CN1289248A - Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases - Google Patents
Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases Download PDFInfo
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- CN1289248A CN1289248A CN99802500A CN99802500A CN1289248A CN 1289248 A CN1289248 A CN 1289248A CN 99802500 A CN99802500 A CN 99802500A CN 99802500 A CN99802500 A CN 99802500A CN 1289248 A CN1289248 A CN 1289248A
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- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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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- C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
Compounds, compositions and methods are provided for the prophylaxis and treatment of infections caused by viruses of the Pneumovirinae subfamily of Paramyxoviridae and diseases associated with such infections.
Description
Invention field
The present invention relates to prevention and treatment viral infection and with its diseases associated, especially by the viral caused viral infection of the Pneumovirinae of Paramyxo virus and chemical compound, compositions and the method for diseases related.
Background of invention
The Pneumovirinae of Paramyxoviridae is made up of various Pneumovirinaes, and this viroid can be in human body and many animal bodies, as cause serious disease in cattle, goat, sheep, mice and birds.
Human body respiration syncytial virus (RSV), promptly the prototype member of Pneumovirinae group is main department of pediatrics virus respiratory pathogen, can cause pneumonia and bronchiolitis in infant and child.The RSV disease is seasonal, in the U.S.'s this disease that generally begins to happen suddenly in November, proceeds to April subsequently.During this annual epidemic diseases, nearly 250,000 infant infection RSV pneumonia have the patient up to 35% to want hospitalization.According to reports, in the patient that these are in hospital mortality rate up to 5%.In the child who has such as diseases such as precocity, congenital heart disease, broncho-pulmonary dysplasia and various congenital or acquired immune deficiency syndrome (AIDS), the M ﹠ M of serious RSV is the highest.In the adult, RSV often causes upper airway symptoms, but also can cause lower respiratory illness, especially in the middle of the people of old people and immunodeficiency.Mortality rate height after old people and the Infections in immunodeficiency patients.The RSV natural infection can not provide the full guard immunity.Therefore, RSV can cause repeatedly symptomatic infection throughout one's life.
Pneumovirinae in animal and the birds is from antigen, and is aspect the polypeptide composition and the cause of disease, similar to the human virus.
Though people are developing the work of RSV vaccine, up to this point also there is not a kind of safety and effective that is proved to be.The side reaction that the RSV vaccine of the initial formalin deactivation that the development work of vaccine is introduced for the later stage by nineteen sixty always demonstrates is covered.The sickness rate that the child of immunity demonstrates the RSV lower respiratory illness increases, and develops into unusual serious disease, comprises death.
With ribavirin (1-β-D-ribofuranosyl-1H-1; 2; 4-triazole-3-carboxylic acid amides); a kind of unique medicine-anti-viral nucleoside of the treatment RSV disease by food and drug administration (FDA) approval; the chemotherapy of carrying out is considered to only be applicable to some RSV patient (for example, the high-risk patient of severe complication or the serious patient of this infection).But its effect and value are still disputable.Nearest research is pointed out, is that clinical effectiveness or economic benefit all can not obtain proof with this patient of ribavirin therapy.In addition, ribavirin has some toxicity side reaction, and therefore, in order to reduce side reaction as far as possible, this medicine must pass through the inhalation administration with aerocolloidal form in the environment of sealing.
Immunoglobulin (IVIG) preparation has got permission to be used to prevent some RSV disease high-risk patient in the human vein.This medicine requires in suffer from the damaged child of limited vein morbidity and cardiopulmonary merit owing to previous brute force treatment at 2～4 hours angular vein infusion large volume preparations.In addition, venoclysis required during the RSV epidemic season every month to go to hospital one time, and this can place the child the dangerous condition of hospital infection again.
Therefore, need the antiviral agent and the therapeutic agent to rsv infection that can overcome existing pharmaceutical preparation shortcoming.
Summary of the invention
According to an aspect, the invention provides the isomer of the chemical compound of following formula, described chemical compound and the pharmaceutically acceptable salt of described chemical compound:
Wherein Het representative replaces or unsubstituted 5-7 unit heterocycle, contains 1-3 hetero atom that is selected from nitrogen, oxygen or sulfur in the ring, and described heterocyclic substituent group is at least 1 group that is selected from following: hydrogen, alkyl, amino, an alkylamino or dialkylamino;
R
1Representative is selected from the group in following a group: hydrogen, halogen; Perfluoroalkyl; Alkoxyalkyl; Amino; Alkylamino; Dialkylamino; Acylamino-; Alkyl amino alkyl; Do not replace or replace, saturated or undersaturated straight chain-or branched chain alkyl, the substituent group of described alkyl chain is at least 1 hydroxyl; Carboxyl; Replace or unsubstituted phenyl (C
6H
5), the substituent group of described phenyl is at least 1 group that is selected from following a group: hydroxyl, alkoxyl, alkoxyalkyl, halogen, perfluoroalkyl, sulfo-, nitro, carboxyl, carboxyalkyl, alkoxy carbonyl group, alkoxycarbonyl alkyl, carboxylic acid amides, carboxamido alkyl, alkyl, cycloalkyl, alkylthio group, alkyl sulphinyl, alkyl sulphonyl, sulfonamides, amidino groups, cyano group, amino, acylamino-, alkylamino, dialkylamino, alkyl amino alkyl or be selected from the monobasic alkoxyl of substituent group in this group of carboxyl, amino, alkylamino or dialkylamino; Cycloalkyl; Or be selected from heterocyclic radical in following one group: pyridine, thiophene, oxazole, oxadiazole, thiadiazoles, pyrazoles, tetrazolium, furan, pyrroles, isoxazole, imidazoles, triazole and thiazole comprise all position isomers of described heterocyclic radical;
R
2Representative is selected from following one group group: hydrogen, hydroxyl, sulfo-, alkoxyl, carboxyl, carboxyalkyl, amino, alkylamino, dialkylamino, carboxamido, carboxamido alkyl, sulfonamides, acetylamino;
X represent 1 valence link or be selected from following one group divalent linker :-N=CH-,-CH=N-,-(CH
2)
n-NH-,-NH-(CH
2)
n-,-(CH
2)
n-,-CH=CH-or-N=N-, n is the integer of 1-8;
The Z representative is selected from following one group substituent group: hydrogen, formoxyl, hydroxyl or X-Het, wherein the definition of X and Het is the same.
Particularly preferably be the chemical compound shown in the following formula:
Wherein X be selected from-N=C-or-divalent linker of CH=CH-; R is selected from following one group group: hydrogen, hydroxyl, alkoxyl, alkyl, halogen, nitro or be selected from the monobasic alkoxyl of substituent group in carboxyl, an amino alkylamino, dialkylamino and this group of acetylamino; R
2It is hydroxyl; R
3Be to be selected from following one group heterocyclic radical: 1-pyrazolyl, 1-triazolyl (comprise its 1,2,3-, 1,2,4-or 1,3,4-isomer), the amino and the alkyl derivative of 4-triazolyl, 1-tetrazole radical or 2-tetrazole radical (comprising its isomer) and these groups, comprise, but be not limited to 5-amino-1H-tetrazole radical, 3-amino-4H-1,2,4-triazolyl, 5-amino-1H-1,2,4-triazolyl, 5-amino-2H-tetrazole radical and 5-methyl isophthalic acid H-tetrazole radical.
According to a further aspect, the invention provides the new intermediate that a class can be used for preparing antiviral agent as herein described.The general formula of this class intermediate is as follows:
Wherein the Q representative is selected from 5,5-dimethyl-1, the reactive group of 3-diox and formoxyl; R
5It is the group that is selected from hydrogen and hydroxyl; R
6Be the group that is selected from hydroxyl, alkoxyl, aryloxy group and aralkoxy, R
7Be to be selected from following one group group: hydrogen; hydroxyl; alkoxyl; alkoxyalkyl; halogen; perfluoroalkyl; sulfo-; nitro; carboxyl; carboxyalkyl; alkoxy carbonyl group; alkoxycarbonyl alkyl; carboxylic acid amides; the carboxamido alkyl; alkyl; cycloalkyl; alkylthio group; alkyl sulphinyl; alkyl sulphonyl; sulfonamides; amidino groups; cyano group; amino; acylamino-; alkylamino; dialkylamino; alkyl amino alkyl; or quilt is selected from carboxyl; amino; the monobasic alkoxyl of substituent group in this group of alkylamino or dialkylamino.
The present invention also provides the new synthetic method of preparation chemical compound described herein.A kind of method comprise the aldehyde radical of benzaldehyde that 3-halogen replacement-4-alkoxyl is replaced-wherein with the protecting group protection-with the reaction of alkylation alkali metal, exchange to realize halogen-alkali metal; Under the condition of the tritanol. derivant that can generate the dialkoxy-R-replacement that comprises described blocking group, in this reactant mixture, add the benzoic Arrcostab that R-replaces; Tritanol. derivant deprotection and reduction that described dialkoxy-R-is replaced recovering described aldehyde functional group, and partly are converted into the tritan. part with tritanol.; The alkyl that removes in any alkoxy substituent makes it to become hydroxyl substituent; And the heterocycle reactant reaction that described aldehyde functional group and amine are replaced, to generate needed product.R substituent group on the benzoate is selected from following one group of group: hydrogen; hydroxyl; alkoxyl; alkoxyalkyl; halogen; perfluoroalkyl; sulfo-; nitro; carboxyl; carboxyalkyl; alkoxy carbonyl group; alkoxycarbonyl alkyl; carboxylic acid amides; the carboxamido alkyl; alkyl; cycloalkyl; alkylthio group; alkyl sulphinyl; alkyl sulphonyl; sulfonamides; amidino groups; cyano group; amino; acylamino-; alkylamino; dialkylamino; alkyl amino alkyl; or quilt is selected from carboxyl; amino; the monobasic alkoxyl of substituent group in this group of alkylamino or dialkylamino.
The another kind of method for preparing The compounds of this invention comprises makes 4,4 '-dihydroxy-3,3 '-hydroxyl of (4-R-replace phenyl) methylene two benzaldehydes-wherein etherificate-with the heterocycle hydroxyalkyl derivant of the tritan. of the R-replacement of the anionic reactive generation etherificate of the heterocycle reactant of methyl-replacements as intermediate product; Make this intermediate product dehydration then and take off etherificate to generate required product.
According to yet another aspect, the invention provides and contain one or more above-claimed cpds, and with the pharmaceutical composition of pharmaceutically acceptable mounting medium combination.
According to more on the one hand, the invention provides a kind of method of in the live body host, preventing and treating pneumovirus infection and prevention and treatment and pneumovirus infection diseases associated, comprise the chemical compound of the said structure of the live body host drug treatment effective dose that is subjected to pneumovirus infection easily and/or the pharmaceutically acceptable salt of isomer and described chemical compound, or contain their pharmaceutical composition.
Detailed Description Of The Invention
Can prepare chemical compound of the present invention according to one of following illustrated synthetic schemes easily from known initiation material, wherein R and Het's is described as defined above.
Option A
The Alk=alkyl; The Z=halogen is as Br or I; R
a=alkyl; The definition of R and Het is the same.
Synthetic schemes A comprises the protection of the aldehyde part of bromobenzaldehyde, then is that the reaction of halogen-metal exchange and the desired aryl lithium compounds of 2 equivalents and ester group generates triaryl methanol.The reduction of aldehyde and the available formic acid of regenerating reach.(or pyridine hydrochloride removes phenolic group, makes aldehyde radical and suitable heterocyclic amine carry out condensation then and just generated chemical compound of the present invention with Boron tribromide.
Option b
The Alk=alkyl; The definition of R and Het is the same.
Synthetic schemes B comprises that the heterocycle hydroxyalkyl derivant of the tritan. that the R-of the heterocyclic anionic reactive generation of dialdehyde for preparing by the described method of such scheme A and the methyl that is generated by normal-butyl etherificate replaces is as intermediate product.Obtain unsaturated compound after making the dehydration of this intermediate product with mesyl chloride, the reuse Boron tribromide makes it take off etherificate and just obtains required compound.
Here employed term " alkyl " is meant that length is the aliphatic hydrocarbyl of 1-6 carbon atom.Similarly, with combining form use, in order to represent various substituent groups, as alkoxyl (O-alkyl), alkylthio group (S-alkyl), alkylamino (NH-alkyl), alkyl sulphonyl (S (O)
2-alkyl), (term " alkyl " or its any variant form of alkyl-COOH) etc. are meant that also its length is the aliphatic hydrocarbyl of 1-6 carbon atom to carboxyalkyl, and preferably its length is 1-4 carbon atom.
Here the symbol that uses " Het " be meant that nothing on the The compounds of this invention replaces or have the 5-7 unit heterocyclic substituent of replacement, this substituent group contains the hetero atom that 1-3 is selected from nitrogen, oxygen or sulfur, and wherein this heterocyclic substituent group is at least 1 and is selected from following one group group: hydrogen, alkyl, amino, alkylamino or dialkylamino.This heterocyclic exemplary includes, but are not limited to from pyrazoles, triazole, tetrazolium, oxadiazole, thiadiazoles, imidazoles, oxazole, thiazole, isoxazole, pyridine, pyrimidine, triazine, morpholine, piperidines, piperazine, 1,2, deutero-groups such as 4-diaza .
Here employed term " acylamino-" is meant general formula-NR " C (=O) group shown in the R or substituent group, wherein R " represent hydrogen or alkyl with R .
Here employed term " carboxylic acid amides " be meant general formula-C (=O)-definition of NR " group shown in the R or substituent group, wherein R " and R is the same.
Here employed term " sulfonamides " is meant general formula-SO
2NR " R or-NR " SO
2" and the definition of R is the same for group shown in the R or substituent group, wherein R.
Here employed term " alkoxy carbonyl group " be meant general formula-C (=O)-definition of OR " shown in group or substituent group, R wherein " is the same.
The preparation method of the anti-Pneumovirinae chemical compound object lesson in the scope of the invention is exemplified below.
Carried out now showing that the described chemical compound of the application can be used as the in vitro study of the antiviral agent that resists Pneumovirinae.According in the cell culture sample to the determination of activity of RSV antiviral activity.
The all possible isomer of chemical compound described here all within the scope of the invention.The exemplary of this isomer includes, but are not limited to cis and transisomer.
Chemical compound described here, its isomer and pharmaceutically acceptable salt all demonstrate the antiviral activity of antagonism Pneumovirinae, therefore all within the scope of the present invention.
Chemical compound of the present invention can form salt with mineral acid and organic acid, comprises for example hydrochlorate, hydrobromate, mesylate etc., also can form salt with inorganic base, for example sodium salt or potassium salt.
The pharmaceutically acceptable salt of The compounds of this invention prepares according to method well-known to those skilled in the art.
Anti-viral pharmaceutical compositions of the present invention comprises a kind or multiple above-claimed cpd or its precursor as main active and the combination of pharmaceutically acceptable mounting medium, and randomly a kind or multiple additional effective agent.
Said composition can be made into various form of medication, comprises tablet, capsule, pill or dragee, maybe can insert in the proper container, and for example capsule perhaps, can charge in the bottle under the situation of suspension." pharmaceutically acceptable mounting medium " as used herein comprises any and all solvent, diluent or other liquid carrier, dispersion or suspension aids, surfactant, isotonic agent, thickening agent or emulsifying agents, antiseptic, solid binder, lubricant etc., and these all are suitable for desired concrete dosage form.Remington ' sPharmaceutical the Sciences that E.W.Martin showed, the 15th edition (Mack publishing company, Easton, PA, 1975) disclose various carriers and the known technology of preparing thereof that is used for the compounding pharmaceutical compositions.Except any conventional carriers medium incompatible with antiviral compound of the present invention, for example produce any undesirable biological effect or with outside any other interaction between component this point in harmful mode and this pharmaceutical composition, its purposes should belong within the scope of the present invention.
Chemical compound of the present invention, its any precursor and their isomer and pharmaceutically acceptable salt are when being used in combination with the effective agent that replenishes, also can be used for treatment and prevention pneumovirus infection and disease, described additional effective agent can randomly be incorporated in the pharmaceutical composition of the present invention, perhaps also can be to patient's administration in therapeutic process.These medicaments comprise, but be not limited to interferon, ribavirin and immunomodulator, immunoglobulin, antiinflammatory, antibiotic, antiviral agent, anti-infective etc., these medicaments and a kind or multiple combination of compounds of the present invention provide additional or synergistic therapeutic effect.
In pharmaceutical composition of the present invention, effective agent can exist with any treatment effective dose, and this amount is generally compositions, comprise mounting medium and/or additional effective agent (if any words), gross weight at least 0.1%, and generally be no more than 90% (weight).The ratio of effective agent is preferably between the 1-50% of composition weight and does not wait.
Be applicable to that enteral or non-organic or inorganic solid or liquid medicine mounting medium through enteral administration can be used to compositions formulated.Gelatin, lactose, starch, magnesium stearate, Talcum, plant and animal oils and fats, natural gum, poly alkylene glycol or other known pharmaceutical carrier or excipient all are suitable for use as mounting medium.
Chemical compound of the present invention can be used for treating and preventing the pneumovirus infection (and disease) of people and domestic animal, can be used for treating cattle, pig and sheep, or treatment birds such as turkey, or other is to the animal of pneumovirus infection sensitivity.Therefore, as used herein, " patient " speech includes, but are not limited to above-mentioned whole.
Chemical compound described here also can be used for preventing or the cell culture that disappears, tissue culture and organ cultures in pneumovirus infection, and other external application.For example, with chemical compound of the present invention as a supplement thing join in the cell or tissue culture somatomedin and cell or tissue culture composition in produced pneumovirus infection before can preventing by the culture of pneumovirus infection.Above-claimed cpd also can be used to eliminate and infects or polluted the culture of Pneumovirinae or the Pneumovirinae in other material, as long as warp is after the suitable processing time under the treatment conditions of any number that the skilled craftsman stipulates.
Chemical compound of the present invention can adopt any amount and any route of administration that can effectively weaken the Pneumovirinae infectivity to come administration.Here employed term " can effectively weaken the amount of Pneumovirinae infectivity " and be meant not toxigenicity, but the quantity of the antiviral agent of the treatment of viral infections effect that can be enough to provide required.Required definite quantity is different for each treatment target, and this depends on the order of severity of the kind, age of object and general situation, infection, concrete antiviral agent and administering mode etc.
Antiviral compound preferably is mixed with dosage unit form, is convenient to administration and helps the uniformity of dosage.Here used dosage unit form is meant the antiviral agent of the physics concrete unit that is suitable for patient treatment.Each dosage must contain the amount of the active substance that calculates in order to produce desired therapeutic effect, and this amount can be meant active substance itself or with selected pharmaceutical carrier medium.Generally speaking, antiviral compound of the present invention will be to contain the dosage unit administration of the 0.1 μ g～about 50mg antiviral agent of having an appointment, and preferred value is about 0.001mg～about 25mg.
Chemical compound of the present invention comprises its isomer and pharmaceutically acceptable salt, can as the prodrug forms administration, can derive active agents from precursor with itself or with its precursor.Prodrug is a kind of derivant of chemical compound described here, and the transformation by chemical process in the body or metabolic process can obtain its pharmacological action.The prodrug of The compounds of this invention can comprise, just is not limited to one, two or three esters of simple or functionalized aliphatic carboxylic acid; Esters (the R of amino methyl
a-(O-CO-NR
bR
c)
n); Amino acid whose esters (R
a-(O-CO-CH (NH
2) R
b)
n); There is not the esters (R that replaces or the aromatic acid of replacement is arranged
a-(O-CO-aryl)
n), wherein aromatic ring can have hydroxyl, carboxyl, low alkyl group, alkylthio group, alkyl sulphinyl, alkyl sulphonyl, phosphoric acid, amino, alkyl amido and halogen group to replace; Deutero-phosphate ester; (acyloxy) methyl or acyloxy (ethyl) ether (R
a-(O-CH
2-O-CO-R
b)
nOr R
a-(O-CH (CH
3)-O-CO-R
b)
n); (alkyl oxy carbonyl oxygen) methyl or (alkyl oxy carbonyl oxygen) ethylether (R
a-(O-CH
2-O-CO-O-R
b)
n); With O-glucoside, wherein R
aBe the residue of The compounds of this invention, R
bAnd R
cBe aliphatic group (C
1-C
10), and n=1-3.This class prodrug can prepare by the method for knowing in pharmaceutical chemistry and the medicine formulation science, and belongs in the scope of the present invention.
Chemical compound of the present invention can be by oral, non-through enteral administration, for example by method administrations such as intramuscular injection, peritoneal injection, venoclysises, perhaps pass through inhalation, for example by administrations such as aerosol, solution or dry powder forms, perhaps, depend on the character and the order of severity of the infection that will treat by the intubation administration.Chemical compound of the present invention can by oral, non-through intestinal or by inhalation or intubation with about 10
-6The dosage level administration of mg～about 1000mg/kg, every day 1 time or several times is to obtain desired therapeutic effect.
Typically administration in day 1-4 time of chemical compound of the present invention is to provide above-mentioned daily dose.But the definite administering mode of chemical compound described here and compositions need depend on that each is treated host's needs, treatment type of being implemented and the doctor in charge, veterinary or medical expert's judgement.
The inhibitory action that the used pair cell culture Pneumovirinae that chemical compound produced duplicates from the inventive method, unforeseeable is that this compounds not only can be used for treating pneumovirus infection, but also can be used for the prevention of Pneumovirinae.No matter be used for the treatment of or the prevention pneumovirus infection, its dosage is all basic identical.
The following examples are used to further describe the present invention.These embodiment have proposed present plan and have implemented optimal way of the present invention, are to be used for explanation rather than to limit of the present invention.
Embodiment 1-14 has illustrated the chemical synthesis process of representational chemical compound of the present invention.
Embodiment 1
5,5 '-two (1-(((5-amino-1H-tetrazole radical) imino group) methyl))-2,2 ', the 4 " preparations of methine trisphenol
A.2-(3-bromo-4-methoxyphenyl)-5,5-dimethyl-1,3-diox
Will by 3-bromo-4-methoxybenzaldehyde (74.65g, 0.347mol), neopentyl glycol (43.35g, 0.416mol), to toluene sulphur pyridiniujm (0.87g, 0.035mol) and reflux azeotropic water removing 6 hours of the solution formed of benzene (1.8 liters).Reactant mixture cooling back dilute with water.The water ethyl acetate extraction.The organic facies that merges salt water washing, drying (Na
2SO
4), add active carbon, pass through Florisil
TMShort column filters and vacuum concentration.Obtain the pink solid ketal of 102.8g (98%).
B.5,5 '-two (5,5-dimethyl-1,3-diox-2-yl)-2,2 ', 4 " trimethoxy triphenylcarbinols
Top step a is obtained the De dioxane derivatives, and (150.6g, 0.500mol) solution in anhydrous THF (2.0 liters) is cooled to-78 ℃.With the speed adding n-BuLi (50ml 10.0 M hexane solutions) of syringe pump with about 1.0ml/ minute.After 15 minutes, drip 4-methoxyl methyl benzoate (33.24g, 0.200mol) solution in THF (350ml).This mixture stirred 15 minutes at-78 ℃, stirred 2.5 hours at 0 ℃, used 10% NH then
4Cl (1 liter) makes reaction terminating.Add t-butyl methyl ether (1 liter), and each layer separated.Water extracts (2 times, 1 liter) with t-butyl methyl ether.The organic facies that merges salt water washing, drying (MgSO
4), pass through Florisil
TMFilter and vacuum concentration.The yellow oil that obtains is dissolved in the methanol (1 liter), adds the net product crystalline seed, and is cooled to 0 ℃.Isolate formed white solid, wash, behind vacuum drying, obtain required product 102.8g (88.8%) with cold methanol.
4 c.4, '-dimethoxy-3,3 '-(4-methoxyphenyl) methylene two benzaldehydes
(15.9g 0.0275mol) is dissolved in the formic acid (137ml) the triaryl carbinol derivatives for preparing by the described method of top step b.This dense white resin color solution is cooled to room temperature then 100 ℃ of heating 13 hours, and concentrates under vacuum.The gained white solid suspends in water, and uses saturated NaHCO
3Neutralization, filtration, water and hexane wash (removing the neopentyl glycol dicarboxylic acid esters) obtain the almost pure product of 10.8g (～100%) behind vacuum drying, be dim shallow blue powder.
4 d.4, '-dihydroxy-3,3 '-(4-hydroxy phenyl) methylene two benzaldehydes
Boron tribromide solution (80ml, 1M is in dichloromethane) is added drop-wise to the trimethyl ether that is generated by above-mentioned deketalization, and (5.23g is 0.0133mol) in the solution in anhydrous methylene chloride.In the dropping process, observe exothermic medium to～35 ℃.At room temperature after 18 hours, this reactant mixture is poured on the trash ice (500g), and at room temperature stirred 1 hour.Gained gray solid thing is extracted in the ethyl acetate.This ethyl acetate solution 10%Na
2CO
3Extract 3 times.The water extract that merges carries out acidify with 6N HCl then carefully with charcoal treatment, by diatomite filtration.Isolate the pale precipitation thing, wash with water, behind vacuum drying, be dissolved among the THF (45ml),, pass through Florisil with t-butyl methyl ether (45ml) dilution
TMFilter, with 1: 1 eluting of THF/t-BME.Filtrate obtains the pure dialdehyde of 3.85g (85%) after concentrating, and wherein contains the small amount of residual solvent.
E. with 1, the condensation of 5-diaminourea tetrazolium
Contain the dialdehyde (3.00g that obtains from above-mentioned demethylating reaction, 8.61mmol), anhydrous N, dinethylformamide (120ml), 1,5-diaminourea tetrazolium (2.58g, 25.8mmol) and p-methyl benzenesulfonic acid (0.33g, solution 1.7mmol) stirred 6 hours at 60 ℃.Reactant mixture is cooled to room temperature, water (400ml) dilution then.Isolate formed pale precipitation thing, wash with water, be dissolved in the oxolane (150ml), use charcoal treatment, obtain the 4.46g title compound after reaching vacuum drying after filtration, be pale yellow powder.
Embodiment 2
5,5 '-two (1-(((5-amino-1H-tetrazole radical) imino group) methyl))-4 " methoxyphenyl-2,2 '-preparation of benzal bis-phenol
A.3-bromo-4-hydroxy benzaldehyde
25.1g (117mmol) 3-bromo-4-methoxybenzaldehyde and 54.47g (471mmol) pyridine hydrochloride is heated to 100 ℃ under nitrogen protection, keeps 2 hours.Mixture dilutes with 1 premium on currency and 500ml ethyl acetate after being cooled to room temperature.Collected organic layer, water layer ethyl acetate extraction 3 times, each 500ml carries out drying after the organic layer of merging washes with water.Obtain 22g orange solids thing except that after desolvating.
B.4-phenyl methoxyl group-3-bromobenzaldehyde
At room temperature add potassium carbonate and 17.0ml (143mmol) benzyl bromide a-bromotoluene that 24.3g (161mmol) pulverizes in the solution of 22g (109mmol) 3-bromo-4-hydroxy benzaldehyde in 600ml acetone under nitrogen protection, mixture is reflux 2 hours under agitation.The water cessation reaction is concentrated into half volume under vacuum, 200ml is used in mixture ethyl acetate extraction 3 times at every turn.The organic layer that merges is concentrated into dried.The residual solids thing is dissolved in the 500ml acetone again, and passes through siliceous earth column.In this acetone soln, add water.Collect isolated yellow solid, obtain the 24.5g material after drying.
C.2-(3-bromo-4-phenyl methoxyphenyl)-5,5-dimethyl-1,3-diox
24.5g (84.2mmol) benzaldehyde that has just obtained from preceding step, 12.3g (112mmol) neopentyl alcohol and the vlil of 220mg p-methyl benzenesulfonic acid 350ml benzene are 5 hours.Collect the water that produces in the course of reaction with Dean-Stark trap.With 1ml triethylamine cessation reaction, at room temperature stirred then 12 hours.Mixture is poured in the 300ml water collected organic layer.100ml is used in water layer ethyl acetate extraction 3 times at every turn.With the organic layer drying that merges, obtain yellow solid except that after desolvating, with obtaining 19.2g orange solids thing behind the ethyl alcohol recrystallization.
5 d.5, '-two (5,5-dimethyl-1,3-diox-2-yl)-4 " methoxyl group-2,2 '-diphenyl methoxy base tritanol.
The material that has just obtained from preceding step toward 1.9g (5.04mmol) under nitrogen protection is cooled to the hexane solution that drips 2.3ml 2.5M n-BuLi in the solution-100 ℃ the distillatory oxolane at 15ml.After dropwising, add 4-methoxybenzoic acid ethyl ester (2.5mmol) solution, this solution stirred 1.5 hours at-78 ℃, 0 ℃ of restir 12 hours, and water cessation reaction then.Under vacuum, be concentrated into half volume after being warmed to room temperature, use 25ml water and 25ml ethyl acetate then mixture diluted.Isolate each layer, 25ml is used in water layer ethyl acetate extraction 3 times at every turn.Organic layer drying with merging is concentrated into dried.The residual solids thing is refining with silica gel column chromatography, and the hexane/ethyl acetate eluting with 80: 20 obtains the 60mg material.
4 e.4, '-dihydroxy-3,3 '-(4-methoxyphenyl) methylene two benzaldehydes
The intermediate 50.4mg (0.069mmol) that just obtains from preceding step is dissolved in the 3ml formic acid, and gained solution to room temperature, adds 3ml water at 4 hours postcooling of 100 ℃ of heating then, the white suspension body occurs.Mixture at room temperature stirs and spends the night.Allow this mixture between water and ethyl acetate, distribute, drying and remove ethyl acetate after the gained residual solids refining with silica gel column chromatography, the hexane/ethyl acetate eluting with 40: 60 obtains the white solid thing.
F. with 1, the condensation of 5-diaminourea tetrazolium
Firm dialdehyde 11.6mg (0.032mmol), the anhydrous N that obtains from above-mentioned reaction, dinethylformamide, 9.2mg (0.0999mmol) 1, the p-methyl benzenesulfonic acid solution of 5-diaminourea tetrazolium and 0.25ml 0.025M is heated to 60 ℃, keeps 17 hours.The development of residue water obtains the beige solid thing remove solvent under vacuum after, will obtain the 10mg title compound after its collection, the drying.
In addition, replace 1 with other various heterocycle reactants, 5-diaminourea tetrazolium can be made has various heterocyclic radical (R
3) the chemical compound of last facial II, as described in following embodiment 3-6.
Embodiment 3
5,5 '-two (1-(((5-amino-1H-1,2,4-triazolyl) imino group) methyl))-2,2 ', the 4 " preparations of methine trisphenol
This title compound synthesizes according to embodiment 1 described basic skills basically, still, with 2, the 3-diaminostilbene, 2, the 4-triazole replaces 1,5-diaminourea tetrazolium.
Embodiment 4
5,5 '-two (4-(((3-amino-4H-1,2,4-triazolyl) imino group) methyl))-2,2 ', the 4 " preparations of methine trisphenol
This title compound prepares according to embodiment 1 described basic skills basically, still, with 3, the 4-diaminostilbene, 2, the 4-triazole replaces 1,5-diaminourea tetrazolium.
Embodiment 5
5,5 '-two (2-(((5-amino-2H-tetrazole radical) imino group) methyl))-2,2 ', the 4 " preparations of methine trisphenol
This title compound prepares according to the synthetic method that embodiment 1 proposes basically, and still, with 2,5-diaminourea tetrazolium replaces 1 among the embodiment 1,5-diaminourea tetrazolium.
Embodiment 6
5,5 '-two (1-(((5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,2 ', the 4 " preparations of methine trisphenol
This title compound synthesizes according to embodiment 1 described basic skills basically, still, replaces 1 with 1-amino-5-methyl tetrazolium, 5-diaminourea tetrazolium.
As described in following embodiment, R among the above-mentioned formula I
1The chemical compound that is not hydroxyphenyl can prepare by the 4-methoxyl methyl benzoate among the step b in the reaction sequence of embodiment 1 above replacing with suitable ester.
Embodiment 7
5,5 '-two (1-(((5-amino-1H-tetrazole radical) imino group) methyl))-2,2 '-preparation of benzal bis-phenol
This title compound synthesizes according to embodiment 1 described basic skills basically, still, and with 4,4 '-dihydroxy-3,3 '-benzal two benzaldehydes replace 4,4 '-dihydroxy-3,3 '-(4-hydroxy phenyl) methylene two benzaldehydes.This intermediate is by replacing the 4-methoxyl methyl benzoate among the foregoing description 1 step b to make with methyl benzoic acid ester.
Other example of ester that can be used to prepare the replacement of some other chemical compound with said structure formula I comprises the ester of the carboxylic acid of benzoate that alkoxyl, halogen, perfluoroalkyl, alkoxy carbonyl group, alkane aminocarbonyl, alkylthio group, alkyl sulphinyl, alkyl sulphonyl, alkyl, alkoxyalkyl replace and pyridine, thiophene, imidazoles, furan, pyrroles, oxazole, triazole, oxadiazole, thiadiazoles, pyrazoles, tetrazolium, isoxazole, thiazole etc.
Embodiment 8
5,5 '-two (1-(((5-amino-1H-tetrazole radical) imino group) methyl))-2,2 '-preparation of methylene bis-phenol
4 a.4, '-dihydroxy-3,3 '-methylene two benzaldehydes
At-78 ℃ of under agitation past 5.0g (21.9mmol) 2 under nitrogen protection; 2 '-drip 19.89g (87.6mmol) 2 in the solution of di-2-ethylhexylphosphine oxide (4-methylphenol) in 100ml methanol; 3-two chloro-5, the solution of 6-dicyano benzoquinone in 100ml methanol.After 2 hours, this solution with water dilution was stirred 30 minutes.This mixture is with 2 parts of 100ml ethyl acetate extractions.The organic layer that merges washs with saturated nacl aqueous solution, uses dried over mgso then.Mixture is filtered, and filtrate is concentrated into dried, obtains the brown solid thing.This material is dissolved in the ethyl acetate, by containing Florisil
TMPillar, pillar reuse ethyl acetate washing.Collect each fraction, obtain the 22g yellow solid after removing solvent.
B. with 1, the condensation of 5-diaminourea tetrazolium
This title compound makes according to the method for the foregoing description 1 step e.
Embodiment 9
5,5 '-two (1-(2-(5-(1-methyl isophthalic acid H-tetrazole radical)) ethylidine))-2,2 ', the 4 " preparations of methine trisphenol
A. α, α '-two (5-(1-methyl isophthalic acid H-tetrazolium) methyl)-4,4 '-dimethoxy-3,3 '-(4-methoxyphenyl) methylene benzhydrol
With 5 fens clock times toward 294g (3.0mmol) 1, the butane solution that is cooled in-78 ℃ solution drip 1.8ml 1.7M tert-butyl lithium of 5-dimethyl-1H-tetrazolium in new distillatory oxolane.With this solution stirring 50 minutes, then with 5 fens clock times add in this yellow suspension 390mg (1.0mmol) 4,4 '-dimethoxy-3,3 '-solution of (4-methoxyphenyl) methylene two benzaldehydes in the 15ml anhydrous tetrahydro furan.In reactant mixture, add 10ml 10% ammonium chloride solution.Mixture is warmed to room temperature, is allowed to condition between water (25ml) and the ethyl acetate (25ml) and distributes.Collect water layer, wash with saturated nacl aqueous solution with the organic layer after 25ml ethyl acetate extraction, the merging, dry then.Obtain 346mg faint yellow solid thing after removing solvent.
B.5,5 '-two (1-(2-(5-(1-methyl isophthalic acid H-tetrazole radical)) ethylidine))-2,2 ', 4 " trimethoxy tritan .s
Material, 0.28ml triethylamine, the solution of 12mg (0.1mmol) 4-dimethylaminopyridine (DMAP) the 5ml anhydrous methylene chloride that 346mg (0.592mmol) is obtained from top step a place ice bath to cool off.In this solution, add 0.15ml (2.0mmol) mesyl chloride, this solution was stirred in ice bath 2 hours, allow it slowly be warmed to room temperature then, placed 16 hours.In this solution, add the 10ml ethyl acetate,, use dried over mgso then with 2 parts of 10ml water, 1N hydrochloric acid and saturated nacl aqueous solution washing.Obtain the 348mg solids after removing solvent, it is dissolved in the 5ml oxolane.In this solution, add 90mg 1,8-diazabicyclo (5.4.0)-hendecene-7.Grease occurs, this mixture was stirred 16 hours.This mixture is with the dilution of 15ml ethyl acetate, then with the extraction of 15ml water.Collected organic layer washes after drying with water.Obtain the required product of 348g after removing solvent.
C. use the Boron tribromide demethylation
The material of step b preparation is dissolved in the dichloromethane solution that adds 1.2ml 1.0M Boron tribromide in 0 ℃ the solution that is cooled in the 1ml anhydrous methylene chloride above 110mg (0.2mmol).This mixture was stirred 2 hours, collect formed yellow solid, wash with water, be suspended in then in the 15ml water.In this suspension, add 5% sodium hydroxide, till obtaining solution.This solution charcoal treatment, the gained suspension filters by Celite 503, and filtrate is used the 1N hcl acidifying.Filter and collect formed white solid thing, wash with water, obtain the 73mg product after the drying.
Embodiment 10
5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-propyl group phenyl)-2,2 '-preparation of benzal bis-phenol
5 a.5, '-two (5,5-dimethyl-1,3-diox-2-yl)-2.2 '-dimethoxy-4 ' " propyl group tritanol.
At-78 ℃ of past 15.0g (49.8mmol) 2-(3-bromo-4-methoxyphenyl)-5,5-dimethyl-1 drips the 24ml2.5M n-BuLi in the solution of 3-diox in the anhydrous THF of 120ml.Drip the solution of 3.82g (59.7mmol) 4-propylbenzoic acid ethyl ester in 30ml THF after dropwising again, dropwise the relief mixture and be warmed to room temperature, stirred 12 hours.Add the 100ml saturated ammonium chloride, then add 100ml isobutyl group methyl ether.Isolate organic layer, wash with water, dry then, obtain the 6.41g crude product after removing solvent.It by silicagel column, with the mixed liquor eluting of 50% ethyl acetate/50% hexane, is obtained the 4.92g product after removing solvent.
4 b.4, '-dimethoxy-3,3 '-(4-propyl group phenyl) methylene two benzaldehydes
With the vlil of material in 30ml formic acid of step a preparation above the 3.7g (7.28mmol) 4 hours.Add water (100ml) after the cooling, the gained mixture extracts with 2 parts of 100ml methyl tertiary butyl ether(MTBE)s.Organic extract after the merging washes with water, dry also removing desolvated.Residual solids is by silicagel column, with the mixed liquor eluting of 50% ethyl acetate/50% hexane, obtains the required solid of 1.98g after removing solvent.
4 c.4, '-dihydroxy-3,3 '-(4-propyl group phenyl) methylene two benzaldehydes
At room temperature used 5 fens to add 10.9ml (10.9mmol) Boron tribromide in the clock time solution of methyl ether in the 15ml dichloromethane that step b obtains above 1.1g (2.73mmol), at room temperature stirred then 12 hours.Reactant mixture is poured in the frozen water, isolated organic layer, and be dried.Obtain the green brown solid thing of 750mg after removing solvent.
D. with 1-amino-5-methyl tetrazolium condensation
This reaction is undertaken by the same manner noted earlier.
Embodiment 11
5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4 '-propoxyl group phenyl)-2,2 '-preparation of benzal bis-phenol
A.4,4 '-two allyloxys-3,3 '-(4-propoxyl group phenyl) methylene two benzaldehydes
Toward 5.0g (11.8mmol) 4,4 '-two allyloxys-3,3 '-add 2.3ml (23.6mmol) n-propyl iodide in (4-hydroxy phenyl) methylene two benzaldehydes and the solution of 3.26g (23.6mmol) potassium carbonate in the 40ml N-Methyl pyrrolidone.This mixture is warmed to 90 ℃, kept 3 hours, and then add the 5ml n-propyl iodide.This reactant mixture reheat 12 hours is then with the dilution of 100ml water, with 50ml t-butyl methyl ether extraction 3 times.Organic extract after the merging washes with water, obtains the 6.86g crude product after the drying, it is passed through silicagel column, with the mixed liquor eluting of 50% ethyl acetate/50% hexane.Obtain the 4.43g yellow solid after removing solvent.
4 b.4, '-dihydroxy-3,3 '-(4-propoxyl group phenyl) methylene two benzaldehydes
230mg (0.89mmol) ruthenium trichloride is joined in the solution that is refluxing of ether in 120ml ethanol of the dialkylene protection that step a prepares above the 4.12g (8.95mmol).Add the 100mg ruthenium trichloride after 90 minutes again.Remove after 6 hours and desolvate, residue is dissolved in the ethyl acetate, by silicagel column, with the mixed liquor eluting of 60% ethyl acetate/40% hexane.Obtain the 2.95g brown solid after removing solvent, with its dissolving and once more by silicagel column, obtain the 1.73g product again.
C. with 1-amino-5-methylene tetrazolium condensation
This reaction is undertaken by front embodiment 6 described methods.
Embodiment 12
5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-fluorophenyls)-2,2 '-preparation of benzal bis-phenol
A.5,5-pair (5,5 '-dimethyl-1,3-diox-3-yl)-2,2 '-dimethoxy-4 ' " fluorine triphenylbenzene methanol
This reaction is by method noted earlier 2-(3-bromo-4-methoxyphenyl)-5,5 '-dimethyl-1, and 3-diox and 4-fluorophenyl carbamate carry out.
4 b.4, '-dihydroxy-3,3 '-(4-fluorophenyl) methylene two benzaldehydes
This chemical compound removes methyl with Boron tribromide subsequently by the chemical compound and the formic acid preparation of method noted earlier from top step a preparation.
C. with 1-amino-5-methyl tetrazolium condensation
This reaction is undertaken by method noted earlier.
Embodiment 13
5,5 '-two (1-(2-(4-methylthiazol base) ethylidine))-2,2 ', the 4 " preparations of methine trisphenol
4 a.4, '-benzyloxy-3,3 '-(4-benzyloxy phenyl) methylene two benzaldehydes
Add 7.95g (5.76mmol) potassium carbonate and 4.09g (23.9mmol) benzyl bromide a-bromotoluene in past 2.0g (5.74mmol) 4,4 '-dihydroxy-3, the 3 '-solution of (4-hydroxy phenyl) methylene two benzaldehydes in 57ml DMF.Mixture at room temperature stirred 12 hours, and reflux is 2 hours then.Ethyl acetate extraction is used in reactant mixture water (100ml) dilution then.With organic extract merge, dry and remove solvent.Residue is refining with the HPLC method, and the ethyl acetate/hexane eluting with 60/40 obtains the 3.25g product.
B. α, α '-two (2-(4-methylthiazol base) methyl)-4,4 '-benzyloxy-3,3 '-(4-benzyloxy phenyl) methylene benzhydrol
With 2.4ml (21.3mmol) 2, the solution of 4-dimethylthiazole in the anhydrous THF of 48ml is cooled to-78 ℃, drips the hexane solution of 11.64ml 2.5M n-BuLi then in this solution.Stir after 1 hour, drip the solution of aldehyde in 20ml THF of step a preparation above the 6.0g (9.7mmol).With reactant mixture restir 2 hours, allow it go up, and then stirred 12 hours to room temperature.Mixture carries out vacuum concentration to remove THF with the dilution of 60ml saturated ammonium chloride solution with mixture.Residue is with ethyl acetate extraction 3 times, with the organic layer drying after merging, is concentrated into and obtains the 8.72g crude product after doing, and refining with the HPLC method, the hexane/ethyl acetate eluting with 70/30 obtains the 2.49g product.
C.5,5 '-two (1-(2-(2-(4-methylthiazol base)) ethylidine))-2,2 ', 4 " three benzyloxy tritan .s
500mg (0.592mmol) is made the vlil of alcohol the 16ml acetic anhydride 5 hours from top step b.After the cooling, ethyl acetate extraction 3 times are used in this solution with water dilution.Extract after the merging washes with water, drying, and removes solvent.Crude product is refining with the HPLC method, with 70/30 hexane/ethyl acetate eluting, obtains the 390mg product.
D.5,5 '-two (1-(2-(4-methylthiazol base) ethylidine))-2,2 ', 4 " methine trisphenols
The vlil of material in 46ml formic acid that step c above the 570mg (0.705mmol) is made 12 hours.Cooling back dilute with water is used ethyl acetate extraction 3 times.Organic extract after the merging washes with water, drying, and solvent evaporation is to doing.Crude product carries out recrystallizing and refining with dichloromethane.
Embodiment 14
5,5 '-two (1-(2-(5-(3-methyl-isoxazole base) ethylidine))-phenyl-2,2 '-preparation of benzal bis-phenol
A. α, α '-two (5-(3-methyl-isoxazole base) methyl)-4,4 '-dimethoxy-3,3 '-(phenyl) methylene two benzaldehydes
With 2.9ml (3.0mmol) 3, the solution of 5-dimethyl isoxazole in the anhydrous THF of 150ml is cooled to-80 ℃.The hexane solution that adds 12ml 2.5M n-BuLi in this solution.Add the back with time of 1 hour add 3.6g (1.0mmol) 4,4 '-dimethoxy-3,3 '-(phenyl) methylene two benzaldehydes, add and add saturated ammonium chloride solution afterwards.Allow mixture between water and methyl tertiary butyl ether(MTBE), distribute.Collected organic layer, drying and remove solvent after obtain the 5.59g product.
B. this reaction is undertaken by the described identical universal method of embodiment 9 step b.
C. demethylation
The chemical compound that step b above the 260mg (0.5mmol) is obtained and the mixture heated to 220 of 3.5g pyridine hydrochloride ℃ kept 6 hours.Water is isolated solids with this mixture diluted then.This solids is dissolved in the ethyl acetate, the extraction of this solution with water, uses charcoal treatment, after filtration, obtain 128mg purpose product after removing solvent and drying.
Having active other chemical compound of the present invention of anti-Pneumovirinae can be according to above-mentioned various synthetic route preparation.Other example includes, but are not limited to:
5,5 '-two (2-(2-(5-methyl-2H-tetrazole radical) ethyls))-2,2 ', 4 " methine trisphenols;
5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,2 ', 4 " methine trisphenols;
5-(((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,2 ', 4 " methine trisphenols;
5-(((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,4 ', 4 " methine trisphenols;
3-(5-(((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,4 '-dihydroxy diphenyl methylene)-the 4-hydroxy benzaldehyde;
5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-((2-lignocaine) ethyoxyl) phenyl)-2,2 '-the benzal bis-phenol;
4-(5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,2 '-dihydroxy diphenyl methylene) phenoxyacetic acid;
5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-pyridine radicals)-2,2 '-the benzal bis-phenol;
5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-nitrobenzophenones)-2,2 '-the benzal bis-phenol;
5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-nitrobenzophenones)-2,2 '-the benzal bis-phenol;
5,5 '-two (1-(2-(2-(1-methylimidazolyl) ethylidine))-2,2 ', 4 " methine trisphenols; With
5,5 '-two (1-(((5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-phenyl-2,2 '-the benzal bis-phenol.
Illustrative example according to the preparation method of prodrug of the present invention is described in down.
Embodiment 15
The preparation of prodrug
A) 255mg (0.5mmol) at room temperature places by the solution of chemical compound in 2.5ml anhydrous pyridine and 0.243ml acetic anhydride of top embodiment 1 described method preparation and spends the night.In residue, add 5ml water after removing solvent, add acetic acid and make this mixture show acid slightly.Collect solids, first water, hexane wash is used in the back, obtains the required triacetate prodrug of 240mg after drying.
B) made 220mg triacetate derivant from 200mg according to the chemical compound that top embodiment 6 described methods prepare after the same method basically.
Chemical compound used in embodiment 16 explanation the inventive method is for the effect that suppresses the virus replication of RSV in the cell culture.
Embodiment 16
Pneumovirinae duplicates the cell culture test of inhibition
Many viruses duplicate can be in laboratory in various cell or tissue culture systems qualitative assessment.It is can obtain with utilizable that this in vitro cultural method of the quantitative assay that is used for the Pneumovirinae breeding and duplicates is learned for the people that are proficient in present technique.Following method is used for the external quantitative assay that RSV duplicates.
Adopt method described in the present embodiment, assessed the ability of virus replication in the The compounds of this invention inhibition cell culture.Join by chemical compound and to measure the dose response effect of chemical compound in the culture medium virus replication with various concentration.To duplicate effective quantitative assay of inhibition be that the amount of suppression of virus replication in the cell culture is 50% o'clock compound concentrations (50% inhibition concentration, IC of viewed amount of suppression when not having chemical compound to RSV in this test
50).Under the situation of RSV, IC
50Value defined is avoided the compound concentration of viral-induced cytopathic effect (syncytium formation) for protecting 50% cell monolayer.
Antiviral compound of the present invention screens on the HEp2 cell of cultivating with regard to regard to the antiviral activity of RSV (bacterial strain Long).Inoculated on standard 96 well culture plates at 200 μ L and replenished 4 * 10 among the MinimalEssential Medium (EMEM) that contains Earles salt of 10% hyclone (FBS)
4The HEp2 cell.After 24～30 hours, this cell infects with the diluent of the RSV that contains 5%FBS in Medium 199 (GIBCO/BRL), and this diluent can make cell monolayer destroy more than 85% in 60 hours through the titration proof.37 ℃ through after 1 hour, chemical compound is joined in each hole of culture plate, as a series of 10 double diluents of chemical compound, the concentration of final DMSO is 0.5%.Virus control hole (VC, no test compound) and cell culture control wells (CC, virus-free, no test compound) be also included within on each plate.Place 37 ℃ of humid air that contain 5% carbon dioxide to cultivate these plates.Add the aqueous solution of 100 μ L, 5% glutaraldehyde after 60 hours in each hole, cultivated 1 hour in room temperature in each hole.Remove fixative, cell was dyeed 15-30 minute with 0.1% Gentian Violet aqueous solution.After culture plate rinsing and drying, measure the optical density (OD in each hole at the 570nm place
570).
IC for the determination test chemical compound
50Value will be from foraminous OD on a certain plate
570Deduct the OD in the virus control hole (VC) on this plate in the reading
570The meansigma methods of reading.Calculate IC according to following formula then
50Value:
IC
50Y represents the average OD of cell control well (CC) in=[(Y-B)/(A-B)] x (H-L)+L formula
570/ 2nd of a reading, B representative is the most approaching and be lower than the average OD in the diluted chemical compound liquid hole of Y
570Reading; A representative is the most approaching and be higher than the average OD in the diluted chemical compound liquid hole of Y
570Reading; L representative compound concentration when B; The compound concentration of H representative when A.
Similarly test comprise subclass A and subclass B virus, and other Pneumovirinae is useful for the various bacterium pearls of human RSV.
The representational chemical compound of some that use in the inventive method the results are shown in table 1 to the inhibiting cell culture test that several Pneumovirinaes duplicate.
Table 1
1Embodiment RSV-A RSV-B BRSV ORSV GRSV
1 0．001 0．008 0．003 0．002 0．001
2 0.001 0.008 0.001 survey survey
3 0.050 0.46 0.010 0.17 do not survey
4 0.110 0.15 0.270 survey survey
5 0.090 1.9 1.7 1.2 do not survey
6 0．001 0．002 0．001 0．001 0．001
7 0.001 survey survey surveys survey
8 0.370 47.3 16.2 do not survey ribavirin 24.3 17.7 7.5 15.5 3.3
1.All data represented IC that represent with μ M
50Value; The human RSV subclass of abbreviation: RSV-A=A; The human RSV subclass of RSV-B=B; BRSV=cattle RSV; ORSV=sheep RSV; GRSV=goat RSV.
Reaching 50%RSV in cell culture, to duplicate the concentration of the test compound that suppresses required low, and this shows that employed chemical compound is effective for the reproduction process that suppresses Pneumovirinae in the inventive method.These data show that also chemical compound of the present invention has the ability of much better than inhibition virus replication than Ribavirin.
Embodiment 17 explanation chemical compound of the present invention is than not having toxicity or harmless for Normocellular health when Pneumovirinae duplicates the much higher concentration of needed concentration for suppressing.
Embodiment 17
The cell toxicity test of Pneumovirinae replication inhibitors
In order to illustrate that chemical compound of the present invention is nontoxic, or be harmless, chemical compound of the present invention has been carried out the vitro cytotoxicity test assessment Normocellular health.A kind of effective test method of measuring the cytotoxic effect of chemical compound cell growth be based on the colorimetry of tetrazolium (Mossman, T., J.Immun.Methods (immunization method magazine),
65(1-2): 55-63 (1983)).The bromination 3-that this method is caused by living cells by quantitative assay (4,5-dimethylthiazole-2-yl)-2, the in-situ reducing of 5-diphenyl tetrazolium (MTT) is measured the vitality of cell, thereby measures its cytotoxicity.With 4 * 10
3The density of individual cells/well is with in 96 well culture plates of cell inoculation in containing the DMEM of 5%FBS.At 37 ℃ and 5%CO
2Cultivate under the condition after 4 hours, in quadruplicate hole, add the 2 times serial dilutions (or solvent independent) of chemical compound in 1%DMSO, then at 37 ℃ and 5%CO
2Condition under these culture plates were cultivated 68 hours again, it is double that this is equivalent to 3～4 cells.Remove culture medium, at 37 ℃ and 5%CO
2The pH 7.2 solution pair cells of MTT in phosphate buffered saline (PBS) with 1mg/ml under the condition were handled 4 hours.The solution of adding 0.04 N HCl in isopropyl alcohol dissolves the blue color formazan crystallization after the living cells generation is reduced after removing unreduced MTT.Read the optical density (OD of each hole with suitable microplate reader at the 570nm place
570).Cell viability is represented the percentage rate of the optical density of the control wells of solvent individual processing with the optical density of the cell of compound treatment.Cause optical density 〉=75% maximum compound concentration in the same old way the is expressed as cytotoxicity values (CC of cell
75).
The MTT cell toxicity test that the chemical compound that makes with embodiment 1-8 carries out the results are shown in table 2.
Table 2
Embodiment C C
75(μ M) IC
50(μ M)
1SI
1 ＞12．5 0．001 ＞12，500
2 ＞150 0．001 ＞150，000
3 12．5 0．05 250
4 18．8 0．11
2 171
5 ＞50．0 0．09
2 ＞556
6 3．1 0．001 3，100
7 ＞6．3 0．001 ＞6，250
8 9．4 0．37
2 25
Ribavirin 9.4 24.3＜1
1Activity to human body RSV subclass A
2Under the highest test compound concentration, protect cell culture to avoid the sick influence of virocyte and only reach 70-90%.
As shown in table 2, for the chemical compound of embodiment 1-8, the cytotoxicity (CC of its cell
75) value is significantly higher than the antiviral (IC of these chemical compounds
50) value.These results show that chemical compound of the present invention has the selectivity of height under the effective dosage of treatment, can not damage Normocellular health.This optionally tolerance by high selectivity exponential quantity (SI) provides, and this value defined is CC
75/ IC
50The high SI value that The compounds of this invention shows shows that these chemical compounds have highly desirable character.
Though the present invention has been made detailed description, and enumerated the example of some preferred embodiment, some other specific embodiments will be conspicuous for the people that are proficient in present technique.Therefore, institute's specific embodiments of describing and enumerating above the present invention is not limited to, but energy correct and do some change, and do not deviate from spirit of the present invention, gamut of the present invention is defined by appending claims.
Claims (40)
1. the pharmaceutically acceptable salt of the isomer of the chemical compound shown in the following formula, described chemical compound and described chemical compound:
Wherein Het representative replaces or unsubstituted 5-7 unit heterocycle, contains 1-3 hetero atom that is selected from nitrogen, oxygen or sulfur in the ring, and described heterocyclic substituent group is at least 1 group that is selected from following: hydrogen, alkyl, amino, an alkylamino or dialkylamino;
R
1Representative is selected from the group in following a group: hydrogen, halogen; Perfluoroalkyl; Alkoxyalkyl; Amino; Alkylamino; Dialkylamino; Acylamino-; Alkyl amino alkyl; Do not replace or replace, saturated or undersaturated straight chain-or branched chain alkyl, the substituent group of described alkyl chain is at least 1 hydroxyl; Carboxyl; Replace or unsubstituted phenyl (C
6H
5), the substituent group of described phenyl is at least 1 group that is selected from following a group: hydroxyl, halogen, perfluoroalkyl, sulfo-, nitro, carboxyl, carboxyalkyl, alkoxy carbonyl group, alkoxycarbonyl alkyl, carboxylic acid amides, carboxamido alkyl, alkyl, cycloalkyl, alkoxyl, alkoxyalkyl, alkylthio group, alkyl sulphinyl, alkyl sulphonyl, sulfonamides, amidino groups, cyano group, amino, acylamino-, alkylamino, dialkylamino, alkyl amino alkyl or be selected from the monobasic alkoxyl of substituent group in this group of carboxyl, amino, alkylamino or dialkylamino; Cycloalkyl; Or be selected from heterocyclic radical in following one group: pyridine, thiophene, oxazole, oxadiazole, thiadiazoles, pyrazoles, tetrazolium, furan, pyrroles, isoxazole, imidazoles, triazole and thiazole comprise all position isomers of described heterocyclic radical;
R
2Representative is selected from following one group group: hydrogen, hydroxyl, sulfo-, alkoxyl, carboxyl, carboxyalkyl, amino, alkylamino, dialkylamino, carboxamido, carboxamido alkyl or sulfonamides:
X represent 1 valence link or be selected from following one group divalent linker :-N=CH-,-CH=N-,-(CH
2)
n-NH-,-NH-(CH
2)
n-,-(CH
2)
n-,-CH=CH-or-N=N-, n is the integer of 1-8;
The Z representative is selected from following one group substituent group: hydrogen, formoxyl, hydroxyl or X-Het, wherein the definition of X and Het is the same.
2. prodrug, this prodrug in vivo stand to change, and become as the desired chemical compound of claim 1.
3. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(((5-amino-1H-tetrazole radical) imino group) methyl))-2,2 ', 4 " methine trisphenols.
4. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(((5-amino-1H-tetrazole radical) imino group) methyl))-4 " methoxyphenyl-2,2 '-the benzal bis-phenol.
5. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(((5-amino-1H-1,2,4-triazolyl) imino group) methyl))-2,2 ', 4 " methine trisphenols.
6. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (4-(((3-amino-4H-1,2,4-triazolyl) imino group) methyl))-2,2 ', 4 " methine trisphenols.
7. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (2-(((5-amino-2H-tetrazole radical) imino group) methyl))-2,2 ', 4 " methine trisphenols.
8. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(((5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,2 ', 4 " methine trisphenols.
9. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(((5-amino-1H-tetrazole radical) imino group) methyl))-2,2 '-the benzal bis-phenol.
10. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(((5-amino-1H-tetrazole radical) imino group) methyl))-2,2 '-the methylene bis-phenol.
11. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(2-(5-(1-methyl isophthalic acid H-tetrazole radical)) ethylidine))-2,2 ', 4 " methine trisphenols.
12. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-propyl group phenyl)-2,2 '-the benzal bis-phenol.
13. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-propoxyl group phenyl)-2,2 '-the benzal bis-phenol.
14. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-fluorophenyls)-2,2 '-the benzal bis-phenol.
15. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(2-(4-methylthiazol base) ethylidine))-2,2 ', 4 " methine trisphenols.
16. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(2-(5-(3-methyl-isoxazole base) ethylidine))-phenyl-2,2 '-the benzal bis-phenol.
17. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (2-(2-(5-methyl-2H-tetrazole radical) ethyls))-2,2 ', 4 " methine trisphenols.
18. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) amino) methyl))-2,2 ', 4 " methine trisphenols.
19. as the desired chemical compound of claim 1, this chemical compound is: 5-(((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,2 ', 4 " methine trisphenols.
20. as the desired chemical compound of claim 1, this chemical compound is: 5-(((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,4 ', 4 " methine trisphenols.
21. as the desired chemical compound of claim 1, this chemical compound is: 3-(5-(((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,4 '-dihydroxy diphenyl methylene)-the 4-hydroxy benzaldehyde.
22. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-((2-lignocaine) ethyoxyl) phenyl)-2,2 '-the benzal bis-phenol.
23. as the desired chemical compound of claim 1, this chemical compound is: 4-(5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-2,2 '-dihydroxy diphenyl methylene) phenoxyacetic acid.
24. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-pyridine radicals)-2,2 '-the benzal bis-phenol.
25. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-nitrobenzophenones)-2,2 '-the benzal bis-phenol.
26. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (((1-(5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-(4-aminophenyls)-2,2 '-the benzal bis-phenol.
27. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(2-(2-(1-methylimidazolyl) ethylidine))-2,2 ', 4 " methine trisphenols.
28. as the desired chemical compound of claim 1, this chemical compound is: 5,5 '-two (1-(((5-methyl isophthalic acid H-tetrazole radical) imino group) methyl))-phenyl-2,2 '-the benzal bis-phenol.
29. a kind of intermediate that preparation is used as the desired chemical compound of claim 1, described intermediate has following general formula:
Wherein the Q representative is selected from 5,5-dimethyl-1, the reactive group of 3-diox and formoxyl; R
5It is the group that is selected from hydrogen and hydroxyl; R
6Be the group that is selected from hydroxyl, alkoxyl, aryloxy group and aralkoxy, R
7Be to be selected from following one group group: hydrogen; hydroxyl; alkoxyl; alkoxyalkyl; halogen; perfluoroalkyl; sulfo-; nitro; carboxyl; carboxyalkyl; alkoxy carbonyl group; alkoxycarbonyl alkyl; carboxylic acid amides; the carboxamido alkyl; alkyl; cycloalkyl; alkylthio group; alkyl sulphinyl; alkyl sulphonyl; sulfonamides; amidino groups; cyano group; amino; acylamino-; alkylamino; dialkylamino; alkyl amino alkyl; or quilt is selected from carboxyl; amino; the monobasic alkoxyl of substituent group in this group of alkylamino or dialkylamino.
30. one kind the treatment or the prevention pneumovirus infection pharmaceutical composition, described compositions comprise weaken described viral infection effective dose as the desired chemical compound of claim 1 and a kind of pharmaceutically acceptable mounting medium.
31., further comprise at least a following one group additional medicament that is selected from: interferon, ribavirin and immunomodulator, immunoglobulin antiinflammatory, antibiotic, antiviral agent and anti-infective as the desired pharmaceutical composition of claim 30.
32. the method for a treatment pneumovirus infection in the patient of needs treatments pneumovirus infection, described method comprise to described patient's drug treatment effective dose as the desired chemical compound of claim 1 or as described in the precursor of chemical compound.
33. as the desired method of claim 32, the precursor of wherein said chemical compound is with a kind of form administration of prodrug.
34. the method for the described infection of prevention in being subject to the host of pneumovirus infection, described method comprise to described host's administration prevention effective dose as the desired chemical compound of claim 1 or as described in the precursor of chemical compound.
35. as the desired method of claim 34, the precursor of wherein said chemical compound is with a kind of form administration of prodrug.
36. one kind is being subject to or is being subjected to pneumovirus infection, or handles the method for cell in the culture that pollutes, described method comprise to described culture use effective dose as the desired chemical compound of claim 1.
37. a processing is subject to or has been subjected to the method for the biological substance of pneumovirus infection or pollution, described method comprise to described material use effective dose as the desired chemical compound of claim 1.
38. a method for preparing as the desired chemical compound of claim 1, described method comprise the aldehyde radical of benzaldehyde that 3-halogen replacement-4-alkoxyl is replaced-wherein with the protecting group protection-with the reaction of alkylation alkali metal, exchange to realize halogen-alkali metal; Under the condition of the tritanol. derivant that can generate the dialkoxy-R-replacement that comprises described blocking group, in this reactant mixture, add the benzoic Arrcostab that R-replaces; Tritanol. derivant deprotection and reduction that described dialkoxy-R-is replaced recovering described aldehyde functional group, and partly are converted into the tritan. part with tritanol.; The alkyl that removes in any alkoxy substituent makes it to become hydroxyl substituent; And the heterocycle reactant reaction that described aldehyde functional group and amine are replaced; to generate needed product, described R substituent group is selected from following one group of group: hydrogen; hydroxyl; alkoxyl; alkoxyalkyl; halogen; perfluoroalkyl; sulfo-; nitro; carboxyl; carboxyalkyl; alkoxy carbonyl group; alkoxycarbonyl alkyl; carboxylic acid amides; the carboxamido alkyl; alkyl; cycloalkyl; alkylthio group; alkyl sulphinyl; alkyl sulphonyl; sulfonamides; amidino groups; cyano group; amino; acylamino-; alkylamino; dialkylamino; alkyl amino alkyl; or quilt is selected from carboxyl; amino; the monobasic alkoxyl of substituent group in this group of alkylamino or dialkylamino.
39. as the desired method of claim 38, the benzoic acid that wherein said R-replaces is a para-orientation.
40. method for preparing as the desired chemical compound of claim 1, described method comprises makes 4,4 '-dihydroxy-3,3 '-hydroxyl of (4-R-replace phenyl) methylene two benzaldehydes-wherein etherificate-with the heterocycle hydroxyalkyl derivant of the tritan. of the R-replacement of the anionic reactive generation etherificate of the heterocycle reactant of methyl-replacements as intermediate product; Make this intermediate product dehydration then and take off etherificate to generate required product, described R substituent group is selected from following one group of group: hydrogen; hydroxyl; alkoxyl; alkoxyalkyl; halogen; perfluoroalkyl; sulfo-; nitro; carboxyl; carboxyalkyl; alkoxy carbonyl group; alkoxycarbonyl alkyl; carboxylic acid amides; the carboxamido alkyl; alkyl; cycloalkyl; alkylthio group; alkyl sulphinyl; alkyl sulphonyl; sulfonamides; amidino groups; cyano group; amino; acylamino-; alkylamino; dialkylamino; alkyl amino alkyl; or quilt is selected from carboxyl; amino; the monobasic alkoxyl of substituent group in this group of alkylamino or dialkylamino.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7303898P | 1998-01-29 | 1998-01-29 | |
| US7307898P | 1998-01-30 | 1998-01-30 | |
| US60/073,078 | 1998-01-30 | ||
| US60/073,038 | 1998-01-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1289248A true CN1289248A (en) | 2001-03-28 |
Family
ID=26754055
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99802500A Pending CN1289248A (en) | 1998-01-29 | 1999-01-29 | Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP1051169A4 (en) |
| JP (1) | JP2002501894A (en) |
| CN (1) | CN1289248A (en) |
| AU (1) | AU759772B2 (en) |
| BR (1) | BR9908522A (en) |
| CA (1) | CA2319465C (en) |
| MX (1) | MXPA00007394A (en) |
| NZ (1) | NZ505894A (en) |
| WO (1) | WO1999038508A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104507918A (en) * | 2012-06-29 | 2015-04-08 | 微剂量治疗公司 | Compositions and methods for treating or preventing pneumovirus infection and associated diseases |
| CN114390929A (en) * | 2019-06-13 | 2022-04-22 | 奇达拉治疗公司 | Compositions and methods for treating respiratory syncytial virus |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6489338B2 (en) | 2000-06-13 | 2002-12-03 | Bristol-Myers Squibb Company | Imidazopyridine and imidazopyrimidine antiviral agents |
| WO2003059251A2 (en) | 2001-10-22 | 2003-07-24 | The Scripps Research Institute | Antibody targeting compounds |
| CA2495266A1 (en) * | 2002-08-09 | 2004-02-19 | Viropharma Incorporated | Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases |
| EP1539691A2 (en) | 2002-08-09 | 2005-06-15 | Viropharma Incorporated | Compounds, compositions and methods for treating or preventing pneumovirus infection and associated diseases |
| WO2005042530A1 (en) | 2003-10-30 | 2005-05-12 | Boehringer Ingelheim (Canada) Ltd. | Rsv polymerase inhibitors |
| AU2004303602C1 (en) | 2003-12-23 | 2009-05-28 | Astex Therapeutics Limited | Pyrazole derivatives as protein kinase modulators |
| US8343953B2 (en) | 2005-06-22 | 2013-01-01 | Astex Therapeutics Limited | Pharmaceutical compounds |
| EP1933832A2 (en) | 2005-06-23 | 2008-06-25 | Astex Therapeutics Limited | Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators |
| GB0704932D0 (en) | 2007-03-14 | 2007-04-25 | Astex Therapeutics Ltd | Pharmaceutical compounds |
| WO2010093706A2 (en) | 2009-02-10 | 2010-08-19 | The Scripps Research Institute | Chemically programmed vaccination |
| US9850251B2 (en) | 2013-12-10 | 2017-12-26 | Shandong Danhong Pharmaceutical Co., Ltd. | Imidazole derivative used as antiviral agent and use therof in preparation of medicament |
| US10227309B2 (en) | 2015-06-08 | 2019-03-12 | Shandong Danhong Pharmaceutical Co., Ltd. | Crystal form A of 1-isobutyryl-1′-((1-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydro-1H-benzo [d]imidazol-2-yl)methyl)spiro[azetidine-3,3′-indolin]-2′-one |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1508392A (en) * | 1975-01-20 | 1978-04-26 | Sterling Drug Inc | Phenylalkanoylamines |
| US4324794A (en) * | 1980-08-26 | 1982-04-13 | Research Triangle Institute | Inhibition of respiratory syncytial virus-induced cell fusion by amidino compounds |
| US5098920A (en) * | 1990-05-04 | 1992-03-24 | G. D. Searle & Co. | 1h-substituted-1,2,4-triazole compounds and methods of use thereof for treatment of cardiovascular disorders |
| ZA944513B (en) * | 1993-06-23 | 1996-01-16 | Cambridge Neuroscience Inc | Sigma receptor ligands |
| WO1997005125A1 (en) * | 1995-07-27 | 1997-02-13 | Warner-Lambert Company | Substituted phenols as novel calcium channel blockers |
| CN1163401A (en) * | 1996-02-13 | 1997-10-29 | 李占元 | Fully automatic hemacytometer reagent and preparing method |
| ES2162676T3 (en) * | 1996-03-29 | 2002-01-01 | Searle & Co | PHENYLENE DERIVATIVES REPLACED IN META AND ITS USE AS ANTAGONISTS OR INHIBITORS OF INTEGRINA ALFAV, BETA3. |
-
1999
- 1999-01-29 NZ NZ505894A patent/NZ505894A/en unknown
- 1999-01-29 WO PCT/US1999/001985 patent/WO1999038508A1/en not_active Application Discontinuation
- 1999-01-29 BR BR9908522-4A patent/BR9908522A/en not_active Application Discontinuation
- 1999-01-29 AU AU25685/99A patent/AU759772B2/en not_active Ceased
- 1999-01-29 EP EP99905546A patent/EP1051169A4/en not_active Withdrawn
- 1999-01-29 JP JP2000529241A patent/JP2002501894A/en active Pending
- 1999-01-29 CN CN99802500A patent/CN1289248A/en active Pending
- 1999-01-29 CA CA2319465A patent/CA2319465C/en not_active Expired - Lifetime
- 1999-01-29 MX MXPA00007394A patent/MXPA00007394A/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104507918A (en) * | 2012-06-29 | 2015-04-08 | 微剂量治疗公司 | Compositions and methods for treating or preventing pneumovirus infection and associated diseases |
| US9504672B2 (en) | 2012-06-29 | 2016-11-29 | Microdose Therapeutx, Inc. | Compositions and methods for treating or preventing pneumovirus infection and associated diseases |
| CN114390929A (en) * | 2019-06-13 | 2022-04-22 | 奇达拉治疗公司 | Compositions and methods for treating respiratory syncytial virus |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1051169A1 (en) | 2000-11-15 |
| CA2319465C (en) | 2013-03-19 |
| EP1051169A4 (en) | 2002-05-29 |
| MXPA00007394A (en) | 2003-08-01 |
| WO1999038508A1 (en) | 1999-08-05 |
| CA2319465A1 (en) | 1999-08-05 |
| BR9908522A (en) | 2001-10-02 |
| JP2002501894A (en) | 2002-01-22 |
| NZ505894A (en) | 2002-12-20 |
| AU759772B2 (en) | 2003-05-01 |
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