CN101928283A - Compound with anti-HCV activity and application thereof - Google Patents
Compound with anti-HCV activity and application thereof Download PDFInfo
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- CN101928283A CN101928283A CN2009100538278A CN200910053827A CN101928283A CN 101928283 A CN101928283 A CN 101928283A CN 2009100538278 A CN2009100538278 A CN 2009100538278A CN 200910053827 A CN200910053827 A CN 200910053827A CN 101928283 A CN101928283 A CN 101928283A
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
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Abstract
The invention discloses a compound shown in the general formula (I) or pharmaceutically acceptable salt or hydrates thereof. In the general formula (I), Ar is substituted or unsubstituted acryl or heteroaryl; Z is selected from N and substituted or unsubstituted C; R1 and R2 are selected from the substituted or unsubstituted substitutes in the following groups independently: -CH2Ra, -NH-S(O)2Ra, -CH2-NH-S(O)2Ra, -S(O)2Ra, -C(O)-NH-Ra, -C(O)-NH-CH2Ra, -NH-C(O)-Ra, -NH-C(O)-Rb, -C(O)O-Ra, -C(O)-O-Rb, -ORa, -C(O)-Ra, -C(O)-Rb, hydrogen atoms, C1-C10 alkyl, phenyl, five-six membered heteroaryl, benzo-five-six membered naphthenic base or hetero-naphthenic base and eight-ten membered bicyclic heteroaryl; or R1 and R2 are combined to form C3-C14 single, two or three cycle containing heteroatoms; Ra is randomly selected from substituted or unsubstituted substitutes in the following groups: hetero-naphthenic base, phenyl and five-six membered heteroaryl; Rb is substituted or unsubstituted C1-C6 alkyl; and R is selected from hydrogen atoms, hydroxyl, amino, C1-C5 alkyl, C1-C5 alkoxyl, halogenated C1-C5 alkyl and halogenated C1-C5 alkoxyl. The compound has excellent anti-HCV activity. The general formula (I) is shown in the specification.
Description
Technical field
The present invention relates to a kind of compound, refer to a kind of compound and uses thereof especially with anti-HCV activity with antiviral activity.
Background technology
Hepatitis C virus (Hepatitis C Virus, HCV) be a kind of virus that causes hepatitis C, the nearly 1.7 hundred million people's HCV infection in the whole world, can cause chronic hepatitis C (CHC) behind the patient infection HCV more than 70%, along with the prolongation of the course of disease has certain proportion to develop into hepatopathy in late period such as liver cirrhosis, liver cancer
So far, the treatment of HCV does not have the specific medicine yet.(interferon, though IFN) be present only effective relatively anti-HCV medicine, low and recurrence rate is high with IFN treatment CHC response rate, some patient also can be because of the drug side effect abandoning cure for Interferon, rabbit.
Hepatitis C virus (HCV) is a positive chain RNA that is about 9.6kb, comprise 5 ' non-coding region (5 '-UTR), open reading frame (ORF) and 3 ' non-coding region (3 '-UTR).The ORF translation produces a polypeptide chain, and it is processed at least 10 kinds of different protein subsequently, comprising a kind of shell (core) albumen, and two kinds of envelope proteins (E1 and E2) and five kinds of Nonstructural Proteins (NS2, NS3, NS4, NS5A and NS5B).Can be contemplated that the specially clinical applications of target spot inhibitor such as the NS3 of HCV and NS5B district proteolytic enzyme, can further improve persistent virus and reply.
Therefore, the medicine of the suppressed HCV of necessary development of new virus replication satisfies patient's demand.
Summary of the invention
One of purpose of the present invention is to provide a kind of antiviral compound or its pharmaceutically acceptable salt or hydrate with general formula (I),
Wherein, Ar is aryl or heteroaryl, the bicyclic heteroaryl of preferred fluorenyl, phenyl, naphthyl, 5 to 6 yuan of heteroaryls or 9 to 10 yuan, and Ar can be by R
3And R
4Replace;
R
3One of be selected from following group substituting group: hydrogen atom, halogen, hydroxyl, amino, cyano group, nitro, C
1-C
5Alkyl, C
1-C
5Alkoxyl group, halo C
1-C
5Alkyl, halo C
1-C
5Alkoxyl group, C
1-C
6Alkyl C (O)-, phenyl-C (O)-and 5 to 6 yuan of heteroaryl-C (O)-;
R
4Be selected from (a) group or (b) substituting group one of in the group, wherein (a) group substituting group is: hydrogen atom, halogen, hydroxyl, amino, cyano group, nitro ,-COOH ,-SO
2NH
2, halo C
1-C
2Alkyl and halo C
1-C
2Alkoxyl group; (b) the group substituting group is: C
1-C
10Alkyl, C
2-C
10Thiazolinyl, C
2-C
10Alkynyl, C
2-C
10Alkyloyl, C
2-C
10Carbalkoxy, C
2-C
10Alkoxyl group, (C
1-C
10Alkyl)
1-2Formamido-and-YW;
Y is covalent linkage, C
1-C
10Alkyl, C
2-C
10Thiazolinyl or C
2-C
10Alkynyl wherein, can optionally have 0,1 or 2 O or N on alkyl, alkenyl or alkynyl chain;
W is halogen, C
3-C
7Cycloalkyl, C
3-C
7Cycloalkenyl group, Heterocyclylalkyl, phenyl, naphthyl, indanyl, C
3-C
7Cycloalkyl oxy, (C
3-C
7Cycloalkyl) C
1-C
10Alkoxyl group or 5 to 6 yuan and contain 1～4 the heteroatomic heteroaryl that independently is selected from N, O and S;
Wherein, (b) the group substituting group can be replaced by 0, one or more substituting groups that are selected from following group: halogen, hydroxyl, amino, cyano group, nitro, oxo, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halo C
1-C
2Alkyl and halo C
1-C
2Alkoxyl group;
Perhaps, R
3With with neck nearly carbon atom covalently bound R
4Formation has the fragrance of 1 or 2 ring or the carbocyclic ring system of fractional saturation together, and each ring has 3 to 6 carbon atoms;
Preferably, Ar is the substituting group that is selected from following group:
Z is selected from N and by 0,1 or 2 R
ZThe C that replaces; R
ZFor halogen, oxo ,-CONH
2,-C (O) OCH
3,-C (O) CH
3,-NHC (O) OH or amino.
R
1And R
2Be by 0, one or more R independently
1' replace be selected from substituting group in following group :-CH
2R
a,-NH-S (O)
2R
a,-CH
2-NH-S (O)
2R
a,-S (O)
2R
a,-C (O)-NH-R
a,-C (O)-NH-CH
2R
a,-NH-C (O)-R
a,-NH-C (O)-R
b,-C (O) O-R
a,-C (O)-O-R
b,-OR
a,-C (O)-R
a,-C (O)-R
b, hydrogen atom, C
1-C
10The bicyclic heteroaryl of alkyl, phenyl, 5 to 6 yuan of heteroaryls, 5 to 6 yuan of cycloalkyl of benzo or Heterocyclylalkyls and 8 to 10 yuan; Perhaps, R
1And R
2Join together form to replace or unsubstituted contain 0, one or more are selected from N, O, the heteroatomic C of S
3-C
14Single, two or three rings, R
1R
2N-is preferably by 0, one or more R
1' 5 to 6 yuan Heterocyclylalkyl replacing or heteroaryl, bicyclic heterocycle alkyl or bicyclic heteroaryl or aryl or heteroaryl and 5 to 6 yuan of Heterocyclylalkyls of 8 to 10 yuan;
R
1' following for being selected from (c), (d) or (e) substituting group one of in the group:
(c) the group substituting group is: halogen, hydroxyl, oxo, cyano group, amino, nitro ,-C (O) NH
2,-C (O) OH ,-S (O) NH
2, halo C
1-C
2Alkyl and halo C
1-C
2Alkoxyl group;
(d) the group substituting group is: C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
2-C
4Thiazolinyl, (C
1-C
6)
1-2Alkylamino, (C
1-C
4Alkyl)
1-2Formamido-, (C
1-C
4Alkyl)
1-2Sulfoamido and C
1-C
4Carbalkoxy, (d) each substituting group can be replaced by 0, one or more substituting groups that are selected from following group in the group: oxo, halogen, hydroxyl, cyano group, amino, nitro ,-C (O) NH
2,-C (O) OH ,-S (O) NH
2, C
1-C
4Alkoxyl group, (C
1-C
6)
1-2Alkylamino, (C
1-C
4Alkyl)
1-2Formamido-, (C
1-C
4Alkyl)
1-2Sulfoamido, C
1-C
4Carbalkoxy, halo C
1-C
2Alkyl and halo C
1-C
2Alkoxyl group;
(e) the group substituting group is: C
3-C
7Cycloalkyl, Heterocyclylalkyl, phenyl, (C
3-C
7Cycloalkyl) C
1-C
4Alkyl, (Heterocyclylalkyl) C
1-C
4Alkyl and (phenyl) C
1-C
4Alkyl, (e) each substituting group can be replaced by 0, one or more substituting groups that are selected from following group in the group: oxo, halogen, hydroxyl, cyano group, amino, nitro ,-C (O) NH
2,-C (O) OH ,-S (O) NH
2, halo C
1-C
2Alkyl and halo C
1-C
2Alkoxyl group;
Wherein, R
aBe selected from randomly by 0, one or more R
aSubstituting group in following group of ' replacement: Heterocyclylalkyl, phenyl and 5 to 6 yuan of heteroaryls, R
a' be halogen, hydroxyl, amino, cyano group, C
1-C
4Alkyl or C
1-C
4Alkoxyl group; R
bFor replacing or not replacing C
1-C
6Alkyl, C
1-C
6Substituting group on the alkyl can be: halogen, hydroxyl ,-C (O) OH, phenyl and/or 4-(NH
2S (O)
2)-phenyl;
Preferably, R
1R
2N-is the substituting group that is selected from following group:
R is selected from hydrogen atom, hydroxyl, amino, C
1-C
5Alkyl, C
1-C
5Alkoxyl group, halo C
1-C
5Alkyl and halo C
1-C
5Alkoxyl group.
The preferred particular compound of the present invention is:
Two of purpose of the present invention is to provide a kind of pharmaceutical composition, it comprises that the present invention has the antiviral compound and the pharmaceutically acceptable carrier of general formula (I), pharmaceutical composition wherein of the present invention can also be united use with other antiviral, as Interferon, rabbit or ribavirin.
Three of purpose of the present invention is to provide the purposes of a kind of general formula of the present invention (I) compound in preparation prophylaxis of viral infections or antiviral drug, the preferred hepatitis virus of described virus, preferred especially hepatitis C virus.
Four of purpose of the present invention is to provide a kind of method that the infection hepatitis virus especially patient of HCV is given general formula of the present invention (I) compound of significant quantity.
Synthesis technique flow process with antiviral compound of general formula (I) of the present invention is divided into the synthetic of general formula (IA) compound and general formula (IB) compound, and is as follows respectively:
When Z=C, the synthesis technique flow process of general formula (IA) compound is:
Steps A: at NH
4The acetone soln that adds Benzoyl chloride in the acetone soln of SCN, stirring reaction got formula A after two hours under the room temperature
2Compound; The acetone soln that adds HNRAr continues stirring reaction and spends the night, after reaction finishes acetone is removed, and separate formula A
3Compound; Make its dissolving with tetrahydrofuran (THF) then, add sodium hydroxide solution subsequently, stir down at 30 ℃ and spend the night, and separate formula A
4Compound;
Step B: with formula A
4Compound dissolution is in ethanol and be warming up to 60 ℃, adds ethyl bromoacetate, and 60 ℃ were continued reacting by heating 2 hours, removed ethanol and crystallization, can get crystal formula A
5Compound;
Step C: with formula A
5Compound and POX
3Mixture heating up refluxed 1 hour, reaction finishes postcooling to room temperature, with POX
3Decompression is removed, and separation and purification is formula A
6Compound;
Step D: with formula A
6Compound is dissolved among the DMF, adds HNR
1R
2, 80 ℃ of following stirring reactions 2 days, reaction is cooled to room temperature after finishing, and adds 5%NaHCO
3Solution stirs and separates out suspended solids, suction filtration, the dry formula (IA that gets
1One of) target compound.
Step e: with formula (IA
1) compound is dissolved in the dimethyl formamide, when temperature is reduced to 0 ℃, adds halide reagent such as fluorination reagent, slowly rises to room temperature, continue stirring reaction 24 hours, and added the ammonia methanol in water, continued stirring reaction 48 hours, add water and stir, have solid to separate out, be formula (IA) target compound.
When Z=N, the synthesis technique flow process of general formula (IB) compound is:
Positive progressive effect of the present invention is: general formula of the present invention (I) compound has excellent antiviral activity, as hepatitis virus, especially has the activity that suppresses the HCV virus replication.
Compound of the present invention can exist with the form of pharmaceutically acceptable salt.At this, the salt or the zwitterionic form of The compounds of this invention represented in term " pharmaceutically acceptable salt ", its can be water-soluble, oil soluble or be scattered in water or oil in.This salt can prepare in the last purification procedures of compound, also can be individually obtain with suitable acid and suitable nitrogen-atoms prepared in reaction.Representational acid salt comprises: acetate, adipate, alginate, Citrate trianion, aspartate, benzoic acid salt, benzene sulfonate, hydrosulfate, butyric acid salt, camphorate, camphorsulfonic acid, gluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, formate, fumarate, hydrochloride, bromate, iodate, the 2-isethionate, lactic acid salt, maleate, sym-toluenesulfonic acid salt, methylmethanesulfonate salt, naphthalenesulfonate, nicotinate, the 2-naphthalenesulfonate, oxalate, pectate, persulphate, phenpropionate, picrate, pivalate, propionic salt, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphoric acid salt, glutaminate, hydrocarbonate, tosilate and undecane hydrochlorate.The acid that can be used for forming pharmaceutically acceptable additive salt comprises mineral acid: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, and organic acid: oxalic acid, toxilic acid, succsinic acid, citric acid.
Base addition salt can prepare by hydroxy-acid group and suitable alkali such as metallic cation, oxyhydroxide, carbonate, hydrocarbonate or the organic primary amine of ammonium radical ion, secondary amine, reactive tertiary amine in the last purification procedures of compound.The positively charged ion of pharmaceutically acceptable salt comprises: lithium, sodium, potassium, calcium, magnesium, aluminium and nontoxic quaternary ammonium cation such as ammonium, tetramethylammonium, Tetrylammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, diethylamine, ethamine, Tributylamine, pyridine, N, N-xylidene(s), N-methyl piperidine, N-methylmorpholine, dicyclohexylamine, PROCAINE HCL, PHARMA GRADE, dibenzylamine, N, N-dibenzyl phenylethylamine, N, N '-dibenzyl-ethylenediamin.Other representational amine that are used for base addition salt comprise: quadrol, thanomin, diethanolamine, piperidines and piperazine.
Term " pharmaceutical composition " is meant a kind of composition, it comprises: the combination of compound of the present invention and at least a other pharmaceutical carrier, be adjuvant, vehicle such as thinner, sanitas, filler, disintegrating agent, wetting agent, emulsifying agent, suspending agent, sweeting agent, correctives, perfume compound, antibacterial agent, anti-mycotic agent, lubricant, adjustment, specifically depend on administering mode and dosage form.
Embodiment
Synthesizing of embodiment 1 4-(1H-imidazoles-1-yl)-N-(4-octyloxy-3-trifluoromethylbenzene) thiazole-2-amine
At this moment, the raw material HNRAr in the synthesis type (I) is 2-octyloxy-5-5 amido benzotrifluoride, and the synthesis technique flow process of HNRAr is as follows:
Synthesizing of 2-octyloxy-5-nitro-trifluoromethyl toluene (formula a2)
In the there-necked flask that methyl-sulphoxide (50mL) and tetrahydrofuran (THF) (10mL) are housed, add KOH (2.0g, 35.6mmol), while stirring with n-Octanol (6.2g, 47.4mmol) add, at room temperature continue to stir 30 minutes, be cooled to 10 ℃, with 2-chloro-5-nitro-trifluoromethyl toluene (5.4g, 23.7mmol) dropwise add, at ambient temperature, stirring is spent the night, reaction solution is poured in the frozen water, with 50mL ethyl acetate extraction three times, organic layer water and saturated common salt water washing, anhydrous sodium sulfate drying, filter, underpressure distillation is removed ethyl acetate and n-Octanol obtains oily liquids then, and this liquid is obtained 2-octyloxy-5-nitro-trifluoromethyl toluene (7.1g) by silica gel column chromatography (petroleum ether-ethyl acetate) purifying, is product.
1HNMR (CDCl
3): δ ppm:8.51 (bimodal, J=2.6Hz, 1H), 8.40-8.43 (dd peak, J=2.7Hz, J=2.7Hz, 1H), 7.11 is (bimodal, J=9.2Hz, 1H), 4.17-4.20 (three peaks, J=12.6Hz, 2H), and 1.76-1.80 (multiplet, 2H), 1.48 (multiplet, 2H), 1.34 (multiplets, 8H), 0.92 (multiplet, 3H).MS(ESI)：M
++1＝320.3。Molecular formula: C
15H
20NO
3F
3
Synthesizing of 2-octyloxy-5-5 amido benzotrifluoride (formula a3)
With 2-octyloxy-5-nitro-trifluoromethyl toluene (3.0g, 9.4mmol) be dissolved in the 100mL methyl alcohol, add 10% palladium carbon (0.15g), logical hydrogen reaction 2 hours, filter, the solvent underpressure distillation in the filtrate is removed promptly get 2-octyloxy-5-5 amido benzotrifluoride (2.6g).
1HNMR (CDCl
3): δ ppm:6.92 (unimodal, 1H), 6.84-6.86 (bimodal, J=8.8Hz, 1H), 6.78-6.81 (dd peak, J=1.6Hz, J=2.0Hz, 1H), and 3.95-3.98 (triplet, J=12.8Hz, 2H), 3.55 (unimodal, 2H), 1.76-1.81 (multiplet, 2H), 1.46-1.50 (multiplet, 2H), 1.33 (multiplets, 8H), 0.91 (multiplet, 3H).MS(ESI)：M
++1＝290.3。Molecular formula: (C
15H
22NOF
3).
The technical process of 4-(1H-imidazoles-1-yl)-N-(4-octyloxy-3-trifluoromethylbenzene) thiazole-2-amine
1-(4-octyloxy-3-phenylfluoroform) thiocarbamide (formula A
4) synthetic
At thiocyanic acid amine (4.8g, 63.0mmol) acetone (20mL) solution in add Benzoyl chloride (3.4g, 24.2mmol) acetone (20mL) solution, at room temperature stirring reaction is after two hours, add 2-octyloxy-5-5 amido benzotrifluoride (5g, 17.3mmol) acetone (20mL) solution, continue stirring reaction, at room temperature spend the night, reaction is removed acetone after finishing under the condition of underpressure distillation, water is joined in the last residue, with ethyl acetate extraction three times, merge organic layer, with sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, filter, with the ethyl acetate underpressure distillation remove faint yellow solid, in this solid, add tetrahydrofuran (THF) and make its dissolving, add 6% sodium hydroxide (6.8g) aqueous solution subsequently, under 30 ℃ condition, stir and spend the night, reaction finishes the back ethyl acetate extraction, organic layer sodium hydroxide solution and saturated common salt water washing, anhydrous sodium sulfate drying filters, the pressure reducing and steaming solvent gets oily matter, and this oily matter obtains solid 1-(4-octyloxy-3-phenylfluoroform) thiocarbamide (4.6g) of white with ethyl acetate and sherwood oil (1/10) crystallization.
1HNMR (CDCl
3): δ ppm=8.00-8.59 (broad peak, 1H), 7.48 (bimodal, J=2.4Hz, 1H), 7.39-7.42 (the dd peak, J=2.4Hz, J=2.4Hz, 1H), 7.03-7.06 is (bimodal, J=8.8Hz, 1H), 5.52-6.45 (the steamed bun peak, 2H), 4.05-4.08 (triplet, J=12.8Hz, 2H), 1.83 (multiplets, 2H), 1.46 (multiplet, 2H), 1.29-1.34 (multiplet, 8H), 0.89 (triplet, J=13.6Hz, 3H).MS(ESI)：M
++1＝349.4。Molecular formula: (C
15H
23N
2OSF
3).
2-(4-octyloxy-3-5-trifluoromethylaniline) thiazole-4 (5H)-1 (formula A
5) synthetic
With 1-(4-octyloxy-3-phenylfluoroform) thiocarbamide (5g, 14.4mmol) be dissolved in and be warming up to 60 ℃ in the ethanol, this moment is with ethyl bromoacetate (3.6g, 18.7mmol) join in the reaction solution, keep temperature-resistant, continued reacting by heating 2 hours, question response finishes ethanol is boiled off slightly, low temperature crystallization can get yellow crystals 2-(4-octyloxy-3-5-trifluoromethylaniline) thiazole-4 (5H)-1 (4.2g).
1HNMR (CDCl
3): δ ppm=7.48 (bimodal, J=2.0Hz, 1H), 7.38-7.41 (dd peak, J=0.8Hz, J=2.0Hz, 1H), 7.02 is (bimodal, J=8.8Hz, 1H), 4.05 (three peaks, J=6.4Hz, 2H), 3.89 (unimodal, 2H), 1.83 (multiplets, 2H), 1.49 (multiplet, 2H), 1.26-1.35 (multiplet, 8H), 0.90 (triplet, J=13.2Hz, 3H).MS(ESI)：M
++1＝389.5。Molecular formula: (C
18H
23N
2O
2SF
3).
4-chloro-N-(4-octyloxy-3-phenylfluoroform) thiazole-2-amine (formula A
6) synthetic
With 2-(4-octyloxy-3-5-trifluoromethylaniline) thiazole-4 (5H)-1 (2g, 5.1mol) and 6mLPOCl
3Mixture heating up refluxed 1 hour, reaction finishes postcooling to room temperature, with POCl
3Under the condition of underpressure distillation, remove, remaining residue is dissolved in the ethyl acetate, use saturated sodium bicarbonate solution, water and saturated aqueous common salt wash respectively, the organic layer anhydrous sodium sulfate drying filters, and underpressure distillation is removed ethyl acetate and obtained mashed prod, this thick product is obtained light brown solid by silica gel column chromatography (petroleum ether-ethyl acetate) purifying, be target product 4-chloro-N-(4-octyloxy-3-phenylfluoroform) thiazole-2-amine (0.7g).
1HNMR (CDCl
3): δ ppm:8.94 (unimodal, 1H), 7.59 (triplet, J=2.8Hz, 2H), and 7.00-7.03 (bimodal, J=8.4Hz, 1H), 6.30 (unimodal, 1H), 4.07-4.04 (triplet, J=12.8Hz, 2H), and 1.85-1.81 (multiplet, 2H), 1.36 (multiplets, 2H), and 1.27-1.30 (multiplet, 8H), 0.90 (triplet, J=13.6Hz, 3H).MS(ESI)：M
++1＝407.8。Molecular formula: C
18H
22ClF
3N
2OS.
(0.47g 1.16mmol) is dissolved among the 3mLDMF, adds imidazoles (0.39g with 4-chloro-N-(4-octyloxy-3-phenylfluoroform) thiazole-2-amine, 5.78mmol), 80 ℃ of following stirring reactions two days, the some plate detects, reaction is cooled to room temperature after finishing, and adds the NaHCO of 100mL 5%
3Solution stirs, and has a large amount of suspended solidss to separate out, suction filtration, and drying obtains target product (0.51g, yield 100%).
1HNMR (DMSO) (δ, ppm): 10.63-10.65 (broad peak, J=8Hz, 1H), 8.22 (unimodal, 1H), 8.01 (bimodal, J=4Hz, 1H), and 7.81-7.84 (dd, J=12Hz, 1H), 7.71 (triplet J=1.4Hz, 1H), 7.24-7.27 (bimodal, J=12Hz, 1H), 7.07 (triplet, J=4Hz, 1H), 6.95 (unimodal, J=4Hz, 1H), 4.02-4.06 (triplet, J=16Hz, 2H), 1.66-1.73 (multiplet, J=28Hz, 2H), and 1.39-1.44 (multiplet, J=20Hz, 2H), 1.26-1.29 (multiplet, J=12Hz, 8H), 0.84-0.88 (multiplet, J=16Hz, 3H).MS(ESI)：M
++1＝439.1。Molecular formula: C
21H
25F
3N
4OS.
Synthesizing of embodiment 25-fluoro-4-(1H-imidazoles-1-yl)-N-(4-octyloxy-3-trifluoromethylbenzene)-thiazole-2-amine
The technical process of 5-fluoro-4-(1H-imidazoles-1-yl)-N-(4-octyloxy-3-trifluoromethylbenzene)-thiazole-2-amine is as follows:
4-(1H-imidazoles-1-yl)-N-(4-octyloxy-3-trifluoromethylbenzene) thiazole-2-amine (4.38g that embodiment 1 is made, in the 50mL dimethyl formamide that 10mmol) is dissolved in, when temperature is reduced to 0 ℃, add fluorination reagent (1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt) (3.55g 10mmol), slowly rises to room temperature with 2 hours times, stirring reaction 24 hours, accelerate stirring velocity this moment, add ammonia methanol in water (ammonia methyl alcohol 50～100mmol, water 50～100mmol), continued stirring reaction 48 hours, after reaction finishes, add 60mL water, stir, there is solid to separate out, filter, drying is passed through column chromatography purification, obtain white solid and be target product (3.42g, productive rate 75%).MS(ESI)：M
++1＝457.1。Molecular formula: C
21H
24F
4N
4OS.
Claims (9)
1. compound with general formula (I),
Perhaps its pharmaceutically acceptable salt or hydrate, wherein,
Ar is for replacing or unsubstituted aryl or heteroaryl;
Z is selected from N and replacement or unsubstituted C;
R
1And R
2Independently for replacing or the unsubstituted substituting group that is selected from following group :-CH
2R
a,-NH-S (O)
2R
a,-CH
2-NH-S (O)
2R
a,-S (O)
2R
a,-C (O)-NH-R
a,-C (O)-NH-CH
2R
a,-NH-C (O)-R
a,-NH-C (O)-R
b,-C (O) O-R
a,-C (O)-O-R
b,-OR
a,-C (O)-R
a,-C (O)-R
b, hydrogen atom, C
1-C
10The bicyclic heteroaryl of alkyl, phenyl, 5 to 6 yuan of heteroaryls, 5 to 6 yuan of cycloalkyl of benzo or Heterocyclylalkyls and 8 to 10 yuan; Perhaps, R
1And R
2Join together form to replace or unsubstituted contain 0, one or more are selected from N, O, the heteroatomic C of S
3-C
14Single, two or three rings; Wherein, R
aBe selected from randomly replace or unsubstituted following group in substituting group: Heterocyclylalkyl, phenyl and 5 to 6 yuan of heteroaryls; R
bFor replacing or not replacing C
1-C
6Alkyl;
R is selected from hydrogen atom, hydroxyl, amino, C
1-C
5Alkyl, C
1-C
5Alkoxyl group, halo C
1-C
5Alkyl and halo C
1-C
5Alkoxyl group.
2. compound as claimed in claim 1 is characterized in that, Ar is by R
3And R
4The bicyclic heteroaryl of the fluorenyl that replaces, phenyl, naphthyl, 5 to 6 yuan of heteroaryls or 9 to 10 yuan;
R
3One of be selected from following group substituting group: hydrogen atom, halogen, hydroxyl, amino, cyano group, nitro, C
1-C
5Alkyl, C
1-C
5Alkoxyl group, halo C
1-C
5Alkyl, halo C
1-C
5Alkoxyl group, C
1-C
6Alkyl C (O)-, phenyl-C (O)-and 5 to 6 yuan of heteroaryl-C (O)-;
R
4Be selected from (a) group or (b) substituting group one of in the group, wherein (a) group substituting group is: hydrogen atom, halogen, hydroxyl, amino, cyano group, nitro ,-COOH ,-SO
2NH
2, halo C
1-C
2Alkyl and halo C
1-C
2Alkoxyl group; (b) the group substituting group is: C
1-C
10Alkyl, C
2-C
10Thiazolinyl, C
2-C
10Alkynyl, C
2-C
10Alkyloyl, C
2-C
10Carbalkoxy, C
2-C
10Alkoxyl group, (C
1-C
10Alkyl)
1-2Formamido-and-YW;
Y is covalent linkage, C
1-C
10Alkyl, C
2-C
10Thiazolinyl or C
2-C
10Alkynyl wherein, can optionally have 0,1 or 2 O or N on alkyl, alkenyl or alkynyl chain;
W is halogen, C
3-C
7Cycloalkyl, C
3-C
7Cycloalkenyl group, Heterocyclylalkyl, phenyl, naphthyl, indanyl, C
3-C
7Cycloalkyl oxy, (C
3-C
7Cycloalkyl) C
1-C
10Alkoxyl group or 5 to 6 yuan and contain 1～4 the heteroatomic heteroaryl that independently is selected from N, O and S;
Wherein, (b) the group substituting group can be replaced by 0, one or more substituting groups that are selected from following group: halogen, hydroxyl, amino, cyano group, nitro, oxo, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halo C
1-C
2Alkyl and halo C
1-C
2Alkoxyl group;
Perhaps, R
3With with neck nearly carbon atom covalently bound R
4Formation has the fragrance of 1 or 2 ring or the carbocyclic ring system of fractional saturation together, and each ring has 3 to 6 carbon atoms.
3. compound as claimed in claim 2 is characterized in that, Ar is the substituting group that is selected from following group:
4. as each described compound of claim 1～3, it is characterized in that Z is selected from N and by R
ZThe C that replaces, R
ZFor halogen, oxo ,-CONH
2,-C (O) OCH
3,-C (O) CH
3,-NHC (O) OH or amino.
5. as each described compound of claim 1～3, it is characterized in that R
1And R
2For by one or more R
1' replace be independently selected from substituting group in following group :-CH
2R
a,-NH-S (O)
2R
a,-CH
2-NH-S (O)
2R
a,-S (O)
2R
a,-C (O)-NH-R
a,-C (O)-NH-CH
2R
a,-NH-C (O)-R
a,-NH-C (O)-R
b,-C (O) O-R
a,-C (O)-O-R
b,-OR
a,-C (O)-R
a,-C (O)-R
b, C
1-C
10Alkyl, phenyl, 5 to 6 yuan of heteroaryls, 5 to 6 yuan of cycloalkyl of benzo or Heterocyclylalkyl and 8 to 10 yuan of bicyclic heteroaryls; Perhaps, R
1R
2N-is unsubstituted or by one or more R
1' 5 to 6 yuan Heterocyclylalkyl replacing or heteroaryl, bicyclic heterocycle alkyl or bicyclic heteroaryl or aryl or heteroaryl and 5 to 6 yuan of Heterocyclylalkyls of 8 to 10 yuan;
R
1' following for being selected from (c), (d) or (e) substituting group one of in the group:
(c) the group substituting group is: halogen, hydroxyl, oxo, cyano group, amino, nitro ,-C (O) NH
2,-C (O) OH ,-S (O) NH
2, halo C
1-C
2Alkyl and halo C
1-C
2Alkoxyl group;
(d) the group substituting group is: C
1-C
4Alkyl, C
1-C
4Alkoxyl group, C
2-C
4Thiazolinyl, (C
1-C
6)
1-2Alkylamino, (C
1-C
4Alkyl)
1-2Formamido-, (C
1-C
4Alkyl)
1-2Sulfoamido and C
1-C
4Carbalkoxy, (d) each substituting group can be replaced by 0, one or more substituting groups that are selected from following group in the group: oxo, halogen, hydroxyl, cyano group, amino, nitro ,-C (O) NH
2,-C (O) OH ,-S (O) NH
2, C
1-C
4Alkoxyl group, (C
1-C
6)
1-2Alkylamino, (C
1-C
4Alkyl)
1-2Formamido-, (C
1-C
4Alkyl)
1-2Sulfoamido, C
1-C
4Carbalkoxy, halo C
1-C
2Alkyl and halo C
1-C
2Alkoxyl group;
(e) the group substituting group is: C
3-C
7Cycloalkyl, Heterocyclylalkyl, phenyl, (C
3-C
7Cycloalkyl) C
1-C
4Alkyl, (Heterocyclylalkyl) C
1-C
4Alkyl and (phenyl) C
1-C
4Alkyl, (e) each substituting group can be replaced by 0, one or more substituting groups that are selected from following group in the group: oxo, halogen, hydroxyl, cyano group, amino, nitro ,-C (O) NH
2,-C (O) OH ,-S (O) NH
2, halo C
1-C
2Alkyl and halo C
1-C
2Alkoxyl group;
R
aFor replacing or the unsubstituted substituting group that is selected from randomly in following group: Heterocyclylalkyl, phenyl and 5 to 6 yuan of heteroaryls;
R
bFor replacing or unsubstituted C
1-C
6Alkyl.
6. compound as claimed in claim 5 is characterized in that R
aFor by one or more R
a' replace be selected from substituting group in following group randomly: Heterocyclylalkyl, phenyl and 5 to 6 yuan of heteroaryls; R
a' be halogen, hydroxyl, amino, cyano group, C
1-C
4Alkyl or C
1-C
4Alkoxyl group.
7. compound as claimed in claim 5 is characterized in that R
bFor by halogen, hydroxyl ,-C (O) OH, phenyl and/or 4-(NH
2S (O)
2The C that)-phenyl replaces
1-C
6Alkyl.
8. compound as claimed in claim 1 is characterized in that,
R
1R
2N-is the substituting group that is selected from following group:
9. the purposes of the described compound of claim 1 in preparation prophylaxis of viral infections or antiviral drug, the preferred hepatitis virus of described virus, preferred especially hepatitis C virus.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100538278A CN101928283A (en) | 2009-06-25 | 2009-06-25 | Compound with anti-HCV activity and application thereof |
| PCT/CN2010/073819 WO2010148963A1 (en) | 2009-06-25 | 2010-06-11 | Compounds having activity against hepatitis virus and use thereof |
| CN2010800245282A CN102388028B (en) | 2009-06-25 | 2010-06-11 | Compounds having activity against hepatitis virus and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100538278A CN101928283A (en) | 2009-06-25 | 2009-06-25 | Compound with anti-HCV activity and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
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Family
ID=43367760
Family Applications (2)
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|---|---|---|---|
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| AU2005232753A1 (en) * | 2004-04-13 | 2005-10-27 | Astellas Pharma Inc. | Polycylic thiazoles as potassium ion channel modulators |
| CN101123962A (en) * | 2004-12-01 | 2008-02-13 | 凯利普西斯公司 | Inducible nitric oxide synthase dimerization inhibitors |
| KR20080019213A (en) * | 2005-05-09 | 2008-03-03 | 아칠리온 파르마세우티칼스 인코포레이티드 | Thiazole compounds and methods of use |
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