.Gently blow cell, put in the test tube of 15ml, and rotation 4 minutes under 1200rpm.Remove Regular Insulin/medium solution.Add medium (500mlDMEM (high glucose)) 10%FBS of 5ml, 50ml, 5% the Geneticin G418 (50mg/ml, BRL 10131-035) of BRL numbering #12430-054, MEM non-essential amino acid (100x BRL #11140-050) and the 5ml pen-strep (penicillin-strep) (BRL #15140-148) of 5ml.Cell and medium are carefully mixed.
The FBS (BRL #10082-147) of screening culture medium 500ml DMEM (BRL #21063-029), 50ml and the MEM non-essential amino acid (BRL#11140-050) of 5ml are arranged in the culture dish of cell, and in 6000-7500 cell/100ul/96 orifice plate (6-7.5 * 10
5Cell/10ml/ plate) cultivates.Then culture dish under 37 ℃ in 5% CO
2Cultivate a night in the incubator.
9D: test
The next morning, medicine (test compounds and alpha-interferon) on the U-shaped chassis in 97 holes according to detecting (screening) selected ultimate density with medium or DMSO/ medium.Common every kind of test compounds 10 micromoles to having used 6 kinds of concentration between 0.03 micromole.The test substances diluent of 100ul is placed in the hole of 96 orifice plates that contain HCV replicon cell.In some holes, add and do not contain the medium of medicine as negative control.The growth that DMSO influences cell is known.Therefore, detect for single dose, if dilute medicine with DMSO, then must contain the DMSO of same concentration in the hole of negative control (medium is only arranged), positive control (alpha-interferon), culture dish is at 37 ℃, 5%CO
2Environment in cultivated 3 days.
At the 4th day, test was measured to NTPII.Medium is poured out from culture dish, and culture dish cleans once with the PBS of 200ul then.Then this PBS is decanted, culture dish is removed remaining PBS with the paper handkerchief wiping.Cell is with precooling (20 ℃) methane in 100ul/ hole: acetone (1: 1) is fixed, and culture dish was placed 30 minutes in-20 ℃.
Stationary liquid is poured out from culture dish, and culture dish is complete drying (about 1 hour) in air.Note the outward appearance of exsiccant cellular layer, the density of cell detects by an unaided eye in the poisonous hole.The viability of cell is measured by cell concn 96 aqueous solution cell proliferation tests (Promega), the colorimetric estimation of a kind of mensuration viable count purpose.In the method, before fixed cell, join in each hole according to the producer's the instruction MTS reagent with 10-20ul, culture dish is cultivated in 37 ℃, and can read at OD 490nm.
200ul blocker (10%FBS is at room temperature used in the hole; 3%NGS among the PBS) blocking-up.Remove blocker, with the rabbit of the 100ul of the blocker of 1: 1000 ratio dilution anti--NPTII joins in each hole.Culture dish was at room temperature cultivated 45-60 minute then.After the cultivation, the hole is cleaned 6 times with PBS-0.05%Tween-20 solution.The sub-europium of conjugated goat antirabbit (EU) of the 100ul dilution in 1: 15000 in the blocking-up damping fluid joins in each hole, and at room temperature cultivates 30-45 minute.Culture dish cleans once more, joins in each hole with the enhancing liquid (Perkin Elmer #4001-0010) of 100ul.Each culture dish rocked (about 30rpm) 3 minutes in the culture dish vibrator.95ul transfers to from each hole in the blackboard (black plate); The quantitative analysis in Perkin-Elmer VICTOR culture dish reader (EU-Lance) of EU signal.
Test result:
Compound 1,3,5-8,12-42 and 44-62 test in this HCV replicon test, and find the activity inhibitor that it duplicates for the HCV replicon, the EC of demonstration
50Value is less than 1 micromole.
Example 10: pharmaceutical preparation
Example 10A is the example that contains the pharmaceutical composition of formula I compound to 10G.What abbreviation " A.I. " was represented is thiocarbamide viral inhibitors of the present invention.
Example 10A: oral drops
The A.I. of 5 grams are dissolved in the time of about 60 ℃-80 ℃ in the polyoxyethylene glycol of the 2 hydroxy propanoic acid of 5ml and 15ml.After being cooled to 30 ℃-40 ℃, add the polyoxyethylene glycol of 350ml, mixture stirs.Add the solution that dissolves in 17.5 gram soluble saccharins in the 25ml pure water then.When stirring, add spices and polyoxyethylene glycol capacity in the mixture to 500ml, the content of A.I. is 10mg/ml in the oral drops.
Example 10B: capsule
The colloidal silicon dioxide of the lactose of the starch of the sodium laurylsulfate of the A.I. of 20 grams, 6 grams, 56 grams, 56 grams, 0.8 gram stirs with the Magnesium Stearate of 1.2 grams fully together.The mixture that obtains fills in the gelatinum capsule of 1000 suitable stiffness subsequently, and each capsule contains the active ingredient of 20mg.
Example 10C: film clothing tablet
The preparation of tablet nuclear: the mixture of 10 gram A.I., 57 gram lactose nuclears, 20 gram starch carries out thorough mixing, carries out moistening with the about 20ml water that wherein contains 0.5 gram sodium lauryl sulphate, 1.0 gram polyvinylpyrrolidones (KOLLIDON-K 90) thereafter.Moistening powdered mixture sieves, drying, and sieves once more.The hydrogenated vegetable oil (STEROTEX) that adds 100 gram Microcrystalline Celluloses (AVICEL) and 15 grams then.All components all well mixes, and is pressed into 1000 tablets, contains the active ingredient of 10mg in every tablet.
The film clothing: the 15ml dichloromethane that contains ethyl cellulose (0.5 gram, ETHOCEL 22CPS) joins in the 7.5ml Denatured alcohol solution that contains 1.0 gram methylcellulose gum (Methocel 60HG.RTM.).Add 1,2 of the dichloromethane of 7.5ml and 0.25ml then, the 3-glycerol.Polyoxyethylene glycol (1.0 gram) fusion is also dissolved in the dichloromethane of 7.5ml, joins then and contains in the cellulosic solution.Add the concentrated colored suspension liquid (OPASPRAY K-1-2109) of magnesium octadecanate (0.25 gram), 0.5 gram polyvinylpyrrolidone and 3.0ml, whole mixture mixes.Tablet nuclear applies with said mixture in film clothing equipment.
Example 10D: injection liquid
1.8 gram methyl 4-Para Hydroxy Benzoic Acid salt and 0.2 gram propyl group 4-benzoate dissolve in about 0.5 liter boiling water.After being cooled to about 50 ℃, when stirring, add 4 gram lactic acid, 0.05 gram propylene glycol and 4 gram A.M.The solution cool to room temperature, and add the water of injecting capacity, make the A.I. that contains 4mg/ml in the solution.Solution passes through filtration sterilization, and in the container of the sterilization of packing into.
The 100.0 gram hydrochlorates of A.I. of the present invention dissolve in the boiling water.After being cooled to about 50 ℃, when stirring, add the lactic acid (90wt%) of 37.5 grams.The solution cool to room temperature adds 1 liter water.Solution passes through filtration sterilization, and in the container of the sterilization of packing into.
The 5.00 gram hydrochlorates of A.I. of the present invention dissolve in the boiling water.After being cooled to about 50 ℃, when stirring, add the lactic acid (90wt%) of 2.20 grams.The solution cool to room temperature, the water of adding 100ml.
Example 10E: gel
Compound of the present invention or salt can be used for topical application (topicalapplication) by gel.
Gel is prepared by the suspension A.M in the benzylalcohol under the room temperature (0.2 gram-5.0 grams).The hydroxypropylcellulose (2.5 gram) and the mixture of softening water (capacity to 100 gram) join in the suspension liquid under condition of stirring.
Embodiment 10F: paste
Phase I contains sorbitanic monostearate (2.0 gram), polyethylene (20) sorbitanic monostearate (1.5 gram), synthetic whale oil (3.0 gram), 16 stearic alkanols (10.0 gram) and 2-Standamul G (13.5 gram).The mixture heating up to 75 of Phase I ℃ stirs also and mixes.
Phase I contains A.I. (1.0g).Phase joins in the Phase I, stirs and suspension.
Phase I contains benzylalcohol (1.0 gram) and softening water (capacity to 100 gram).Phase I is heated to 75 ℃, and joins in the Phase.After the paste intense mixing, slowly cool to room temperature, and further stirring.Behind the cool to room temperature, paste mixes.
Example 10G: sprays
Active compounds solution or suspension according to example 10D preparation also can be processed into sprays.For example, the mixing of the active compounds solution of 60-90% and the conventional propellant of 20-40% gets final product conventional propellant such as N
2, N
2O, CO
2, propane, butane, halocarbon and analogue.
Claims (51)
1, a kind of compound or its pharmacy acceptable salt with following formula structure,
Wherein:
Z is 0,1 or 2;
R is hydrogen, methyl or ethyl;
A
1Be nitrogen or CR
1
A
2Be nitrogen or CR
2
A
3Be nitrogen or CR
3
A
4Be nitrogen or CR
4
A
5Be nitrogen or CR
5
A
1, A
2, A
3, A
4Or A
5In one of be nitrogen, or do not have;
R
1, R
4And R
5Be respectively hydrogen, hydroxyl, amino, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group;
When z is zero:
R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another be:
(a) C
3-C
6Alkyl or C
3-C
6Alkoxyl group, wherein each are at least by a C
1-C
4Alkoxyl group or single or two-C
1-C
4Alkylamino replaces;
(b) C
4-C
8Carbalkoxy;
(c) (phenyl) C
1-C
2Alkoxyl group, (phenyl) C
1-C
2Alkylamino radical, (aniline) C
1-C
2Alkyl, (phenoxy group) C
1-C
2Alkyl and (pyridyl) L-, wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group ,-C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl-;
(d) (cyclopentyl) L-or (pyrrolidyl) L-;
(e) (cyclohexyl) C
0-C
2Alkyl, (cyclopentyl) C
0-C
2Alkyl, (piperidyl) C
0-C
2Alkyl or (pyrrolidyl) C
0-C
2Alkyl, each group condensed ring is to 6-unit's carbocyclic ring or contain 1-2 the first heterocycle of heteroatomic 6-that is selected from N, O, S; Or
(f) (benzene) C
1-C
2Alkyl or (pyridine) C
1-C
2Alkyl, each group condensed ring are to containing 1-2 heteroatomic 5-or 6-unit heterocycle;
Wherein (a) and (b), (c), (d), (e) and (f) in each group be selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
4Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces;
(g) cyclohexyl, piperidyl, bridge-type cyclohexyl or bridge-type piperidyl, each is selected from C at least
2-C
6Carbalkoxy, phenyl, pyridyl, C
4-C
8Alkyl and C
4-C
8Alkoxyl group replaces; And further be selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group and C
1-C
2The substituting group of halogen alkoxyl group replaces;
Perhaps R
2And R
3In one be halogen, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group, another is cyclohexyl, piperidyl, C
5-C
8Alkyl, C
5-C
8Thiazolinyl, C
5-C
8Alkynyl or C
4-C
8Alkoxyl group;
When z is 1 or 2:
One among R2 and the R3 is hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another is:
(i) C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or single or two-C
1-C
4Alkylamino replaces;
(ii) C
4-C
8Carbalkoxy, C
5-C
8Alkene or C
5-C
8Alkynyl;
(iii) (phenyl) L-or (pyridyl) L-, each group be condensed ring to 6 yuan carbocyclic ring or contain 1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from as N, O, S optionally;
(iv) (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, the bridge joint of each group selectivity and the condensed ring to 6 of each group selectivity yuan carbocyclic ring or contain 1 or 2 heteroatoms such as 6 yuan of heterocycles of N, O, S;
Wherein (i), (ii), (iii) and (iv) each is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces;
Perhaps R
2And R
3In one be halogen, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group, another is C
5-C
8Alkyl or C
4-C
8Alkoxyl group;
Additional condition: work as R
3When being methoxyl group, R
2Not benzyloxy or cyclopentyloxy;
Work as R
6And R
7When existing, they are selected from hydrogen, halogen, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group and phenyl; Or R
6And R
7Add and form 3-7 unit cycloalkyl ring.
2, compound according to claim 1 or salt, wherein said R is a hydrogen.
3, compound according to claim 2 or salt, wherein said R
1, R
4And R
5Be respectively hydrogen, chlorine, fluorine, cyano group, methyl or ethyl.
4, compound according to claim 2 or salt, wherein said R
1, R
4And R
5All be hydrogen.
5, according to described compound of arbitrary claim or salt among the claim 1-4, wherein said A
1Be CR
1, A
2Be CR
2, A
3Be CR
3, A
4Be CR
4, A
5Be CR
5
6, according to described compound of arbitrary claim or salt among the claim 1-4, wherein said A
1Be CR
1, A
2Be CR
2, A
4Be nitrogen, A
4Be CR
4, A
5Be CR
5
7, according to described compound of arbitrary claim or salt among the claim 1-4, wherein said A
1Be CR
1, A
2Be CR
2, A
3Be CR
3, A
4Be nitrogen, A
5Be CR
5
8, according to described compound of arbitrary claim or salt among the claim 1-7, wherein z is zero;
R
2And R
3In one be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another is C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or single or two-C
1-C
4Alkylamino replaces.
9, according to described compound of arbitrary claim or salt among the claim 1-7, wherein z is zero;
R
2And R
3In one be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another is C
4-C
8Carbalkoxy.
10, according to described compound of arbitrary claim or salt among the claim 1-7, wherein z is zero;
R
2And R
3In one be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another is (phenyl) C
1-C
2Alkoxyl group, (phenyl) C
1-C
2Alkylamino radical, (aniline) C
1-C
2Alkyl, (phenoxy group) C
1-C
2Alkyl and (pyridyl) L-; Wherein each is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
4Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
11, compound according to claim 10 or salt, wherein R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another is (phenyl) C
1-C
2Alkoxyl group, (phenyl) C
1-C
2Alkylamino radical, (aniline) C
1-C
2Alkyl, (phenoxy group) C
1-C
2Alkyl and (pyridyl) L-; Wherein each is selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
12, compound according to claim 10 or salt, wherein R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another is (phenyl) C
1-C
2Alkoxyl group, (phenyl) C
1-C
2Alkylamino radical, (aniline) C
1-C
2Alkyl, (phenoxy group) C
1-C
2Alkyl and (pyridyl) L-; Wherein each is selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces;
Wherein L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
13, according to described compound of arbitrary claim or salt among the claim 1-7, wherein z is zero;
R
2And R
3In one be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another be (cyclopentyl) L-or (piperidyl) L-, each group is selected from hydroxyl, amino, cyano group, halogen, C respectively by 0-3
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
4Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
14, compound according to claim 13 or salt, wherein R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another be (cyclopentyl) L-or (piperidyl) L-, each group is selected from cyano group, halogen, C respectively by 0-3
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces;
Wherein L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
15, according to described compound of arbitrary claim or salt among the claim 1-7, wherein z is zero;
R
2And R
3In one be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another be (e) (cyclohexyl) C
0-C
2Alkyl, (cyclopentyl) C
0-C
2Alkyl, (piperidyl) C
0-C
2Alkyl or (pyrrolidyl) C
0-C
2Alkyl, each group condensed ring is to 6-unit carbocyclic ring or contain on 1-2 the heteroatomic 6-unit heterocycle that is selected from N, O, S; (e) each group in is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
4Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
16, compound according to claim 15 or salt, wherein z is zero;
R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another be (e) (cyclohexyl) C
0-C
2Alkyl, (cyclopentyl) C
0-C
2Alkyl, (piperidyl) C
0-C
2Alkyl or (pyrrolidyl) C
0-C
2Alkyl, each group condensed ring is on benzene, hexamethylene, tetrahydrobenzene, piperidines or pyridine ring; And each group (e) is selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
17, according to described compound of arbitrary claim or salt among the claim 1-7, wherein z is zero;
R
2And R
3In one be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another be (phenyl) C
0-C
2Alkyl or (pyridyl) C
0-C
2Alkyl, each group condensed ring is on 5-that contains 1-2 Sauerstoffatom or 6-unit heterocycle; Each group is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
4Alkyloyl, C
1-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
18, compound according to claim 17 or salt, wherein said 5-or 6-unit heterocycle contain 2 Sauerstoffatoms.
19, compound according to claim 17 or salt, wherein R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another be
Wherein, R
8That represent is individual halogen, the C of being selected from respectively of 0-2
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl, C
1-C
2The substituting group of trifluoromethoxy and phenyl.
20, according to described compound of arbitrary claim or salt among the claim 1-7, wherein z is zero;
R
2And R
3In one be hydrogen, hydroxyl, amino, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another be cyclohexyl, piperidyl, bridge-type cyclohexyl or bridge-type piperidyl, each is selected from C at least
2-C
6Carbalkoxy, phenyl, pyridyl, C
4-C
8Alkyl and C
4-C
8Alkoxyl group replaces; And further be selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group and C
1-C
2The substituting group of halogen alkoxyl group replaces.
21, compound according to claim 20 or salt, wherein said R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another be cyclohexyl, piperidyl, bridge-type cyclohexyl or bridge-type piperidyl, each group is selected from C respectively by 1 or 2 at least
2-C
6Carbalkoxy, phenyl, pyridyl, C
4-C
8Alkyl and C
4-C
8The substituting group of alkoxyl group replaces.
22, according to described compound of arbitrary claim or salt among the claim 1-7, wherein said R
2And R
3In one be halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And R
2And R
3In another be cyclohexyl, piperidyl, C
5-C
8Alkyl, C
5-C
8Alkane thiazolinyl, C
5-C
8Alkane alkynyl or C
4-C
8Alkoxyl group.
23, compound according to claim 22 or salt, wherein said R
2And R
3In one be chlorine, fluorine, methoxyl group, trifluoromethyl or trifluoromethoxy; And R
2And R
3In another be cyclohexyl, piperidyl, C
5-C
8Alkyl or C
4-C
8Alkoxyl group.
24, according to described compound of arbitrary claim or salt among the claim 1-7, wherein z is 1.
25, according to described compound of arbitrary claim or salt among the claim 1-7, wherein z is 2.
26, according to claim 24 or 25 described compound or salt, wherein said R
2And R
3In one be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And R
2And R
3In another is C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or single or two-C
1-C
4Alkylamino replaces.
27, according to claim 24 or 25 described compound or salt, wherein said R
2And R
3In one be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And R
2And R
3In another is C
4-C
8Carbalkoxy, C
5-C
8Alkane thiazolinyl or C
5-C
8The alkane alkynyl.
28, according to claim 24 or 25 described compound or salt, wherein said R
2And R
3In one be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another is (phenyl) L-or (pyridyl) L-, each group optionally condensed ring to 5-or 6-unit's carbocyclic ring or contain on 1 or 2 heteroatomic 6 yuan of heterocycle that are selected from N, O, S;
Wherein each group among (phenyl) L-or (pyridyl) L-is selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
29, compound according to claim 28 or salt, wherein said R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another is (phenyl) L-or (pyridyl) L-, each group is selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
30, compound according to claim 28 or salt, wherein said R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another is (phenyl) L-or (pyridyl) L-, each group optionally condensed ring to 5-or 6-unit's carbocyclic ring or contain on 1 or 2 heteroatomic 6 yuan of heterocycle that are selected from N, O, S;
Wherein each group among (phenyl) L-or (pyridyl) L-is selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
31, according to claim 29 or 30 described compound or salt, wherein said L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
32, according to claim 24 or 25 described compound or salt, wherein said R
2And R
3In one be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another is (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, each group are selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces.
33, compound according to claim 32 or salt, wherein said R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another is (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, the bridge joint of each group selectivity, and be selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
34, compound according to claim 32 or salt, wherein said R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another is (cyclohexyl) L-, (cyclopentyl) L-or (piperidyl) L-, each group selectivity condensed ring is on phenyl, pyridine, cyclohexyl, cyclohexenyl or piperidines basic ring;
Every kind of (cyclohexyl) L-, (cyclopentyl) L-or (piperidyl) L-are selected from cyano group, halogen, C respectively by 0-3
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
35, compound according to claim 32 or salt, wherein said R
2And R
3In one be hydrogen, halogen, C
1-C
2Alkyl, C
1-C
2Alkoxyl group, trifluoromethyl or trifluoromethoxy; And
R
2And R
3In another is (cyclohexyl) L-, (cyclopentyl) L-or (piperidyl) L-, each group is selected from cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group and phenyl replaces.
36, according to described compound of arbitrary claim or salt among the claim 33-35, wherein said L is C
0-C
2Alkyl, C
0-C
2Alkoxyl group or C
0-C
2Alkylamino.
37, according to claim 24 or 25 described compound or salt, wherein said R
2And R
3In one be halogen, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; R
2And R
3In another is C
5-C
8Alkyl or C
4-C
8Alkoxyl group.
38, according to described compound of arbitrary claim or salt among claim 1-7 or the 24-37, wherein said R
6And R
7Be respectively hydrogen, halogen, methyl or ethyl.
39, according to described compound of claim 38 or salt, wherein said R
6And R
7Be all hydrogen.
40, a kind of compound or its pharmacy acceptable salt, wherein said compound is:
1-(3-benzyloxy) phenylthiourea;
1-(4-cyclohexyl-phenyl)-thiocarbamide;
1-(3-phenoxy group-phenyl)-thiocarbamide;
1-(4-butoxy carbonyl-phenyl)-thiocarbamide;
1-(3-benzyl-phenyl)-thiocarbamide;
1-(4-pentyloxy-phenyl)-thiocarbamide;
1-(4-amyl group-phenyl)-thiocarbamide;
1-(4-cyclohexyl methoxyl group-phenyl)-thiocarbamide;
1-(3-butoxy-phenyl)-thiocarbamide;
1-(4-(3-(dimethylamino) propoxy-) phenyl) thiocarbamide;
1-[3-fluoro-(4-(3-dimethylamino propoxy-) phenyl)] thiocarbamide;
1-(3-fluoro-(4-pentyloxy)-phenyl)-thiocarbamide;
1-(3-(indane-2-base oxygen) phenyl) thiocarbamide;
1-(3-(3,4-difluoro benzyloxy) phenyl) thiocarbamide;
1-(3-(4-phenyl benzyloxy) phenyl) thiocarbamide;
1-(3-((S)-1-phenyl ethoxy) phenyl) thiocarbamide;
Butyl 4-phenyl-1-(3-thiocarbamide phenyl) piperidines-4-carboxylicesters;
Ethyl 4-phenyl-1-(3-thiocarbamide phenyl) piperidines-4-carboxylicesters;
1-(2-phenyl benzo [d]-[1,3] two oxo bridges-6-yl) thiocarbamide;
1-(3-((R)-1-phenyl ethoxy) phenyl) thiocarbamide;
1-(3-(phenyl ethoxy) phenyl) thiocarbamide;
1-(3-(phenyl) phenyl) thiocarbamide;
1-(4-(phenyl) phenyl) thiocarbamide;
1-(3-fluoro-4 (3,4-dihydro-isoquinoline 99.9-2 (1H)-yl) phenyl) thiocarbamide;
1-(4-(3,4-dihydro-isoquinoline 99.9-2 (1H)-yl) phenyl) thiocarbamide;
1-(4-(octahydro quinoline-2 (1H)-yl) phenyl) thiocarbamide;
1-(4-(octahydro quinoline-1 (2H)-yl) phenyl) thiocarbamide;
1-(4-benzyloxy) phenyl) thiocarbamide;
1-(4-((1s, 4r)-4-hexyl cyclohexyl) phenyl) thiocarbamide;
1-(4-(4-hexyl dicyclo [2.2.2] eight-1-yl) phenyl) thiocarbamide;
1-(4-((1s, 4r)-4-propyl group cyclohexyl) phenyl) thiocarbamide;
1-(3-trifluoromethyl)-4-(piperidines-1-yl) phenyl) thiocarbamide;
1-(4-(six-1-alkynyl) phenyl) thiocarbamide;
1-(4-(phenylamino-ethyl) phenyl) thiocarbamide;
1-(3-(3-methoxyl group) phenyl) thiocarbamide;
1-(4-phenoxy phenyl) thiocarbamide;
1-(5-benzyloxy)-2-tolyl) thiocarbamide;
Butyl 1-(2-fluoro-4-thiocarbamide phenyl) piperidines-4-carboxylicesters;
1-(4-(oxygen base in heptan)-3-(trifluoromethyl) phenyl) thiocarbamide;
1-(1-(4-(benzyloxy) phenyl) ethyl) thiocarbamide;
1-(4-(benzyloxy) phenyl) thiocarbamide;
1-(4-(4-phenyl-benzyloxy) benzyl) thiocarbamide;
1-(4-(trifluoromethyl) benzyl) thiocarbamide;
1-(2-(4-phenoxy phenyl) propane-2-yl) thiocarbamide;
1-(1-(4-phenoxy phenyl) cyclopentyl) thiocarbamide;
1-(1-(4-phenoxy phenyl) ethyl base) thiocarbamide;
The 1-benzylthiourea;
1-(1-(4-phenoxy phenyl) cyclohexyl) thiocarbamide;
1-(2,3-dihydro-1H-indenes-2-yl) thiocarbamide;
1-(3-(benzyloxy) styroyl) thiocarbamide;
1-(3-(methyl)-4-(piperidines-1-yl) phenyl) thiocarbamide;
1-(3-(methyl)-4-(piperidines-1-yl) phenyl) thiocarbamide;
1-(3-(cyclohexyl methylamino-) phenyl) thiocarbamide;
1-(3-(3-(fluoroform amino) benzyloxy) phenyl) thiocarbamide;
1-(3-fluoro-4-(4-Phenylpiperidine-1-yl) phenyl) thiocarbamide;
1-(4-benzyloxy phenoxy base) thiocarbamide;
1-(3-phenylbenzyl) thiocarbamide;
1-(4-phenylbenzyl) thiocarbamide;
1-trityl thiocarbamide;
1-(4-butyl benzyl) thiocarbamide;
1-(3-benzyloxy) phenyl) thiocarbamide;
1-(3-benzyl phenyl) thiocarbamide;
1-(4-(pentyloxy) phenyl) thiocarbamide;
Butyl 1-(2-fluoro-4-thiocarbamide phenyl)-4-Phenylpiperidine-4-carboxylicesters;
1-(4-butyl-2-aminomethyl phenyl) thiocarbamide;
1-(3-phenyl-phenyl) thiocarbamide;
1-(4-phenyl-phenyl) thiocarbamide;
1-(3-fluoro-4-(3,4-dihydro-isoquinoline-2 (1H)-yl) phenyl) thiocarbamide;
1-(4-(3,4-dihydro-isoquinoline-2 (1H)-yl) phenyl) thiocarbamide;
1-(4-(octahydro isoquinoline 99.9-2 (1H)-yl) phenyl) thiocarbamide;
1-(3-fluoro-4-(octahydro isoquinoline 99.9-2 (1H)-yl) phenyl) thiocarbamide;
1-(4-(benzyloxy) phenyl) thiocarbamide;
1-(3-(trifluoromethyl)-4-(piperidines-1-yl) phenyl) thiocarbamide;
1-(3-(3-methoxy-benzyl) phenyl) thiocarbamide;
1-(3-fluoro-4-(4-Phenylpiperidine-1-yl) phenyl) thiocarbamide;
1-(4-(N-benzyl-N-methylamino-)-3-fluorophenyl) thiocarbamide;
1-(4-(N-benzyl-N-penta amino)-3-fluorophenyl) thiocarbamide;
1-(3-(trifluoromethyl)-4-(pentyloxy) phenyl) thiocarbamide;
N-(4-benzene oxygen styroyl) thiocarbamide;
(3-benzyl-phenyl)-thiocarbamide;
(4-pentyloxy-phenyl)-thiocarbamide;
1-(4-(N-benzyl-N-methylamino-) 3-fluorophenyl) thiocarbamide; Or
(4-pentyloxy-3-trifluoromethyl-phenyl)-thiocarbamide.
41, a kind of pharmaceutical composition, this pharmaceutical composition contains pharmaceutically acceptable carrier, thinner or vehicle, and compound or its pharmacy acceptable salt with following formula structure,
Wherein:
Z is 0,1 or 2;
R is hydrogen, methyl or ethyl;
A
1Be nitrogen or CR
1
A
2Be nitrogen or CR
2
A
3Be nitrogen or CR
3
A
4Be nitrogen or CR
4
A
5Be nitrogen or CR
5
The A of one of them
1, A
2, A
3, A
4Or A
5Be nitrogen, or do not have;
R
1, R
4And R
5Be respectively hydrogen, hydroxyl, amino, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group;
When z is zero:
R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another be:
(a) C
3-C
6Alkyl or C
3-C
6Alkoxyl group, wherein each are at least by a C
1-C
4Alkoxyl group or single or two-C
1-C
4Alkylamino replaces;
(b) C
4-C
8Carbalkoxy;
(c) (phenyl) ethyl, (phenyl) C
1-C
2Alkoxyl group, (phenyl) C
1-C
2Alkylamino radical, (aniline) C
1-C
2Alkyl, (phenoxy group) C
1-C
2Alkyl, or (pyridyl) L-, wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group ,-C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl-;
(d) (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, the bridge joint of each group selectivity and the condensed ring to 6 of each group selectivity yuan carbocyclic ring or contain 1 or 2 heteroatoms such as 6 yuan of heterocycles of N, O, S on; Or
(e) (phenyl) L-or (pyridyl) L-, each group optionally condensed ring to containing on 1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from as N, O, S;
Wherein (a) and (b), (c), (d) and (e) in each group be selected from hydroxyl, amino, cyano group, halogen, C by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces;
Perhaps R
2And R
3In one be halogen, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group, another is cyclohexyl, piperidyl, C
5-C
8Alkyl, C
5-C
8Thiazolinyl, C
5-C
8Alkynyl or C
4-C
8Alkoxyl group;
When z is 1 or 2:
R
2And R
3In one be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another is:
(i) C
3-C
6Alkyl or C
3-C
6Alkoxyl group is by at least one C
1-C
4Alkoxyl group or single or two-C
1-C
4Alkylamino replaces;
(ii) C
4-C
8Carbalkoxy, C
5-C
8Alkene or C
5-C
8Alkynyl;
(iii) (phenyl) L-or (pyridyl) L-, each group be condensed ring to 6 yuan carbocyclic ring or contain 1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from as N, O, S optionally; Or
(iv) (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, the bridge joint of each group selectivity and the condensed ring of each group selectivity are to 6 yuan of heterocycles that contain 1 or 2 heteroatoms such as N, O, S;
Wherein (i), (ii), (iii) and (iv) each is selected from hydroxyl, amino, cyano group, halogen, C respectively by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces;
Perhaps R
2And R
3In one be halogen, C
1-C
2Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group, another is C
5-C
8Alkyl or C
4-C
8Alkoxyl group;
Additional condition: work as R
3When being methoxyl group, R
2Not benzyloxy or cyclopentyloxy; And
Work as R
6And R
7When existing, they are selected from hydrogen, halogen, C respectively
1-C
4Alkyl or C
1-C
4Alkoxyl group; Or R
6And R
7Add and form 3-7 unit cycloalkyl ring.
42, according to the described pharmaceutical composition of claim 41, the formulation of said composition is that injecting fluid, aerosol, paste, gel, tablet, pill, capsule, syrup, ophthalmic solution or skin paste.
43, a kind of pharmaceutical composition of packing wherein comprises the described composition of claim 41 in the test kit, and also comprises the specification sheets that uses the said composition treatment to infect C type hepatitis patient.
44, according to described compound of arbitrary claim or salt among the claim 1-40, the EC in the replicon test that HCV duplicates
50Less than 10 micromoles.
45, according to described compound of arbitrary claim or salt among the claim 1-40, the EC in the replicon test that HCV duplicates
50Less than 1 micromole.
46, a kind of method for the treatment of C type hepatitis, this method comprise to the sick body that infects C type hepatitis takes compound or its pharmacy acceptable salt with following formula treatment significant quantity,
Wherein:
Z is 0,1 or 2;
R is hydrogen, methyl or ethyl;
A
1Be nitrogen or CR
1
A
2Be nitrogen or CR
2
A
3Be nitrogen or CR
3
A
4Be nitrogen or CR
4
A
5Be nitrogen or CR
5
The A of one of them
1, A
2, A
3, A
4Or A
5Be nitrogen, or do not have;
R
1, R
4And R
5Be respectively hydrogen, hydroxyl, amino, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group;
R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another be:
(i) C
3-C
6Alkyl or C
3-C
6Alkoxyl group, wherein each are at least by a C
1-C
4Alkoxyl group or single or two-C
1-C
4Alkylamino replaces;
(ii) C
4-C
8Carbalkoxy, C
5-C
8Alkyl, C
5-C
8Alkene, C
5-C
8Alkynyl; Or C
4-C
8Alkoxyl group;
(iii) (phenyl) L-or (pyridyl) L-, each group condensed ring to 6 yuan carbocyclic ring or contain on 1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from N, O, S respectively optionally wherein, wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl-;
(iv) (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, wherein the bridge joint of each group selectivity and wherein each group selectivity condensed ring to 6 yuan carbocyclic ring or contain on 1 or 2 heteroatomic 6 yuan of heterocycle that are selected from N, O, S respectively;
Wherein (i), (ii), (iii) and (iv) each is selected from hydroxyl, amino, cyano group, halogen, C respectively by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces; And
Work as R
6And R
7When existing, they are selected from hydrogen, halogen, C respectively
1-C
4Alkyl or C
1-C
4Alkoxyl group; Or R
6And R
7Add and form 3-7 unit cycloalkyl ring.
47, according to the described method of claim 46, sick body wherein is patient.
48, according to the described method of claim 46, wherein said treatment significant quantity is meant that this amount can reduce the quantity of the HCV antibody in sick body blood or the serum to a great extent.
49, a kind of method that inhibition HCV duplicates in organism, this method comprise to infect C type hepatitis sick body take enough concentration, the described compound or its salt of arbitrary claim among the claim 1-40, this concentration is enough to suppress duplicating of the outer HCV replicon of organism.
50, a kind of compound or its pharmacy acceptable salt with following formula structure,
Wherein:
R is hydrogen, methyl or ethyl;
Z is 2;
A
1Be nitrogen or CR
1A
2Be nitrogen or CR
2A
3Be nitrogen or CR
3A
4Be nitrogen or CR
4A
5Be CR
5The A of one of them
1, A
2, A
3Or A
4Be nitrogen, or do not have;
R
1, R
4And R
5Be respectively hydrogen, hydroxyl, amino, halogen, cyano group, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group;
R
2And R
3One of them be hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group; And
R
2And R
3In another be:
(i) hydrogen, hydroxyl, amino, cyano group, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
1-C
2Alkylhalide group or C
1-C
2The halogen alkoxyl group;
(ii) C
3-C
6Alkyl or C
3-C
6Alkoxyl group, wherein each are at least by a C
1-C
4Alkoxyl group or single or two-C
1-C
4Alkylamino replaces;
(iii) C
4-C
8Carbalkoxy, C
5-C
8Alkyl, C
5-C
8Alkene, C
5-C
8Alkynyl; Or C
4-C
8Alkoxyl group;
(iv) (phenyl) L-or (pyridyl) L-, each group condensed ring to 6 yuan carbocyclic ring or contain on 1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from N, O, S respectively optionally wherein, wherein L is C
0-C
3Alkyl ,-C (phenyl)
2-, C
0-C
2Alkoxyl group, C
0-C
2Alkylamino ,-O-C
1-C
2Alkyl or-NH-C
1-C
2Alkyl-; Or
(iv) (C
5-C
7Cycloalkyl) L-or (Heterocyclylalkyl) L-, wherein the bridge joint of each group selectivity and wherein each group selectivity condensed ring to 6 yuan carbocyclic ring or contain on 1 or 2 heteroatomic 6 yuan of heterocycle that are selected from N, O, S respectively; Wherein (ii), (iii), (iv) and (each v) is selected from hydroxyl, amino, cyano group, halogen, C respectively by 0-3 respectively
1-C
4Alkyl, C
3-C
7Cycloalkyl, C
1-C
4Alkoxyl group, single and two-(C
1-C
4Alkyl) amino, C
2-C
6Carbalkoxy, C
1-C
2Alkylhalide group, C
1-C
2The substituting group of halogen alkoxyl group, phenyl and pyridyl replaces;
R
5With one of them R
6Form the 5-or the 7-unit cycloalkyl ring of condensed ring together; And
Another R
6With two R
7All be selected from hydrogen, halogen, C respectively
1-C
4Alkyl, C
1-C
4Alkoxyl group and phenyl.
51, according to described compound of claim 50 or salt, it has following structural formula.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US48669703P | 2003-07-10 | 2003-07-10 | |
| US60/486,697 | 2003-07-10 | ||
| US60/496,146 | 2003-08-18 | ||
| US60/506,699 | 2003-09-26 | ||
| US60/509,995 | 2003-10-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1849301A true CN1849301A (en) | 2006-10-18 |
Family
ID=37078395
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480026142 Pending CN1849301A (en) | 2003-07-10 | 2004-07-08 | Substituted arylthiourea derivatives useful as inhibitors of viral replication |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1849301A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101525310A (en) * | 2009-04-21 | 2009-09-09 | 大连凯飞精细化工有限公司 | Method for compounding 1-benzoyl-3-(2-oxhydryl-1, 1-dimethylethyl) thiourea |
| CN105026367A (en) * | 2013-03-05 | 2015-11-04 | 旭化成化学株式会社 | Isothiocyanate production method, composition for transporting and storing N-substituted O-substituted thiocarbamate, and isothiocyanate composition |
-
2004
- 2004-07-08 CN CN 200480026142 patent/CN1849301A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101525310A (en) * | 2009-04-21 | 2009-09-09 | 大连凯飞精细化工有限公司 | Method for compounding 1-benzoyl-3-(2-oxhydryl-1, 1-dimethylethyl) thiourea |
| CN101525310B (en) * | 2009-04-21 | 2019-04-16 | 大连九信精细化工有限公司 | The synthetic method of 1- benzoyl -3- (2- hydroxyl -1,1- dimethyl ethyl) thiocarbamide |
| CN105026367A (en) * | 2013-03-05 | 2015-11-04 | 旭化成化学株式会社 | Isothiocyanate production method, composition for transporting and storing N-substituted O-substituted thiocarbamate, and isothiocyanate composition |
| US10308601B2 (en) | 2013-03-05 | 2019-06-04 | Asahi Kasei Chemicals Corporation | Isothiocyanate production method, composition for transporting and storing N-substituted O-substituted thiocarbamate, and isothiocyanate composition |
| US11046645B2 (en) | 2013-03-05 | 2021-06-29 | Asahi Kasei Chemicals Corporation | Isothiocyanate production method, composition for transporting and storing N-substituted O-substituted thiocarbamate, and isothiocyanate composition |
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