CN1258300A - Modified benzimidazole nucleosides as antiviral agents - Google Patents
Modified benzimidazole nucleosides as antiviral agents Download PDFInfo
- Publication number
- CN1258300A CN1258300A CN 97192559 CN97192559A CN1258300A CN 1258300 A CN1258300 A CN 1258300A CN 97192559 CN97192559 CN 97192559 CN 97192559 A CN97192559 A CN 97192559A CN 1258300 A CN1258300 A CN 1258300A
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- fluoro
- compound
- cell
- virus
- benzimidazole
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Abstract
本发明涉及具有抗病毒活性和改善了代谢稳定性的核苷类似物。更具体地,本发明涉及修饰的糖类苯并咪唑核苷,列举的化合物如具有氟化糖类部分的苯并咪唑核苷(例如,2’－氟－呋喃糖基部分或3’－氟－呋喃糖基部分),可用式(Ⅰ)表示,其中R1是氟化糖类部分;及R2,R4,R5,R6和R7是苯并咪唑取代基,如－H,卤素(例如,－F－Cl,－Br,－I),－NO2,－NR2(其中R独立地为－H或具有1—6个碳原子的烷基),－OR(其中R为－H或具有1－6个碳原子的烷基),－SR(其中R为－H,具有1－10个碳原子的烃基),及－CF3。在一个具体实例中,R1是2’－氟－呋喃糖基或3’－氟－呋喃糖基;R2是－H,－F,－Cl,Br,－I或－NR2,其中R独立地为－H或具有1－6个碳原子的烷基;R4,R5,R6和R7分别是－H,－F,－Cl,Br或－I。
The present invention relates to nucleoside analogs having antiviral activity and improved metabolic stability. More specifically, the present invention relates to modified carbohydrate benzimidazole ribavirins, recited as compounds such as benzimidazole ribavirins having fluorinated carbohydrate moieties (e.g., 2'-fluoro-furanosyl moieties or 3'-fluoro -furanosyl moiety), which can be represented by formula (I), wherein R 1 is a fluorinated sugar moiety; and R 2 , R 4 , R 5 , R 6 and R 7 are benzimidazole substituents, such as -H, Halogen (for example, -F-Cl, -Br, -I), -NO 2 , -NR 2 (wherein R is independently -H or an alkyl group with 1-6 carbon atoms), -OR (wherein R is -H or an alkyl group having 1-6 carbon atoms), -SR (wherein R is -H, a hydrocarbon group having 1-10 carbon atoms), and -CF 3 . In a specific example, R 1 is 2'-fluoro-furanosyl or 3'-fluoro-furanosyl; R 2 is -H, -F, -Cl, Br, -I or -NR 2 , wherein R are independently -H or an alkyl group with 1-6 carbon atoms; R 4 , R 5 , R 6 and R 7 are -H, -F, -Cl, Br or -I, respectively.
Description
The application relates to U.S. application number 60/010,463, the associated viscera in the U. S. application in January 23 1996 applying date.
The nucleoside analog that the present invention relates to have antiviral activity and improve metabolic stability.More specifically, the benzimidazole nucleoside that the present invention relates to modify, the compound of enumerating is as having the benzimidazole nucleoside (for example, 2 '-fluoro-furyl glycosyl part or 3 '-fluoro-furyl glycosyl part) of fluoridizing the carbohydrate part.
In whole the application, various publications, patent, and disclosed patent application relates to identical quoting as proof; Comprehensively quoting of these documents can be found before the specification sheets ending is claims.The publication that relates to the application, the content of patent and disclosed patent application are hereby incorporated by reference as the prior art more detailed description to the present invention relates to.
Benzimidazole nucleoside has glamour especially as possible antiviral agent, because they have the ability to avoid some main paties of biological activity purine (dicyclo) nucleosides inactivation, for example, the deaminizing by adenosine deaminase and with the glycosidic bond cracking of purine nucleoside phosphorylase.For example, treat HCMV at present and comprise use medicine such as ganciclovir (also claiming DHPG), phosphine formic acid, and cidofovir.But verified known benzimidazole nucleoside is as 5,6-two chloro-1-(β-D-ribofuranosyl) benzoglyoxaline (DRB) only has the active or common unacceptable cytotoxicity of edge level, perhaps both have both at the same time, and therefore, greatly reduce its application in the treatment virus infection.Have been found that benzimidazole compound recently, as TCRB (2,5,6-three chloro-1-(2 '-β-D-ribofuranosyl) benzoglyoxaline) and 2-bromo-5, it is useful that 6-two chloro-1-(2 '-β-D-ribofuranosyl) benzoglyoxaline (BDCRB) infects for anti-HCMV, referring to, people such as Townsend, 1993,1994,1995.
Synthesized many benzimidazole nucleosides and be better than its antiviral activity of test and cytotoxicity in the effort of ganciclovir and the test of phosphine formic acid in the anti-Human cytomegalic inclusion disease virus (HCMV) activity that confirms compound.Polysubstituted benzimidazoles has been described as 5 in the front, the antiviral activity of 6-two chloro-1-(β-D-ribofuranosyl) benzoglyoxaline (DRB) and some closely-related derivatives.They are also reported as the activity of RNA rhinovirus and the pure property of dna single simplexvirus 1 type and 2 types specific virus.
Several 5 '-deoxyribosyl benzimidazole analogues comprise 2,5, and 6-three chloro-1-(β-D-ribofuranosyl) benzoglyoxaline (TCRB) shows very strong activity and low cytotoxicity to HCMV under the situation that suppresses viral growth concentration.Reported the structure-activity relationship between the derivative of TCRB and heterocycle and carbohydrate modification.Referring to, for example, people such as Ravenkar, 1968a, 1968b; People such as Townsend, in March, 1992; People such as Zou, 1992; People such as Saluja, 1992.But these openly do not disclose the structure of the object of the invention compound or synthesize.
Heterocycle has obtained having more active analogue than TCRB through modifying.But these analogues of great majority are bigger than TCRB cytotoxicity, and the result makes the therapeutic index of compound have to a little improvement.Someone attempts by using pectinose, wood sugar or do not have ring analogues and replace ribose and modify the carbohydrate part, but the compound activity that obtains is less than TCRB.Be more or less astoundingly, 5 ' of TCRB-deoxidation derivative, 2,5, the shown activity of 6-three chloro-(β-D-ribofuranosyl) benzoglyoxaline is 10 times of TCRB approximately, and has the better therapeutic index than TCRB.
The pharmacokinetics of research TCRB and metabolism recently illustrated that its drug half-life in rat was about 0.6 hour and the drug half-life in monkey is 0.5-0.7 hour people such as (, 1994) Good.Short-half-life may be relevant with the metabolism unstable of compound, for example, and cracking sugar moieties from benzoglyoxaline.
One aspect of the present invention relates to and has the above-mentioned benzimidazole nucleoside that carbohydrate is modified of fluoridizing.In an example, fluoridize carbohydrate and partly comprise 2 '-fluoro-furyl glycosyl part or 3 '-fluoro-furyl glycosyl part.
The present invention relates to treatment animal patient medicine for treating viral infections composition on the other hand, and said composition comprises the benzimidazole nucleoside that one or more the invention described above of treatment significant quantity are modified.
Further aspect of the present invention relates to treats the method that animal virus infects, and comprises the step of the benzimidazole nucleoside that uses one or more the invention described above modifications of treatment significant quantity.
The present invention also relates in one aspect to the method that suppresses virus (for example HCMV) propagation in the virus infected cell, comprises under suitable condition cell being contacted with the benzimidazole nucleoside of one or more the invention described above modifications of treatment significant quantity virus multiplication is suppressed.
The present invention relates to the method that prophylactic treatment is easy to the cell that virus (for example HCMV) infects on the other hand, and promptly the benzimidazole nucleoside of under suitable condition cell and one or more the invention described above of treatment significant quantity being modified contacts and makes virus infection obtain preventing.
Obviously, preferred feature of one aspect of the present invention and characteristics are applicable to any others of the present invention.
Fig. 1 is the schema that explanation has the chemical synthesis process of fluoridizing the benzimidazole nucleoside that carbohydrate partly modifies.
Fig. 2 is the schema that explanation has the another kind of chemical synthesis process of fluoridizing the benzimidazole nucleoside that carbohydrate partly modifies.
Fig. 3 is the schema that explanation has the another kind of chemical synthesis process of fluoridizing the benzimidazole nucleoside that carbohydrate partly modifies.A. antiviral compound of the present invention
The present invention relates to have antiviral activity, hypotoxicity, improved metabolic stability and than the long half-lift the benzimidazole nucleoside of modification.
The compounds of this invention can be described to " benzimidazole nucleoside of modification ", and wherein the carbohydrate part in the 1-position of the benzoglyoxaline that replaces (is R
1) be derivatized to, for example, fluoridize the carbohydrate part.The compounds of this invention can be expressed from the next:
R wherein
1Be to fluoridize carbohydrate part and R
2, R
4, R
5, R
6And R
7It is the benzoglyoxaline substituting group.The substituent example of benzoglyoxaline comprises-H, halogen (for example ,-F ,-Cl ,-Br ,-I) ,-NO
2,-NR
2(wherein R independently for-H or have the alkyl of 1-6 carbon atom) ,-OR (wherein R for-H or have the alkyl of 1-6 carbon atom) ,-SR (wherein R is-H, has the alkyl of 1-10 carbon atom) reaches-CF
3
In an example, The compounds of this invention can be represented by following formula, wherein R
1Be to fluoridize carbohydrate part, R
2Be-H ,-F ,-Cl ,-Br ,-I, or-NR
2(wherein R independently for-H or have the alkyl of 1-6 carbon atom); R
4, R
5, R
6And R
7Be to be independently-H ,-F ,-Cl ,-Br, or-I.
In an example, The compounds of this invention can be represented by following formula, wherein R
1Be to fluoridize carbohydrate part, R
2Be-H ,-F ,-Cl ,-Br ,-I, or-NR
2(wherein R independently for-H or have the alkyl of 1-6 carbon atom); R
5And R
6Be to be independently-H ,-F ,-Cl ,-Br, or-I; And R
4And R
7Be-H.
In another example, The compounds of this invention can be represented by following formula, wherein R
1Be to fluoridize carbohydrate part, R
2, R
5And R
6Be-H ,-F ,-Cl ,-Br or-I; And R
4And R
7Be-H.
In another example, The compounds of this invention can be represented by following formula, wherein R
1Be to fluoridize carbohydrate part, R
2Be-NR
2(wherein R independently for-H or have the alkyl of 1-6 carbon atom); R
5And R
6Be to be independently-H ,-F ,-Cl ,-Br, or-I; And R
4And R
7Be-H.
In another example, The compounds of this invention can be represented by following formula, wherein R
1Be to fluoridize carbohydrate part, R
2, R
5And R
6Be independently for-H and-Cl; And R
4And R
7Be-H.
Term used herein " carbohydrate part " refers to the monose part, and preferred carbohydrate partly is an annular form, for example, derive from furanose type (5-person's ring) deutero-or from pyranose type (6-person's ring), but more preferably from the furanose type deutero-.The example of carbohydrate part comprises furans threose base (from threose, erythrose is derived); Furans erythrose base (from erythrose, erythrose is derived); Ribofuranosyl (from ribose, five-carbon sugar is derived); Furyl glycosyl (be also referred to as arabinofuranosyl, from pectinose, five-carbon sugar is derived); Furyl xylose base (from wood sugar, five-carbon sugar is derived).Example with carbohydrate part of further modification comprises " deoxidation ", " ketone group " and " dehydrogenation " derivative, for example, 2 '-deoxidation-ribofuranosyl; 3 '-deoxidation-ribofuranosyl; 3 '-ketone group-2 '-deoxidation-ribofuranosyl; 2 ', 5 '-dihydrofuran-2 '-Ji; With 2 ', 3 '-dihydrofuran-2 '-Ji.The carbohydrate part can be its any enantiomer, and diastereomer, or stereoisomer form comprise, for example, and D-or L-type.The benzimidazole nucleoside that the present invention modifies can be any three-dimensional chemical isomer, comprises, for example, α-or β-anomer form.
Term used herein " is fluoridized the carbohydrate part " and is referred to that deutero-comprises a fluorine atom (carbohydrate part promptly-F) at least.For example, often have 2 '-hydroxyl, 3 '-hydroxyl and 5 '-hydroxyl from pentose (5-carbon) deutero-furyl glycosyl (5-person's ring).The fluoro derivatives of this carbohydrate can pass through, and for example, replaces one or more hydroxyl preparations with fluorine.The example of fluoridizing the carbohydrate part comprises 2 '-fluoro-furyl glycosyl and 3 '-fluoro-furyl glycosyl.The example of preferably fluoridizing the carbohydrate part comprises 2 '-fluoro-furyl glycosyl and 3 '-fluorine furyl xylose base.
What protection " fluoridized the carbohydrate part " and also comprise in term used herein fluoridizes the carbohydrate part.For example, fluoridize 2 '-hydroxyl that the carbohydrate part can comprise one or more protection forms, 3 '-hydroxyl, and/or 5 '-hydroxyl, for example, as ester (for example, acetic ester ,-O (C=O) CH
3), benzoic ether (promptly-OC (=O) C
6H
5), or ether (for example, trityl ether ,-OC (C
6H
5)
3).
The structure of disclosed and claimed compound in whole application, name or number definition are consistent.The compounds of this invention includes but not limited to following compounds.
2,5,6-three chloro-1-(2 '-fluorine furyl glycosyl) benzoglyoxaline (R wherein
1It is 2 '-fluoro-furyl glycosyl; R
2Be-Cl; R
4Be-H; R
5Be-Cl; R
6Be-Cl; And R
7Be-H) (for example compound 6);
2,5,6-three chloro-1-(3 '-fluorine furyl xylose base) benzoglyoxaline (R wherein
1It is 3 '-fluoro-furyl xylose base; R
2Be-Cl; R
4Be-H; R
5Be-Cl; R
6Be-Cl; And R
7Be-H) (for example compound 7);
5,6-two chloro-1-(2 '-fluorine ribofuranosyl) benzoglyoxaline (R wherein
1It is 2 '-fluoro-ribofuranosyl; R
2Be-H; R
4Be-H; R
5Be-Cl; R
6Be-Cl; And R
7Be-H) (for example compound 15);
2-bromo-5,6-two chloro-1-(2 '-fluorine ribofuranosyl) benzoglyoxaline (R wherein
1It is 2 '-fluoro-ribofuranosyl; R
2Be-Br; R
4Be-H; R
5Be-Cl; R
6Be-Cl; And R
7Be-H) (for example compound 19).
2-isopropylamino-5,6-two chloro-1-(2 '-fluorine ribofuranosyl) benzoglyoxaline (R wherein
1It is 2 '-fluoro-ribofuranosyl; R
2Be-NH (CH (CH
3)
2); R
4Be-H; R
5Be-Cl; R
6Be-Cl; And R
7Be-H) (for example compound 20).
The compounds of this invention the following method that provides is provided or is used as the intermediate of other compound of preparation the present invention.Should be appreciated that even without special instruction relevant above-mentioned any The compounds of this invention will comprise its pharmacologically acceptable salt and binding substances thereof.B. the using method of antiviral compound of the present invention
As described below, The compounds of this invention is effective antiviral, and effective especially to HCMV and HSV-1, and is same, when combining with carrier, provides in vitro, suppresses in the external or body composition of virus regeneration and propagation.For example, compound can combine with any liquid vehicle, as aseptic or the aqueous solution and following pharmaceutically acceptable carrier.
The compounds of this invention can combine with other antiviral provides a kind of effective binding substances." effectively binding substances " will comprise that The compounds of this invention and other The compounds of this invention or The compounds of this invention and other the present invention compound in addition are (as ganciclovir, AZT, with phosphine formic acid) the binding substances of chemically compatibility, as long as this combination does not slacken the antiviral activity of The compounds of this invention.
The compounds of this invention can be used for having used the AIDS patient HCMC of antiviral zidovudine (AZT) and the treatment that HSV-1 infects.Can provide the toxic advantage lower with the combined treatment of AZT than the combined treatment of ganciclovir and AZT.The compounds of this invention can produce in people's culturing cell than using the little cytotoxicity (being antagonism) of these medicines separately with combining of AZT.On the contrary, ganciclovir can produce in people's cell than using the high cytotoxicity of these medicines separately with combining of AZT.
The present invention also provides the method for duplicating and breeding that reduces or suppress HCMV in cell that HCMV or HSV-1 infect or the cell mass or HSV-1, be about to cell or cell mass and contact under proper condition, virus replication and propagation are suppressed with the The compounds of this invention of significant quantity.Those skilled in the art can be by record minimizing of virus titer or cells infected survival number increase be untreated, cells infected relatively, whether determine at an easy rate that HCMV or HSV-1 duplicate and breed reduces or is suppressed.The method of measuring cell concn is well known by persons skilled in the art and is listed below.Should be appreciated that by inhibition and minimizing virus replication and also can suppress and reduce viral infection with propagation, and, be suitable for the cell of HCMV or HSV-1 infection is handled.
For the object of the invention, " cell " will include but not limited to mammalian cell, mouse cell for example, rat cell, marmot cell, ape cell, or people's cell.Use The compounds of this invention, composition and the method effectively virus of treatment comprise DNA and RNA viruses, particularly simplexvirus.Simplexvirus, or the example of herpesviridae is herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella-zoster (VZV), Epstein-Barr virus (EBV), Human cytomegalic inclusion disease virus (HCMV), herpes virus hominis 6 (HHV-6), herpes virus hominis 7 (HHV-7), and human herpes virus 8 (HHV-8).The compounds of this invention is specially adapted to treat HCMV and HSV-1 infects.
Significant quantity is easy to be determined by those skilled in the art also can be according to cell, and the virus of outbreak and therapeutic purpose change.For example, use medicine in cell cultures, importantly the dose pair cell does not have cytotoxicity.
" felicity condition " comprise in the glass test tube, in the external or body.When present method is carried out, by can reaching the purpose of effective contact, and then suppress duplicating and breeding of virus in cell or the cell culture effectively with the compound culturing cell of antiviral significant quantity in glass test tube.Can directly compound be added in the substratum or before in adding cell and merge with carrier.In the glass test tube, this method is specially adapted to suppress virus replication, the infection of propagation and laboratory inner cell culture.External, compound is used for importing to patient and suppresses duplicating and breeding of virus before blood and the blood plasma.
The strong biological detecting method of screening new drug or compound (providing similarly or the antiviral activity that improves) also is provided The compounds of this invention and the method purposes in glass test tube.Use following method, under as The compounds of this invention the same terms, detect the medicine that to test.Antiviral and the cytotoxicity of trial drug can compare with The compounds of this invention.
Although The compounds of this invention shown in following is effective especially to HCMV and HSV-1, those skilled in the art can determine other virus of effectively treating with The compounds of this invention at an easy rate by using method described here and other method well known to those skilled in the art.Medicable other virus that belongs to the scope of the invention includes but not limited to human immunodeficiency virus (HIV) and hepatitis virus.
When this method is implemented in patient such as human body, can be added to compound in pharmaceutically acceptable carrier and system or topical in the patient, behave or Mammals such as mouse rat, marmot, or ape as the patient.
Said composition can also deliver medicine to and be easy to or infective virus is arranged, as the patient or the individuality of HCMV or HSV-1 risk of infection.Therefore, the present invention also provides the inhibition host virus replication, and the prevention method of propagation and/or virus infection promptly uses the compound or the composition of prevention significant quantity to make virus replication to the host under proper condition, and propagation and infection are suppressed." prevention significant quantity " refers to suppress to be subjected to the host's that virus threatens virus infection, duplicate and breed and the cell and the host that will treat do not had toxic amount.
Should be appreciated that by prevention or suppress the patient or individual virus multiplication, infect and duplicate, the present composition and method also provide treatment, symptom that prevention or improvement are relevant with virus infection or imbalance, included disease as, blind, mononucleosis, restenosis (HCMV); Varicella, zoster (varicella zoster virus); Infectious monocytosis, glandule, fever and Burkittis lymphoma (Epstein-Barr virus); Cold sore (herpes simplex virus 1); Genital herpes (herpes simplex virus 2); Rose infects (infantum) roseola (herpes virus hominis 6, and the herpes virus hominis 7); Kaposi's sarcoma (human herpes virus 8).Therefore, the present invention also provides improvement, prevention or treatment and virus infection such as HCMV or relevant imbalance or the syndrome of HSV-1 infection, for example, restenosis, opportunistic infection (infects gastro-intestinal infection, pneumonia as retina, CNS infects) and the method for uterine infection, promptly use the The compounds of this invention of significant quantity under proper condition to treatment target, imbalance or syndrome are improved, prevention or treatment.
In whole therapeutic process, can be continuously or intermittent type single dose administration in vivo.The method of determining the most effective administering mode and dosage is well known by persons skilled in the art, and the composition that will use according to treatment, target viral, therapeutic purpose, the cell that treat, and the patient that will treat and changing.The dosage of single or multiple administration and scheme are selected by the treatment doctor.The appropriate dosage forms of compound administration and method can find below.
All fluoro benzimidazole nucleosides of the present invention all show anti-HCMV and HSV-1 activity, and manyly have an acceptable cytotoxicity.Should be appreciated that relative cytotoxicity shows that the The compounds of this invention of suitable high antiviral active (promptly good selectivity) is preferred.It is also understood that antiviral therapy of the present invention comprises the treatment virus infection, and the prophylactic treatment that needs in some cases, for example, immune decline patient is as marrow and organ transplantation patient and the HIV carriers that are easy to HCMV infection or HSV-1 especially.
The compounds of this invention and composition can be used for the preparation of medicine and according to conventional methods, for example, carry out antiviral therapy for people or other animals administer as the activeconstituents in the pharmaceutical composition.The compounds of this invention can be used as pharmaceutically acceptable preparation and/or " prodrug " provides, and includes but not limited to ester, particularly carboxylicesters (preferred C
1To C
20), as 5 '-ethanoyl and 2 ', 3 ', 5 '-triacetyl prodrug and pharmacologically acceptable salt such as thiolate, Citrate trianion and acetate.
Pharmaceutical composition of the present invention can tablet, lozenge, and granula, wafer, pill, ampoule, suppository or spray form are carried out the surface, and be oral, in the nose, parenteral or inhalation.They can also be that activeconstituents is in water-based or non-aqueous thinner, slurries, the ointment that forms in particle or the powder, gel, paste, emulsifiable paste, spray, washing lotion, suspension, solution and emulsion form.Except The compounds of this invention, can also contain the perhaps many The compounds of this invention of other medicines active compound in the pharmaceutical composition.
More specifically, indication comprises per os, rectum as the suitable administration in treatment of the compound in the preparation of the present invention of activeconstituents here, nose, surface (comprise skin, suck cheek and hypogloeeis), vagina, parenteral (comprise subcutaneous, intramuscular, intravenously and skin) and lung administration.Be also to be understood that preferred approach will be according to patient's the state of an illness and the age, the virus that treat and the character of infection and change.
Be suitable for above-mentioned various virus infection as the dosage of HCMV and HSV-1 treatment in the about 0.1-250mg scope of per kilogram weight in patients every day, preferred range is about per kilogram weight in patients 1-100mg every day, most preferably in the about 5-20mg scope of per kilogram weight in patients every day.Except as otherwise noted, all wt of activeconstituents calculates by the salt of the parent compound of preparation of the present invention or the weight of ester, so weight increases in proportion.Preferably in one day, required dosage is divided into two, three by appropriate intervals, four, five, six or more times administration.This a little dosage can the unit dosage form administration, and for example, the per unit dosage form can contain the 10-1000mg that has an appointment, preferably about 20-500mg, most preferably from about 100-400mg activeconstituents.Should be appreciated that the suitable dose of The compounds of this invention and composition depends on the kind and the seriousness of virus infection, and different between patient and the patient.The determining of optimal dose generally considered the level of result of treatment of antiviral therapy of the present invention and the balance of any danger or deleterious side effect.
Ideally, should make behind the delivery of active ingredients that the peak concentration of active compound reaches about 2-100 μ M in the blood plasma, preferably about 5-70 μ M, most preferably from about 1-50 μ M.This can reach, and for example, by salt solution (arbitrarily) solution of the about 0.1-5% activeconstituents of intravenous injection, or oral administration contains the tablet of 0.1-250mg/kg activeconstituents, wafer or syrup.Keep the ideal haemoconcentration by continuous drip (being about 0.01-5.0mg/kg/h), or intermittently instil with the amount of about 0.4-15mg/kg activeconstituents.Effectively bonded uses and is considered to the treatment binding substances that can provide such, and it requires total dose of every kind of antiviral agent composition lower than using single treatment compound or the desired dosage of medicine separately, has therefore reduced side effect such as cytotoxicity.
Though activeconstituents can be individually dosed, be preferably in and contain a kind of above-mentioned activeconstituents and one or more pharmaceutically acceptable carrier in the pharmaceutical preparation at least and contain other therapeutical agent arbitrarily.Every kind of carrier with preparation in must be " acceptable " aspect the consistency of other composition, and be harmless to the patient.
Preparation comprises that those are suitable for per os, rectum, nose, surface (comprise skin, suck, cheek and hypogloeeis), vagina, the preparation of parenteral (comprise subcutaneous, intramuscular, intravenously and skin) and lung administration.Preparation generally can exist and any currently known methods preparation of available field of pharmacology by unit dosage form.These methods comprise the associating step of carrier with activeconstituents and one or more ancillary components formation.In a word, preparation is by homogeneous and best activeconstituents and liquid vehicle or pulverizing solid carrier or both is mixed with, if necessary, product is shaped.
The preparation of the present invention that is suitable for oral administration can be the dispersive unit, as wafer, and cachet or tablet, each contains the activeconstituents of the amount of pre-determining; Pulvis or granula; Solution or water-based or non-aqueous liquid suspension; Water-in-oil liquid emulsion or oil-in-water liquid emulsion.Activeconstituents also can medicine group, and electuary or paste form exist.
Tablet can be by compressing with one or more complementary elements arbitrarily or mold compacting forms.The tablet of compression can suitably made with the activeconstituents of unrestricted flow such as powder or particle shape in the machine, wherein can sneak into wedding agent arbitrarily (as polyvidone, gelatin, Vltra tears), lubricant, inert diluent, sanitas, and disintegrating agent (as sodium glycolate starch, cross-coupled polyvidone, crosslinked Xylo-Mucine), tensio-active agent or dispersion agent.The tablet of mold compacting can be cast pressure then with the moistening powder compound of inert liquid diluent and form in suitable machine.Can be arbitrarily with tablet coating or modification, and available multiple ratio, for example, Vltra tears is made activeconstituents slowly or the preparation of sustained release, and it is discharged according to desired scheme.Tablet can be the enteric coating form also, activeconstituents is discharged rather than release under one's belt in partial enteral.
Be suitable for that the preparation of topical comprises the dragee that contains activeconstituents in the oral cavity, wherein seasonings is generally sucrose and gum arabic or yellow work glue, is basic raw material; Contain activeconstituents and with inert substance such as gelatin and glycerine, or sucrose and gum arabic are the lozenge of basic raw material; And the collutory that in suitable liquid vehicle, contains activeconstituents.
The pharmaceutical composition of topical of the present invention can be made ointment, emulsifiable paste, suspension, washing lotion, pulvis, solution, paste, gel, sprays, the form of aerosol or oil.Perhaps, preparation can comprise sticking patch or binder such as bandage or the surgical adhesive that is soaked with activeconstituents and any one or multiple vehicle or thinner.
For eye or other outside organization such as mouth and skin infections, preparation is preferably made and is contained in right amount, for example, about 0.075-20%w/w, preferably about 0.2-25%w/w, most preferably from about 0.5-10 as, about 0.075-20%w/w, preferred about 0.2-25%w/w, 0.5-10%w/w most preferably from about, the part of activeconstituents is with ointment or emulsifiable paste.If make ointment, both activeconstituents also can be mixed with water-fast ointment base with paraffin.Perhaps, activeconstituents and oil-in-water emulsifiable paste matrix are mixed and made into emulsifiable paste.
If desired, the water in the emulsifiable paste matrix can be, for example, 30%w/w polyvalent alcohol at least promptly has the alcohol of two or more hydroxyls, as propylene glycol, and fourth-1,3-glycol, mannitol, Sorbitol Powder, glycerine and polyoxyethylene glycol, and their mixture.Surface preparation preferably contains and can improve activeconstituents and absorbed by site of action by skin or other and the compound of penetration performance.The examples for compounds of this raising transdermal ability comprises methyl-sulphoxide and related analogs thereof.
Oil phase in the emulsion of the present invention can be made of known composition with currently known methods.Though this can only contain a kind of emulsifying agent mutually, preferably constitute by at least a emulsifying agent and fat or oil or the two mixture.Preferred hydrophilic emulsifying agent mixes with oleophilic emulsifier as stablizer.The emulsifying agent of also preferred oil-containing and fat.Emulsifying agent with or do not form so-called emulsifying wax with stablizer, and wax forms so-called ointment base with oil and/or fat, ointment base constitutes the oily disperse phase of cream formulation.
The emulsifying agent and the emulsion stabilizer that are applicable to preparation of the present invention comprise Tween 60, and Span 80, hexadecyl Stearyl alcohol, tetradecanol, monostearin and Sodium Lauryl Sulphate BP/USP.
Because the stability of active compound in can be used for most of oil of emulsive pharmaceutical preparation is very low, so can suitable oil that preparation is used or fat will be selected according to reaching required skin moisten performance.Therefore, emulsifiable paste should preferably non-grease, and is painted and have a product washed of d spiss, spills from pipe or other container avoiding.Can use the list of straight or branched-or the binary alkyl ester as two dissidents, two acid esters, Standamul 7061, the propylene glycol diesters of theobroma oil fat acid, Isopropyl myristate, decyl oleate, Wickenol 111, butyl stearate, palmitinic acid 2-ethylhexyl or a kind of branched ester that is called Crodamol CAP, wherein last three kinds of esters are preferred.They can use separately according to the character needs, or are used in combination.Perhaps use high-melting-point lipid such as paraffinum molle alba and/or whiteruss or other mineral oil.
The preparation that is suitable for a topical also comprises eye drops, and wherein activeconstituents is dissolved in or is suspended in the suitable carrier, and aqueous solvent is particularly suitable for activeconstituents.The concentration of activeconstituents preferably is about 0.5-20% in this preparation, and about 0.5-10% is better, preferably about 1.5%w/w.
The preparation of rectal administration can be the suppository made from suitable matrix such as theobroma oil or salicylate.
The preparation that is suitable for vagina administration can be vaginal suppository, suppository, emulsifiable paste, gel, paste, foam or the spray that also contains carrier well known by persons skilled in the art except that containing activeconstituents.
Be suitable for intranasal administration and carrier and be about the coarse powder of 20-500 μ m for the solid preparation comprises particle diameter, its mode administration to suck, the container that is about to powder is housed is inhaled into powder rapidly by nearly nose by nasal passage.Carrier is that the preparation of liquid is suitable for, for example, the spray nose, intranasal administration, or carry out spray delivery with atomizer, these preparations comprise the water-based or the oily solution of activeconstituents.
The preparation that is suitable for parenteral admin comprises water-based or non-aqueous etc. oozes sterile solution for injection, wherein can contain antioxidant, buffer reagent, fungistat and make preparation isoosmotic solute in patient's blood; Water-based or non-aqueous sterilization suspension comprise suspension agent and thickening material, liposome or other microparticulate systems, and it makes compound arrive blood or one or more organ.Said preparation can be contained in single dose or the multiple doses sealed vessel, for example, in ampoule and the bottle, and can be stored under the lyophilisation condition, only need add sterile liquid carrier at once before use such as water for injection can use.(making) injection solution or suspension then and there can be by various sterilized powder noted earlier, and particle or tablet are made.
Preferred unit dose formulations is to contain above-mentioned per daily dose or unit, the preparation of day sub-doses or suitable active composition.
Should be appreciated that except the top composition of mentioning especially, preparation of the present invention can also contain this area other reagent commonly used, as long as they are suitable for preparation type, for example, the preparation that is suitable for oral administration can contain sweeting agent in addition, thickening material and seasonings.
The various compound of the present invention dosage form all right for animals uses, for example, and its available this area ordinary method preparation.The general chemical step of preparation of the sugared substituted benzimidazole that C modifies
The fusing point that measures on Thomas-Hoover Unimelt instrument is a unmodified.360 or 300MHz obtain nucleus magnetic resonance (NMR) spectrum of Bruker WP 360 SY or Bruker 300 SY.Ultimate analysis is finished by department of chemistry assay laboratory, University of Michigan--Ann Arbor.Mass spectrum is finished by University of Michigan--Ann Arbor department of chemistry mass spectrum laboratory.Flash column chromatography with silica gel 60 (the 230-400 order, ICN) and the described technology of people such as Still people such as (, 1978) Still finish.(DE carries out on USA) thin-layer chromatography (TLC) for Analtech, Newark at (prescored) of prewashing silica gel G HLF plate.Shine or spray 20% methyl alcohol sulfuric acid with UV light (243nm), then as seen coking makes compound in the heat dish.Except as otherwise noted, evaporative process in water-bath below 40 ℃, reduce pressure (water vent fan) carry out.
It is synthetic with one of two kinds of different approach usually to fluoridize nucleosides.A kind of approach is fluorine to be introduced the nucleosides of due care, and another kind of approach is with heterocycle and fluorizated sugar derivatives condensation (for example, chemistry or enzyme catalysis).These two kinds of schemes are all passed through research.Fluoridizing of benzimidazole nucleoside
A kind of synthetic method of the benzimidazole nucleoside of modifying as shown in Figure 1.In this method, benzimidazole nucleoside is as 2,5,6-three chloro-1-furyl glycosyl-benzoglyoxalines, with trityl chloride (being TrCl), Dimethylamino pyridine (DMAP) and pyridine were handled 4 days at 80 ℃, obtain 2 ', 5 '-two (tritylation) thing and 3 ', 5 '-two (trityl) compound.2 ', 5 '-two (tritylation) compounds and DAST (are SF
3NEt
2) pyridine and methylene dichloride (be CH
2Cl
2) reaction, (be CF then with trifluoroacetic acid
3COOH) reaction obtains 3 ' deoxidation-3 '-fluorine cpd, 2,5,6-three chloro-1-(3 '-deoxidation-3 '-fluoro-furyl glycosyl) benzoglyoxalines.In an example, compound is 2,5,6-three chloro-1-(3 '-deoxidation-3 '-fluoro-beta-furyl xylose base) benzoglyoxalines (compound 7).Similarly, (be SF with DAST
3NEt
2) pyridine and methylene dichloride (be CH
2Cl
2) handle 3 ', 5 '-two (trityl) compound, (be CF then with trifluoroacetic acid
3COOH) handle, obtain 2 ' deoxidation-2 '-fluorine cpd, 2,5,6-three chloro-1-(2 '-deoxidation-2 '-fluoro-furyl glycosyl) benzoglyoxalines.In an example, compound is 2,5,6-three chloro-1-(2 '-deoxidation-2 '-fluoro-beta-furyl glycosyl) benzoglyoxalines (compound 6).
The glycosylation of several purine and 2 '-deoxidation-2 '-fluoro-arbinofuranose radical derivative is (people such as Chu, 1989 after measured; People such as Pankiewicz, 1992).As described herein, people also possess some special knowledge to the derivative of the due care of compound 1 and the fluorination of dialkyl amido sulfur trifluoride (DAST).Though existing report that DAST can be effective fluorizating agent of several nucleosides, the structure of the furanose part of well-known protection is vital (people such as Krezeminski, 1991 to the attack from the weak nucleophilic fluorine of β-Bian that obtains to want; People such as Pankiewicz, 1993).Because leavings group is in the displacement of 2 '-position, it is important that the furanose ring presents the configuration that is unfavorable for anti--cancellation effect.Such configuration can be introduced people such as (, 1985) Theim by use huge protecting group at C-5 ' and C-3 '.
2,5,6-three chloro-1-(3,5-two-O-trityl-β-D-ribofuranosyl) benzoglyoxaline (compound 2) is a synthetic under the described reaction conditions of similar document (people such as Blank, 1970).Pyridine with TrCl and DMAP carries out tritylation reaction 4 days at 80 ℃ to compound 1, obtain two trityl derivatives 2 with 38% comprehensive yied, 5,6-three chloro-1-(3,5-two-O-trityl-β-D-ribofuranosyl) benzoglyoxaline (compound 2) and 2,5, the mixture of 6-three chloro-1-(2,5-two-O-trityl-β-D-ribofuranosyl) benzoglyoxaline (compound 3).Attempt by increasing the reaction times temperature of reaction or replace the DMAP catalyzed reaction to improve productive rate, but not success with alkali.Compound 2 can not separate with flash column chromatography with 3, but can separate (EtOAc/ hexane 1: 2 invades 3/4ths) with tlc.These compounds carry out more separate easily of fractional crystallization from ether, the ratio of obtaining is 1: 3 a compound 3 and 2.Confirm that compound 3 is 2,5-two-O-trityl derivative, compound 2 is 3,5-two-O-trityl derivative is the conclusion that experiment draws according to homonuclear decoupling.
Though desired 3,5-two-O-trityl derivative (compound 2) can only obtain from compound 1 with 10% productive rate, its isomer 2,5-two-O-trityl derivative (compound 3) but can obtain with 30% productive rate.CH with DAST and pyridine
2Cl
2To compound 3 fluoridize can 71% productive rate obtain 2,5,6-three chloro-1-(2,5-two-O-trityl-3-deoxidation-3-fluoro-beta-D-furyl xylose base) benzoglyoxaline (compound 5).With identical condition to compound 2 fluoridize can 63% productive rate obtain 2,5,6-three chloro-1-(3,5-two-O-trityl-2-deoxidation-2-fluoro-beta-D-arbinofuranose base) benzoglyoxaline (compound 4).Use 10%CF
3The CHCl of COOH
3To compound 4 and 5 the two carry out deprotection; productive rate that can be good obtains deprotection nucleosides 2 respectively; 5; 6-three chloro-1-(2-deoxidation-2-fluoro-beta-D-arbinofuranose base) benzoglyoxaline (compound 6) and 2; 5,6-three chloro-1-(3-deoxidation-3-fluoro-beta-D-furyl xylose base) benzoglyoxaline (compound 7).
Because fluoro derivatives 6 and 7 is β-ribofuranose yl nucleosides (compound 1) synthetic with DAST before formation, so they are respectively β-arabinofuranosyl and β-furans people such as (, 1989) Herdewijn.The further support that compound 6 and 7 is called as β-arbinofuranose base and β-furyl xylose radical derivative respectively will be traced back to the following fact: the two all demonstrates C
7Long-range coupling between-H and the F, compound 6 this couplings (J=1.9Hz) are bigger a little than compound 7 (J=1.7Hz).This shows that fluorine and heterocycle are the same one sides at the furanose ring.At last, for pectinose derivative compound 6, the coupling between 1 '-H and the F is 17.7Hz, and this coupling is pointed out the ortho position inverse relation (people such as Wright, 1969) between 1 '-H and the F.Compound 2 and 3
2,5,6-three chloro-1-(3,5-two-O-trityl-β-D-ribofuranosyl) benzoglyoxaline (2) and 2,5,6-three chloro-1-(2,5-two-O-trityl-β-D-ribofuranosyl) benzoglyoxaline (3)
With compound 1 (5.0g, 0.014mol), DMAP (1.25g, 0.014mol) and TrCl (12.0g, anhydrous pyridine 0.043mol) (100mL) mixture 80 ℃ the heating 3 days.Add the 2nd day and the 3rd day TrCl (12.0g, 0.043mol).React with MeOH (60mL) cancellation after 3 days.The concentrating under reduced pressure reaction mixture, and with toluene (3 * 100mL) coevaporations.The gained residuum is stirred in toluene (150mL), filter, and filtrate is evaporated to dried.(toluene 0.5L is toluene/EtOAc 20: 1 to the yellow foam of gained then, 5cm * 20cm) through purification by flash chromatography.Merging contains the cut of two trityl compounds and the mixture (4.5g, 38%) that removal of solvent under reduced pressure obtains compound 2 and 3 afterwards.Obtain almost being full the material of compound 3 from the EtOEt recrystallization, but compound 2 is in the majority in the filtrate.Twice of recrystallize is further purified pure substantially material with compound 3 from EtOEt, obtains 3.0g (25%) compound 3 and is white crystal.The filtrate that almost only contains compound 2 is evaporated to dried,, obtains 1.0g (8.4%) pure compound 2 and be white crystal then from EtOAc/ hexane recrystallization.
174-175 ℃ of compound 2:mp; R
f(0.19 toluene/EtOAc 20: 1); R
f(0.62 EtOAc/ hexane 1: 2);
1H-NMR (300MHz, DMSO-d
6): δ 8.06 (s, 1H), 8.02 (s, 1H), 7.13-7.42 (m, 30H, trityl), 6.24 (d, 1H, 2 '-OH, J
2 ', OH=6.2Hz), 6.18 (d, 1H, 1 '-H, J
1 ', 2 '=8.3Hz), 4.76 (2 '-H uses D for m, 1H
2O flushing becoming quartet J
1 ', 2 '=7.9Hz, J
2 ', 3 '=5.3Hz), 4.23 (d, 1H, 3 '-H, J
2 ', 3 '=5,4Hz), 2.93 (m, 1H, 4 '-H), 2.86 (dm, 1H, 5 '-H), 2.64 (dm, 1H, 5 '-H) .C
50H
39Cl
3N
2O
4The ultimate analysis calculated value: C, 71.65; H, 4.69; N, 3.34; Measured value: C, 71.50; H, 4.85; N, 3.24.
193-195 ℃ of compound 3:mp; R
f(0.19 toluene/EtOAc 20: 1); R
f(0.62 EtOAc/ hexane 1: 2);
1H-NMR (300MHz, DMSO-d
6): δ 7.93 (s, 1H), 7.54 (s, 1H), 7.01-7.41 (m, 30H, trityl), 6.22 (d, 1H, 1 '-H, J
1 ', 2 '=8.4Hz), 5.39 (d, 1H, 3 '-OH, J
3 ', OH=6.0Hz), 4.50 (dd, 1H, 2 '-H, J
1 ', 2 '=8.4Hz, J
2 ', 3 '=4.4Hz), 4.09 (m, 1H, 4 '-H), 3.58 (t, 1H, 3 '-H, J
3 ', OH=6.0Hz, J
2 ', 3 '=4.4Hz: use D
2The bimodal J of O flushing becoming
2 ', 3 '=4.4Hz), 3.04 (dd, 1H, 5 '-H), 3.18 (dd, 1H, 5 '-H) .C
50H
39Cl
3N
2O
41/2H
2The ultimate analysis calculated value of O: C, 70.88; H, 4.76; N, 3.31; Measured value: C, 70.93; H, 4.80; N, 3.31.Compound 4
2,5,6-three chloro-1-(3,5-two-O-trityl-2-deoxidation-2-fluoro-beta-D-arbinofuranose base) benzoglyoxaline (4)
(0.3g 0.36mmol) is dissolved in anhydrous CH with 3 ', 5 '-two-O-trityl compound (compound 2)
2Cl
2(10mL).In solution, add pyridine (0.3mL, 3.6mmol) and DAST (0.24mL, 1.8mmol), and at stirring at room reaction mixture 24hr.In reaction mixture, add CH again
2Cl
2(200mL), and use saturated NaHCO
3(100mL) extraction mixture, water (100mL) washing.The organic phase dried over mgso is filtered and solvent removed in vacuo.(EtOAc/ hexane 1: 2,2cm * 15cm) collect the cut and the solvent removed in vacuo that contain product to the gained slurries, obtain 0.20g (67%) compound 4 behind the EtOH recrystallization and are white solid through purification by flash chromatography.
145 ℃ of compound 4:mp; R
f(0.57 EtOAc/ hexane 1: 2);
1H-NMR (360MHz, CDCl
3): δ 7.65 (d, 1H, C
7-H, J=3.7Hz, long-range coupling is to F), 7.62 (s, 1H, C
4-H), and 7.19-7.45 (m, 30H, Tr), 6.10 (dd, 1H, 1 '-H, J
1 ', F=24.7Hz, J
1 ', 2 '=2.3Hz), 4.57 (m, 1H, 4 '-H), 4.28 (dm, 1H, 3 '-H, J
3 ', F=15.9Hz), 3.60 (dd, 1H, 2 '-H, J
2 ', F=50.3Hz, J
1 ', 2 '=2.3Hz), 3.50 (m, 1H, 5 '-H), 3.27 (m, 1H, 5 '-H) .C
50H
38Cl
3FN
2O
3HRMSm/z analyze calculated value: 838.1932; Measured value: 838.1949.C
50H
38Cl
3FN
2O
3The ultimate analysis calculated value: C, 71.47; H, 4.56; N, 3.33; Measured value: C, 71.15; H, 4.72; N, 3.37.Compound 5
2,5,6-three chloro-1-(2,5-two-O-trityl-3-deoxidation-3-fluoro-beta-D-furyl xylose base) benzoglyoxaline (5)
(1.2g 1.44mmol) is dissolved in anhydrous CH with 2 ', 5 '-two trityl compounds (compound 3)
2Cl
2(30mL).In solution, add pyridine (1.1mL, 14.4mmol) and DAST (1.0mL, 7.2mmol), and at stirring at room reaction mixture 24hr.In reaction mixture, add CH again
2Cl
2(200mL), and use saturated NaHCO
3(100mL) extraction mixture, water (100mL) washing.The organic phase dried over mgso is filtered and solvent removed in vacuo.(EtOAc/ hexane 1: 2,4cm * 15cm) merge the cut and the removal of solvent under reduced pressure that contain product to the gained slurries, obtain 0.85g (70%) compound 5 behind the EtOH recrystallization and are white solid through purification by flash chromatography.
Compound 5:mp＞240 ℃ (decomposition); R
f(0.6 EtOAc/ hexane 1: 2):
1H-NMR (300MHz, CDCl
3): δ 7.73 (s, 1H), 7.17-7.40 (m, 31H, C
4-H and trityl), 6.17 (d, 1H, 1 '-H, J
1 ', 2 '=4.5Hz), 4.54 (dd, 1H, 2 '-H, J
1 ', 2 '=4.5Hz, J
2 ', F=20.9Hz), 4.14 (dm, 1H, 4 '-H, J
4 ', F=31.4Hz), 3.99 (dd, 1H, 3 '-H, J
3 ', F=50.6Hz, J
3 ', 4 '=2.1Hz), 3.50 (m, 1H, 5 '-H), 3.27 (m, 1H, 5 '-H) .C
50H
38Cl
3FN
2O
3HRMS m/z analyze calculated value: 838.1924; Measured value: 838.1957.C
50H
38Cl
3FN
2O
31/2H
2The ultimate analysis calculated value of O: C, 70.72; H, 4.63; N, 7.88; Measured value: C, 70.82; H, 4.77; N, 3.35.Compound 6
2,5,6-three chloro-1-(2-deoxidation-2-fluoro-beta-D-arbinofuranose base) benzoglyoxaline (6)
(0.10g 0.12mmol) is dissolved in 10%CF with compound 4
3The CHCl of COOH
3(10mL), and in the stoppered flask in stirring at room 60 minutes.The vacuum-evaporation reaction mixture is to doing, gained oily residuum through purification by flash chromatography (EtOAc/ hexane 5: 1,2cm * 15cm), collect the cut of wanting and solvent removed in vacuo, with white residuum from MeOH/H
2Obtain 25mg (60%) compound 6 after the O crystallization and be white crystal.
223 ℃ of compound 6:mp; R
f(0.43 EtOAc/ hexane 5: 1);
1H-NMR (360MHz, DMSO-d
6): δ 8.29 (d, 1H, C
7-H, J=1.9Hz, long-range coupling is to F), 7.93 (s, 1H, C
4-H), 6.44 (dd, 1H, 1 '-H, J
1 ', F=17.7Hz, J
1 ', 2 '=4.5Hz), 6.02 (d, 1H, 3 '-OH, D
2O is commutative), 5.31-5.35 (m, 1.5H, 5 '-OH and 0.5 of2 '-H, 5 '-OHD
2O is commutative), 5.25 (dm, 0.5H, 2 '-H, J
2 ', F=53.2Hz, J
2 ', 3 '=2.7Hz), 4.42 (dm, 1H, 3 '-H, D
2O flushing becoming ddd J
3 ', F=24.2Hz, J
2 ', 3 '=2.7Hz and J
3 ', 4 '=5.9Hz), and 3.71-3.86 (m, 3H, 4 '-H and 5 '-H);
13C-NMR (90MHz, DMSO-d
6): δ 140.81,140.60,134.07,126.07,125.68,119.88,115.61,97.38 (2 ' C, J
2 ' C, F=192.5Hz), 84.98 (1 ' C, J
1 ' C, F=17.4Hz), 82.89 (4 ' C), 73.25 (3 ' C, J
2 ' C, F=24.4Hz), 59.05 (5 ' C, J
5 ' C, F=9.9Hz); C
12H
10Cl
3FN
2O
3HRMS m/z analyze calculated value: 353.9741; Measured value: 353.9735.C
12H
10Cl
3FN
2O
3The ultimate analysis calculated value: C, 40.53; H, 2.83; N, 7.88; Measured value: C, 40.55; H, 2.94; N, 7.48.Compound 7
2,5,6-three chloro-1-(3-deoxidation-3-fluoro-beta-D-furyl xylose base) benzoglyoxaline (7)
(0.28g 0.32mmol) is dissolved in 10%CF with compound 5
3The CHCl of COOH
3(20mL), and in the stoppered flask in stirring at room 45 minutes.The vacuum-evaporation reaction mixture is to doing, gained oily residuum through purification by flash chromatography (EtOAc/ hexane 5: 1,2cm * 15cm), collect the cut of wanting and be evaporated to dried, from MeOH/H
2Obtain 85mg (74%) compound 7 after the O crystallization and be white crystal.
238 ℃ of compound 7:mp; R
f(0.42 EtOAc/ hexane 5: 1);
1H-NMR (300MHz, DMSO-d
6): δ 8.01 (s, 1H, C
4-H), 7.93 (d, 1H, C
7-H, J=1.7Hz, long-range coupling is to F), 6.29 (d, 1H, 2 '-OH, D
2O is commutative), 5.91 (d.1H, 1 '-H, J
1 ', 2 '=4.6Hz), 5.17 (dd, 1H, 3 '-H, J
3 ', F=52.8Hz), 5.14 (t, 1H, 5 '-OH, D
2O is commutative), 4.63 (dm, 1H, 2 '-H, J
2 ', F=22.6Hz uses D
2O flushing becoming dd J
2 ' F=22.6Hz and J
1 ', 2 '=4.6Hz), 4.30 (dm, 1H, 4 '-H, J
4 ', F=28.5Hz), 3.69-3.84 (m, 2H, 5 '-H);
13C-NMR (90MHz, DMSO-d
6): δ 141.80,140.94,132.19,125.967,120.40,113.61,113.53,96.90 (3 ' C, J
3 ' C, F=184.1Hz), 91.14 (1 ' C, J
1 ' C, F=4.6Hz), 80.46 (4 ' C, J
4 ' C, F=19.8Hz), 77.81 (2 ' C, J
2 ' C, F=26.89Hz), 57.71 (5 ' C, J
5 ' C, F=9.96Hz); C
12H
10Cl
3FN
2O
3HRMS m/z analyze calculated value: 353.9741; Measured value: 353.9747.C
12H
10Cl
3FN
2O
3The ultimate analysis calculated value: C, 40.53; H, 2.83; N, 7.88; Measured value: C, 40.77; H, 2.88; N, 7.56.Fluoridize the coupling of sugar and benzoglyoxaline
The another kind of synthetic method of the benzimidazole nucleoside of modifying as shown in Figure 2.The fluorizated saccharide compound is synthesized in the method, forms desired compound with the benzoglyoxaline reaction then.For example, 2 ', 3 '-and 5 '-position by the benzoyl protection (promptly-OC (=O) C
6H
5) and 1 '-position by the acetoxyl protection (promptly-OC (=O) CH
3) furanose be converted to 1 '-deoxidation-1 '-bromo-2 '-deoxidation-2 '-fluoro-3 ', 5 '-benzoyl-furanose (seeing people such as Howell, 1995).This bromo furan sugar and benzoglyoxaline are as 2,5, and 6-trichlorine benzoglyoxaline is having 1 of 4 dust molecular sieves, and the 2-ethylene dichloride (is ClCH
2CH
2Cl) in 80 ℃ of reactions 2 days, generate 2,5 in, 6-three chloro-1-(2 '-deoxidation-2 '-fluoro-3 ', 5 '-benzoyl-furyl glycosyl) benzoglyoxaline mixture of isomers (is NH with ammonia then
3) methyl alcohol (be CH
3OH) deprotection obtains 2,5,6-three chloro-1-(2 '-deoxidation-2 '-fluoro-furyl glycosyl) benzoglyoxaline.Compound is 2,5 in an example, 6-three chloro-1-(2 '-deoxidation-2 '-fluoro-beta-furyl glycosyl) benzoglyoxalines (compound 6).
We study the synthetic of compound 6 by fluorizated arbinofuranose compound (as compound 8 and 9) being coupled to benzoglyoxaline (as 2,5,6-three chloro-benzoglyoxalines, compound 6).At first, we attempt with Vorbruggen condition and the basic salt glycosylation of attempting compound 6, but not success.Compound 6 and 1-bromo-3,5-two-O-benzoyl-2-deoxidation-2-fluoro-α-D-arbinofuranose (compound 9 have but successfully been finished with the described condition of people such as similar Montgomery people such as (, 1986) Montgomery; People such as Tann, 1985; People such as Howell, 1988) condensation.Promptly; 80 ℃ in the presence of 4 dust molecular sieves with compound 6 and compound 9 condensation in ethylene dichloride, obtain desired 2,5; 6-three chloro-1-(3,5-two-O-benzoyl-2-deoxidation-2-fluoro-beta-arbinofuranose base) benzoglyoxaline (compound 12) and alpha-isomer (compound 11) thereof.Why compound 12 is known as β-anomer and compound 11, and to be known as α-anomer partly be because their proton spectra.Coupling constant between the fluorine and 1 ' of compound 17-H is J
1 ', F=23.1Hz, the ortho position inverse relation of expression proton and fluorine.For compound 16 these constants are J
1 ', F=17.4Hz, the ortho position of expression proton and fluorine is along concerning (people such as Wright, 1969; People such as Tann, 1985; People such as Howell, 1988; People such as Reichman, 1975).Another basis to the anomer name can be traced back to the following fact: be the C of 7.91ppm in the compound 16
7-H is by dividing (because C with the long-range coupling of fluorine
7It is doublet that coupling between-H and the F makes signal, J=3.2Hz), and the C at the 7.79ppm place of compound 17
7-H does not observe this situation (signal is unimodal under this condition).
The anomeric ratio that further studies show that to condensation condition depends on condensation condition to a great extent.In non-polar solvent such as ethylene dichloride and benzene, what obtain under the above-mentioned condensation condition nearly all is β-anomer compound 17 (ratio of α/β is 1/5-1/10).But α-anomer compound 16 (ratio of α/β is 5/1-10/1) is a primary product in the stronger solvent of polarity such as acetonitrile and Nitromethane 99Min..Productive rate in non-polar solvent such as ethylene dichloride (80%, beta/alpha=8/1) is significantly better than the productive rate in polar solvent such as acetonitrile (9%, beta/alpha=1/7).
2,5,6-three chloro-1-(3,5-two-O-trityl-2-deoxidation-2-fluoro-beta-D-arbinofuranose base) benzoglyoxaline (12) and alpha-isomer (11) thereof
With 2-fluoro sugar compounds 8 (1.20g, 2.6mmol; People such as Tann, 1985) be dissolved in CH
2Cl
2(10mL), the CH that adds 33%HBr then
3COOH solution (2.64mL, 10.4mmol).Reaction mixture is stirred 6hr in the stoppered flask.In reaction mixture, add CH
2Cl
2(100mL), use ice-cold saturated NaHCO then successively
3(100mL) and icy water (100mL) washing organic phase.CH
2Cl
2Solution filters and removal of solvent under reduced pressure through dried over mgso, obtains the colourless slurries of compound 9.
With this slurry dissolved in ClCH
2CH
2Cl (10mL), and be added to make in advance contain 2,5,6-three chloro-benzoglyoxalines (compound 10) (0.6g, 2.6mmol) and the ClCH of activatory 4 dust molecular sieves
2CH
2In Cl (10mL) solution.With the heating 2 days in 80 ℃ and rare gas element of gained mixture, in reaction mixture, add CH then
2Cl
2(100mL) with saturated NaHCO
3Solution (100mL).Separate the washing of organic phase and water (100mL), dried over mgso is filtered and solvent removed in vacuo.The gained solid is through purification by flash chromatography (EtOAc/ hexane 1: 2,4cm * 15cm).Collect the effusive cut that contains nucleosides fast, be concentrated into dry doubling from MeOH/H
2The O crystallization then from the EtOH recrystallization, obtains 0.12g (8%) compound 11 and is white crystal.Be doped with a small amount of compound 10 in the slowly effusive cut that contains nucleosides.Collect these adulterated cuts, be concentrated into dry doubling chromatographic separation (CHCl of 5%MeOH again on second post
3, 4cm * 15cm).Obtain white solid after collecting suitable cut and removal of solvent under reduced pressure, with it from MeOH/H
2The O recrystallization obtains 1.0g (72%) compound 12.
Compound 11:mp78-80 ℃; R
f(0.60 EtOAc/ hexane 1: 2); R
f0.9 (5%MeOH is in CHCl
3);
1H-NMR (360MHz, CDCl
3): δ 8.12 and 8.00 (2m, 4H), 7.79 (s, 1H), 7.72 (s, 1H), 7.24-7.63 (m, 6H, benzoyl), 6.64 (dd, 1H, 1 '-H, J
1 ', 2 '=3.9Hz, J
1 ', F=17.4Hz), 5.82 (dd, 1H, 2 '-H, J
2 ', F=18.7Hz, J
2 ', 3 '=1.9Hz), 5.63 (dm, 1H, 3 '-H, J
3 ', F=49.3Hz), 4.94 (m, 1H, 4 '-H), 4.88 (dd ' 1H, 5 '-H), 4.67 (dd, 1H, 5 '-H); C
26H
18Cl
3FN
2O
5HRMS m/z analyze calculated value: 562.0265; Measured value: 562.0276.C
26H
18Cl
3FN
2O
5The ultimate analysis calculated value: C, 55.39; H, 3.22; N, 4.97; Measured value: C, 55.74; H, 3.23; N, 4.87.
88-90 ℃ of compound 12:mp; R
f(0.36 EtOAc/ hexane 1: 2); R
f0.67 (5%MeOH is in CHCl
3);
1H-NMR (360MHz, CDCl
3): δ 8.07-8.18 (m, 4H), 7.91 (d, 1H, C
7-H, J=3.2Hz long-range coupling is to F), 7.43-7.73 (m, 7H, benzoyl and C
4-H), 6.40 (dd, 1H, 1 '-H, J
1 ' 2 '=2.7Hz, J
1 ', F=23.1Hz), 5.78 (dd, 1H, 3 '-H, J
3 ', F=19.0Hz, J
3 ', 4 '=3.8Hz), 5.39 (dd, 1H, 2 '-H, J
1 ', 2 '=2.7Hz, J
2 ', F=50.3Hz), 4.91 (m, 2H, 5 '-H), 4.57 (q, 1H, 4 '-H, J
3 ', 4 '=3.6Hz); C
26H
18Cl
3FN
2O
5HRMS m/z analyze calculated value: 562.0265; Measured value: 562.0254.C
26H
18Cl
3FN
2O
5The ultimate analysis calculated value: C, 55.39; H, 3.22; N, 4.97; Measured value: C, 55.38; H, 3.23; N, 4.83.Compound 6
2,5,6-three chloro-1-(2-deoxidation-2-fluoro-beta-D-arbinofuranose base) benzoglyoxaline (6)
With compound 12 (0.5g 0.9mmol) is dissolved in methanol ammonia, and with solution at stirring at room 6hr.Solvent removed in vacuo, residuum is through purification by flash chromatography (EtOAc/ hexane 5: 1,2cm * 15cm).Collect suitable cut and be evaporated to driedly, from MeOH, obtain 0.23g (74%) white solid consistent after the crystallization with front compound 6 character.
The another kind of synthetic method of the benzimidazole nucleoside of modifying as shown in Figure 3.The uridine derivatives and the benzoglyoxaline that contain fluorizated carbohydrate part in the method react in the presence of enzyme N-desoxyribofu-based transferase, generate desired compound.The benzoglyoxaline part of this compound can further be derived, and for example in the 2-position, obtains benzimidazole nucleoside (for example, 2-Br, 2-NR that 2-replaces
2).Compound 15
5,6-two chloro-1-(2-deoxidation-2-fluoro-beta-D-ribofuranosyl) benzoglyoxaline (15)
Will with 2 '-deoxidation-the 2 '-fluoro uridine (compound 13) of the described method preparation of people such as Codington people such as (, 1968) Codington (0.99g, 4mmol) be dissolved in the 800mL citrate buffer (50mM, pH6.0).Adding is with 5 of the described method preparation of people such as Townsend people such as (, 1970) Townsend, and (0.30g 1.6mmol), places reaction 50 ℃ water-bath to 6-dichloro benzimidazole (compound 14) then.Add N-deoxidation-ribofuranose based transferase (people such as Cook see in 60,000 units, 1990), then with the soft shaken over night of reaction mixture.Add 5 again, (0.30g 1.6mmol), and continues reaction 2 days to 6-dichloro benzimidazole (compound 14).Add Celite (50-60g), filter reaction mixture then.By 80 ℃ of heating, follow cool to room temperature, obtain the precipitation of enzyme.With ethyl acetate (3 *) extraction product.Vacuum is removed ethyl acetate, and residuum continues chromatogram purification on the 75g alkali alumina, with 95: 5 (v/v) to 9: 1 (v/v) to 2: 1 (v/v) chloroform/methanol gradient elution to 1: 1 (v/v).Merge the cut and the solvent removed in vacuo that contain product, obtain 0.54g (67%) compound 15.
Compound 15:MS (FAB+) m/z, 321, M+1.
1H-NMR (DMSO-d
6) δ 8.62 (s, 1H, H-2), 8.19 (s, 1H, Ar-H), 7.96 (s, 1H, Ar-H), 6.35 (dd, 1H, H-1 ', J
1 ', 2 '=3.5Hz, J
1 ' F=14.9Hz), 5.74 (br s, 1H, OH), 5.23 (dt, 1H, H-2 ', J
1 ', 2 '=3.5Hz, J
2 ', 3 '=4.4Hz, J
2 ', F=52.4Hz), 5.23 (brs, 1H, OH), 4.35 (dt, 1H, H-3 ', J
2 ', 3 '=4.4Hz, J
3 ', 4 '=5.3Hz, J
3 ', F=15.9Hz), 3.98 (m, 1H, H-4 '), 3.66 (dd, 2H, H-5 ', J=3.4Hz, J=12.5Hz). compound 16
5,6-two chloro-1-(2-deoxidation-2-fluoro-3,5-diacetyl-β-D-ribofuranosyl) benzoglyoxaline (16)
(0.45g 1.4mmol) is dissolved in pyridine (20mL) and boil to remove and anhydrate with compound 15.Solution is cooled to 0 ℃ in ice bath.The room temperature that rises to adding diacetyl oxide (260 μ L, 2.9mmol, 2 equivalents), permission reaction mixture stirs simultaneously spends the night.Add methyl alcohol (3mL) and solvent removed in vacuo.Remove remaining pyridine with toluene (3 *) coevaporation.Residuum distributes between water and ethyl acetate.Ethyl acetate solution obtains 0.56g (98%) compound 16 through dried over mgso after filtration and the solvent removed in vacuo.This product need not to be further purified and can use.
Compound 16:MS (FAB+) m/z, 405, M+1.
1H-NMR (DMSO-d
6) δ 8.59 (s, 1H, H-2), 8.05 (s, 1H, Ar-H), 8.01 (s, 1H, Ar-H), 6.45 (dd, 1H, H-1 ', J
1 ', 2 '=4.8Hz, J
1 ', F=14.8Hz), 5.75 (dt, 1H H-2 ', J=5.2Hz, J
2 ', F=51Hz), 5.40 (m, 1H, H-3 '), 4.43 (m, 1H, H-4 '), 4.28 (m, 2H, H-5 '), 2.13 (s, 3H, ethanoyl-CH
3), 2.02 (s, 3H, ethanoyl-CH
3). compound 17,18 and 19
2-bromo-5; 6-two chloro-1-(2-deoxidation-2-fluoro-3; 5-diacetyl-β-D-ribofuranosyl) benzoglyoxaline (17); 2-bromo-5; 6-two chloro-1-(2-deoxidation-2-fluoro-5-diacetyl-β-D-ribofuranosyl) benzoglyoxaline (18); with 2-bromo-5,6-two chloro-1-(2-deoxidation-2-fluoro-beta-D-ribofuranosyl) benzoglyoxaline (19)
(0.55g 1.4mmol) is dissolved in diox (25mL) and boil to remove and anhydrate with compound 16.With solution reflux in 120 ℃ of oil baths.Add N-bromine succinimide (NBS, 0.48g, 2.8mmol, 2 equivalents), and with reaction mixture refluxed 4 minutes.Add second crowd of NBS (0.48g, 2.8mmol, 2 equivalents), and will continue to reflux 6 minutes.Reaction mixture is taken from thermal source, with chloroform (40mL) dilution, and cool to room temperature.Solution also filters with saturated sodium bicarbonate washing (2 *), dried over mgso.Solvent removed in vacuo, residuum is chromatogram purification on 75g silica gel, the usefulness ethyl acetate/hexane (1: 1, v/v) wash-out.Merge the cut and the solvent removed in vacuo that contain product, obtain compound 17.By in methyl alcohol and ethanol (each 17mL), using the hydrolysis of yellow soda ash (0.22g, 2.1mmol, the 2 equivalents) ethanoyl of finishing dealing with that is dissolved in 4.2mL water.With reaction mixture in stirred overnight at room temperature.Water (40mL) diluting soln.With ethyl acetate extraction product (2 *).The ethyl acetate solution dried over mgso is filtered and solvent removed in vacuo.Residuum is chromatogram purification on 75g silica gel, the usefulness ethyl acetate/hexane (1: 4, v/v) be then (1: 2, v/v) gradient elution.The product that very fast wash-out goes out be 5 '-acetyl compounds (compound 18,0.17g), the product of second kind of wash-out be dihydroxy compound (compound 19,0.03g).
Compound 18:MS (FAB+) m/z, 399, M+1.
1H-NMR (DMSO-d
6) δ 8.46 (s, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 6.22 (dd, 1H, H-1 ', J
1 ', 2 '=5.4Hz, J
1 ', F=14.5Hz), 5.82 (d, 1H, OH-3 ', J=5.6Hz), 5.45 (t, 1H, OH-5 ', J=4.5Hz), 5.29 (dt, 1H, H-2 ', J=5.2Hz, J
2 ', F=53Hz), 4.3 (m, 1H, H-3 '), 4.0 (m, 1H, H-4 '), 3.7 (m, 2H, H-5 ').
Compound 19:
1H-NMR (DMSO-d
6) δ 8.00 (s, 1H, Ar-H), 7.90 (s, 1H, Ar-H), 6.25 (dd, 1H, H-1 ', J
1 ', 2 '=5.1Hz, J
1 ', F=16.5Hz), 5.95 (d, 1H, OH-3 ', J=6Hz), 5.40 (dt, 1H, H-2 ', J=5.3Hz, J
2 ', F=53Hz), 4.4-4.1 (m, 4H, H-3 ', 4 ', 5 '), 2.13 (s, 3H, CH
3-ethanoyl). compound 20 2-isopropylaminos-5,6-two chloro-1-(2-deoxidation-2-fluoro-beta-D-ribofuranosyl) benzoglyoxaline (20)
(0.06g 0.14mmol) is dissolved in ethanol (4mL), and adds Isopropylamine (1.3mL) with compound 18.Solution is enclosed in 90 ℃ of oil baths heats 17hr.Solvent removed in vacuo, residuum is chromatogram purification on 6g silica gel, the usefulness chloroform/methanol (95: 5, v/v) wash-out.Merge the cut and the solvent removed in vacuo that contain product, obtain compound 20 (0.03g, 57%).
Compound 20:MS (APCH+) m/z, 378, M+1.
1H-NMR (DMSO-d
6) δ 7.66 (s, 1H, H-2), 7.37 (s, 1H, Ar-H), 6.92 (d, 1H, NH J=7.7Hz), 6.17 (dd, 1H, H-1 ', J
1 ', 2 '=5.3Hz, J
1 ', F=15.4Hz), 5.73 (d, 1H, OH-3 ', J=5.7Hz), 5.63 (t, 1H, OH-5 ', J=4.3Hz), 5.12 (dt, 1H, H-2 ', J=5.3Hz, J
2 ', F=53Hz), 4.29 (dt, 1H, H-3 '), 4.02 (m, 1H, CH), 3.94 (m, 1H, H-4 '), 3.68 (m, 2H, H-5 '), 1.16 (d, 6H, CH
3, J=6.5Hz) .D. antiviral activity and Cytotoxic mensuration cell and virus
The KB cell (is utilized American Type Culture Collection (ATCC) 12301Parklawn Drive, Rockport, MD20852 (ATCC CCL 17)), a kind of human cell line who sets up by epidermis oral carcinoma deutero-, at Hanks salt (MEM (H)) and be supplemented with minimum minimum medium (MEM) that 5% foetal calf serum constitutes (Sigma) in cultivation.Hide fiber cell (HFF cell) (being provided by University of Michigan--Ann Arbor hospital) and African green monkey kidney cell (BSC-1) (ATTC CCL 26) are at Earl salt (MEM (E)) and be supplemented with among the MEM of 10% foetal calf serum formation and cultivate before the people.Allow the passage breeding with the described method of people such as Shipman people such as (, 1976) Shipman according to conventional methods.In brief, according to conventional methods with 0.05% trypsinase add 0.02%EDTA in HEPES buffered salts solution with passage to 1: 2-1: 10 extent of dilution.The HFF cell only passes to 1: 2 extent of dilution.
The pure isolate patch P of the Towne bacterial strain of the HCMV that University of Iowa Dr.Mark Stinski is given
0Be used for all experiments.Also use the KOS bacterial strain of the HSV-1 that the Dr.Sandra K.Weller of University of Connecticut provides.The preparation of HCMV and HSV-1 file layout and titration are undertaken by the described method of people such as people such as well known by persons skilled in the art and Turk people such as (, 1987) Turk and Shipman people such as (, 1990) Shipman.In brief, high titration HSV-1 stock solution can be prepared as follows.The monolayer culture thing that almost merges of KB cell is being equipped with 25mM HEPES and is being supplemented with 5% foetal calf serum and 0.127g/ rises in the 32oz. vial of L-arginine (VGM, viral growth base) MEM (E) damping fluid and cultivates.With low input complexity culture is infected to reduce the formation of incomplete virus.After the cytopathology of cell reaches " 3-4+ " by acutely shaking collecting cell, and by centrifugal (800 * g 5min.) concentrates.Gained virus pond is stored in-76 ℃, when experiment, recovers to use.
Monolayer culture thing titration HSV-1 with the BSC-1 cell.With the plate in one group in 6 holes with 3 * 10
5Cell is cultivated in the configuration of cells/well.The MEM (E) that is supplemented with 10% foetal calf serum is used as substratum.90% cytogamy behind the 22-24hr gives the cell inoculation of 3 times of amounts so that measure with at least 3 10 times dilution 0.2mL viral suspensions, and at the 4%CO of humidity
2Hatching was beneficial to the virus absorption in 1 hour in-90% air.Virus absorbs the back and covers plastidogenetic film with the 5mL MEM (E) that 5% serum adds 0.5% methylcellulose gum (4000CPS), and continues hatching 2-3 days.With 20% methyl alcohol fixed cell of 0.1% amethyst with give cell painted, with the naked eye check the patch number.
By with less infectiosity (m.o.i.), promptly each cell forms 0.01 patch unit (p.f.u.), infects the HFF cell and prepares the HCMV stock solution.Per 4 days of cell growth substrate is changed once up to the cytopathology of all cells obviously (nearly 21 days).Supernatant liquor is preserved as viral stock solution.Freeze-change circulation through 3 after 4 days and make cell fission, cell adds substratum and is retained as another kind of viral source, stores in liquid nitrogen.
HCMV is titrated in the dish in one group in 24 holes, by 5 * 10
4The HFF cells/well is cultivated, and cultural method as above.Add the 0.2mL viral suspension in each hole when cell reaches the 70-80% fusion, absorption process as mentioned above.Use at least 3 goods with 10 times of each goods dilutions.Virus absorbs the back, and [1.1g/ rises NaHCO keeping substratum
3, 100 units/mL penicillin G, the MEM (E) that 100 μ g/mL Streptomycin sulphates and 5% foetal calf serum constitute] in cover plastidogenetic film with 0.5% methylcellulose gum (4000CPS), and at the 4%CO of humidity
2Hatching hatching in 1 hour culture in-90% air.Infect visible viral patch after 5-7 days with the amount of amplifying 10 times at least.Infect back 7-12 days with cellular exposure in 20% methanol solution of 0.1% amethyst 10 minutes with fixed cell with give cell painted.Amplify 20 times with Nikon Profile Projector microscope and check the patch number.The mensuration of antiviral activity
Adopt similar as a reference the experiment of above-mentioned virus titer and the described method of people such as Townsend people such as (, 1995) Townsend carries out the HCMV patch with the monolayer culture thing of HFF cell and the reduction productive rate is tested.The anti-HSV-1 activity of compound is assessed with the described ELISA assay method of people such as Townsend (people such as Townsend, 1995).
The effect that compound duplicates HCMV reduces assay method with patch and productive rate and measures.For the former, adopt aforesaid method to infect HFF cell in the 24 hole culture plates with the about 50p.f.u.HCMV in every hole.The compound that virus will be dissolved in the growth substrate after absorbing is added in the twice hole with the doubly selected concentration of 4-6.37 ℃ of hatchings after 7-10 days as stated above the film that forms of pair cell fix, painted and check the patch number by microscope.The percentage calculation that the effect of medicine reduces with patch quantity, the ratio of the patch quantity when promptly the patch quantity under various drug levels is with no medicine.DHPG (9-(1,3-dihydroxy-2-third oxygen methyl) guanine) is used as positive control in all experiments.Productive rate reduces assay method and presses the described method of people such as Townsend people such as (, 1995) Townsend and carry out.
The described ELISA method of people such as Townsend (people such as Townsend, 1995) is used to measure anti-HSV-1 activity.The percentage calculation that the effect of medicine reduces with virus titer, the ratio of the titre when promptly the virus titer under various drug levels is with no medicine.Acyclovir is used as positive control in all experiments.Cytotoxic mensuration
Cytotoxicity with two kinds of diverse ways assessing compounds.First kind, by the microscopic inspection that is used for the cell that virus that patch measures influences being measured the cytotoxicity of secondary (fixing) HFF cell.Second kind, by compound in two breedings of color measurenent DT Doubling Time of the painted and spectrophotometric quantitative analysis of amethyst wash-out from the cytochrome to the effect of KB cell.This method is used to analyze 9-(1,3-dihydroxy-2-third oxygen methyl) guanine and Zidovodine (seeing people such as Prichard, 1991).
Two kinds of antiviral activity and cell toxicity datas of fluoridizing sugared benzimidazole nucleoside of the present invention, and list in table 1 with the comparative data of known antiviral agent TCRB and 9-(1,3-dihydroxy-2-third oxygen methyl) guanine.
| Table 1 | |||||
| 50% inhibition concentration IC 50(μM) | |||||
| Antiviral activity | Cytotoxicity | ||||
| Compound | ????HCMV | ????HSV-1 | Intuitively | Growth | |
| Patch | Productive rate | (ELISA assay method) | (HFF cell) | (KB cell) | |
| Compound 2 | ??＞10 | ?- | ????＞100 | ????＞10 | ????＞10 |
| Compound 3 | ??＞10 | ?- | ????＞100 | ????＞10 | ????＞10 |
| Compound 62 '-F-Ah-TCRB | ??13.0 | ??8 | ????50 | ????32 | ????60 |
| Compound 73 '-F-wood-TCRB | ??9.4 | ??13 | ????＞100 | ????40 | ????＞100 |
| Compound 12 | ??23 | ??- | ????＞100 | ????＞10 | ????＞100 |
| 9-(1,3-dihydroxy-2-third oxygen methyl) guanine (DHPG) | ??7.4±6.5 | ???1.6±1.2 | ????3.5±2.1 | ????＞100 | ????＞100 |
| TCRB (compound 1) | ??2.76 | ???1.3±0.8 | ????151 | ????238 | ????175 |
| ??BDCRB | ??0.48 | ?????- | ????- | ????141 | ?????- |
Three kinds of antiviral activity and cell toxicity datas of fluoridizing sugared benzimidazole nucleoside of the present invention are listed in table 2.
To cultivate in the individual layer human embryonic lung cell (MRC5 cell) of HCMV strains A D169 in 96 porose discs.Add test compound in respective aperture in triplicate with 6 kinds of different concns behind the ratio injection cell with about 0.01 infecting virus particle of each cell.The compound of same concentrations also is added in the hole of containing the cell that individual layer do not infect so that estimate cytotoxicity.To coil and cultivate 5 days, estimate the smallest cell toxic agent amount by microscopic inspection.By trace and quantitative concrete DNA hybrid method (being similar to Gadler method (seeing Gadler, 1983)) the HCMV DNA in each hole is measured with estimation antiviral effect IC
50
In brief, the probe of hybridization usefulness is made with clay pC7531 and pCS37 (seeing people such as Sullivan, 1993).Clay contains 102 respectively, 000-143,300 nucleosides and 51,600-92, the HCMV AD169 sequence that 900 nucleosides constitute.This probe be with after the nuclease Xbal cutting by α-[
32P]-dCTP adopts 1: 1 mixture of two clays of random primer and T7 archaeal dna polymerase (Pharmacia) mark.This probe process is in 99 ℃ of heating modification in 2 minutes, and the aseptic Corning0.45 μ m filter membrane of process (25933-200) filters.
The prehybridization process of film is at 45 ℃ 6X SSPE (SSPE:0.18M NaCl, 10mMNaPO
4(pH7.7), 1mM EDTA), 1%Ficoll, 1% polyvinylpyrrolidone/, 1%BSA carries out 2-12hr among 0.5%SDS and the 50 μ g/mL salmon serum DNA.
With the probe that contains each heat denatured is 1 * 10
6The hybridization solution of cpm/mL (6XSSPE, 0.5%SDS, 50 μ g/mL salmon serum DNA) replaces prehybridization solution.Crossover process is carried out 16hr at 65 ℃, and it is as follows to wash this film then: 6X SSPE and 0.5%SDS, room temperature, 2 * 2 minutes; 1X SSPE and 0.5%SDS, 65 ℃, 2 * 15 minutes; 0.1XSSPE reach 0.5%SDS, 65 ℃, one time 1 hour.
Film is coated with dried, and with PhosphoImager (Molecular Dynamics, Sunnyvale CA) are bundled into the Saran bag that quantitative analysis uses.The screen of PhosphoImager is exposed to trace 16-24 hour.(MolecularDynamics, Sunnyvale CA) calculate the thick counting of each sample, are counted only by deducting the localized membrane background with ImageQuant software.
With the counting in the counting in drug dilution hole and the untreated control hole curve that relatively meets with a response, be used for calculating IC
50Value.Be weighted linear regression according to the Hill equation and calculate IC
50Value.
| Table 2 | ||
| 50% inhibition concentration IC 50(μM) | ||
| Compound | Antiviral activity HCMV (DNA crossover process) | Cytotoxicity (MRC5 cell) |
| Compound 15 | ????12.5±0.7 | ????＞100 |
| Compound 19 | ????13.7±0.5 | ????72.8 |
| Compound 20 | ????8.9±2.7 | ????49.0 |
The invention described above example is for the present invention is described, rather than in order also not constitute the restriction to the desired invention of following claims by any way.On the other hand, raising within the scope of the invention and improvement all will be conspicuous to the technician in the field involved in the present invention.E. reference
Following publication as a reference, the content of patent and disclosed patent application draw at this does reference disclosed by the invention, so that the prior art that the present invention relates to is described in more detail.Blank, H.U.; Frahne, D.; Myles, A.; Pfleiderer, W., " Uber dieTrityllierung von Adenosin-Derivate. ", " Libiee wishes chemical yearbook ",, the 742nd volume, 34-42 page or leaf Chu, C.K. in 1970; Matulic-Adamic, J.:Huang, J.-T.; Chou, T.-C.; Burchenal, J.H.; Fox, J.J.; Watanabe, K.A., " nucleosides 135, the synthetic and biological activity of some 9-(2-deoxidation-2-fluoro-beta-D-arbinofuranose base)-9H-purine ", " chemicals bulletin ",, the 37th volume, the 336th page of Codington, J.F. in 1989; Doerr, I.L.; Fox, J.J., " organic chemistry magazine ", 1964, the 29th volume, the 558th page of people such as Cook, " journal of biological chemistry ", nineteen ninety, the 265th volume, the 2682nd page of Devivar, people such as R.V., " medical chemistry magazine ", 1994, the 37th volume, 2942-2949 page or leaf Gadler, " chemistry of antibiotics (Antimicrob.Agent Chemother.) ", nineteen eighty-three, the 24th volume, people such as 370-374 page or leaf Good, " antiviral agent research (supplementary issue 1) ", 1994, the 23rd volume, the 103rd page of Herdewijn, P.; Aerchot, A.; Kerremans, L., " synthesizing of sugar moieties fluorizated nucleosides; Diethylaminosulfurtrifluoride is being fluoridized the application of nucleosides in synthetic ", " nucleosides and Nucleotide ",, the 8th volume; 65-96 page or leaf, and people such as reference Howell wherein, " organic chemistry magazine ", nineteen ninety-five in 1989; the 50th volume, 3644-3647 page or leaf Howell, H.G.; Brodfuehrer, P.R.; Brundige, S.P.; Benigne,, D.A.; Sapino, C., " anti-viral nucleoside; A kind of stereospecific whole synthetic 2 '-fluoro-2 '-deoxidation-β-D-arbinofuranose yl nucleosides ", " organic chemistry magazine ",, the 53rd volume, 85-88 page or leaf Krezeminski, J. in 1988; Nawrot, B.; Pankiewicz, K.W.; Watahabe, K.A., " 9-(2-deoxidation-2-fluoro-beta-D-arbinofuranose base) is hypoxanthic synthetic; In preparation purine nucleoside method, directly introduce 2 '-β-fluoro substituents first; Directly the Arabic nucleosides synthetic of 2 '-deoxidation-2 '-replacement is studied ", " nucleosides and Nucleotide ",, the 19th volume, 781-798 page or leaf Montgomery, J.A. in 1991; Shortnacy, A.T.; Carson, D.A.; Secrist III, J.A., " 9-(2-deoxidation-2-fluoro-beta-D-arbinofuranose base) guanine: the cell toxicant analogue of a kind of metabolic stability of 2 '-pancreatic desoxyribonuclease ", " medical chemistry magazine ", 1986, the 29th volume, 2389-2392 page or leaf Pankiewicz, K.W.; Krezeminski, J.; Ciszewski, L.A.; Ren, W.Y.; Watanabe, K.A., " 9-(2-deoxidation-2-fluoro-beta-D-arbinofuranose base) VITAMIN B4 and hypoxanthic synthetic; The drift that C3 '-Nei to C2 '-Nei forms to 2 ' influence of hydroxyl and DAST reaction process ", " organic chemistry magazine ", 1992, the 57th rolled up 553-559 page or leaf Pankiewicz, K.W.; Watanabe, K.A., " a kind of by directly near Synthetic 2 '-method of the purine nucleoside that fluoro-and 3 '-fluorine replaces; Nucleosides as antineoplastic agent and antiviral agent ", Chu, C.K.; Baker, D.C. edits, Plenum press, New York,, 55-71 page or leaf Prichard, people such as M.N., " antiviral summary ",, the 35th volume, 1060-1065 page or leaf Reichman, U. in 1993 in 1991; Watanabe, K.A.; Fox, J.J., " method for practical synthesizing of 2-deoxidation-2-fluoro-D-arbinofuranose derivative " " carbohydrate summary ", 1975, the 42nd volume, 233-240 page or leaf Revenkar, R.G. and Townsend, L.B., " heterocyclic chemistry magazine ", nineteen sixty-eight, the 5th volume, 477-483 page or leaf Revenkar, R.G. and Townsend, L.B., " heterocyclic chemistry magazine ", nineteen sixty-eight, the 5th volume, 615-620 page or leaf Saluja, S. wait the people, "-5 of some 2-replacement, the synthetic and antiviral activity of 6-dichloro benzimidazole acyclic nucleotide ", Poster#146, medical chemistry specialty, the 204th American Chemical Society's annual meeting, the Washington D.C., in August, 1992 23-28 day Shipman, C., Jr. wait the people, " chemistry of antibiotics ", 1976, the 9th volume, the 120th page of Shipman, C., Jr. wait the people, " virological method magazine ", nineteen ninety, the 28th volume, 101-106 page or leaf Still, W.C.; Kahn, M.; Mitra, A., " with the isolating flash chromatography technology of being prepared property of regulator solution ", " organic chemistry magazine ",, the 43rd volume, 2923-2925 page or leaf Tamm, I., " science ",, the 120th volume, 847-848 page or leaf Tann, C.H. in 1978 in 1954; Brodfuehrer, P.R.; Brundige, S.P.; Sapino, C.; Howell, the H.G., " application of fluorocarbohydrate in synthetic; 1-(2-deoxidation-2-fluoro-beta-D-arbinofuranose base)-5-iodouracil (β-FMAU) and 1-(2-deoxidation-2-fluoro-beta-D-arbinofuranose base)-5-iodouracil (thymus pyrimidine of β-FIAU) (β's-FMAU) is effectively synthetic "; " organic chemistry magazine "; 1985; the 50th volume; 3644-3647 page or leaf Thiem, J.; Rash, D., " the synthetic and Perkow reaction of uridine derivatives ", " nucleosides and Nucleotide ", 1985, the 4th volume, the 487th page of Townsend and Revankar, " chemistry summary ", 1970, the 70th volume, the 389th page of Townsend, L.B. and Drach, J.C., the 5th antiviral research international conference, Vancouver, British Columbia, in March, 1970 Townsend, people such as L.B., " medical chemistry magazine ", nineteen ninety-five, the 38th volume, 4098-4105 page or leaf Townsend, people such as L.B., United States Patent (USP) 5,248,672, be disclosed in Townsend on September 28th, 1993, L.B. wait the people, United States Patent (USP) 5,360,795, be disclosed in Turk on November 1st, 1994, S.R. wait the people, " chemistry of antibiotics ", 1987, the 31st volume, 544-550 page or leaf V.Sullivan, K.K.Biron, C.L.Talarico, S.C.Stanat, M.G.Davis, L.S.Pozzi and D.M.Coen, " chemistry of antibiotics ", 1993, the 37th volume, 19-25 page or leaf Wright, J.A.; Taylor, N.F.; Fox, J.J., nucleosides LX, fluorocarbohydrate XXII, " synthesizing of 2-deoxidation-2-fluoro-D-pectinose and 9-(2-deoxidation-2-fluoro-α and β-arbinofuranose base) VITAMIN B4 ", " organic chemistry magazine ", 1969, the 34th volume, 2632-2636 page or leaf Zou, people such as R., " some are in the design of the partially modified TCRB analogue of benzene; synthetic and antiviral evaluation ", Poster#142, medical chemistry specialty, the 204th American Chemical Society's annual meeting, the Washington D.C., 23-28 day in August, 1992
Claims (16)
1. benzimidazole nucleoside and the pharmacologically acceptable salt thereof modified shown in the following structural formula,
R wherein
1Be to fluoridize the carbohydrate part; R
2Be-H ,-F ,-Cl ,-Br ,-I or-NR
2, wherein R is independently for-H or have the alkyl of 1-6 carbon atom; R
4Be-H ,-F ,-Cl ,-Br or-I; R
5Be-H ,-F ,-Cl ,-Br or-I; R
6Be-H ,-F ,-Cl ,-Br or-I; R
7Be-H ,-F ,-Cl ,-Br or-I.
2. the benzimidazole nucleoside of the modification of claim 1, the wherein said carbohydrate of fluoridizing partly comprises 2 '-fluoro-furyl glycosyl part or 3 '-fluoro-furyl glycosyl part.
3. the benzimidazole nucleoside of the modification of claim 2, the wherein said carbohydrate of fluoridizing partly comprises the part that is selected from following group:
2 '-fluoro-furans threose base; 3 '-fluoro-furans threose base;
The red glycosyl of 2 '-fluoro-furans; The red glycosyl of 3 '-fluoro-furans;
2 '-fluoro-ribofuranosyl; 3 '-fluoro-ribofuranosyl;
2 '-fluoro-furyl glycosyl; 3 '-fluoro-furyl glycosyl;
2 '-fluoro-furyl xylose base; And 3 '-fluoro-furyl xylose base.
4. the benzimidazole nucleoside of the modification of claim 3, the wherein said carbohydrate of fluoridizing partly comprises the part that is selected from following group:
2 '-fluoro-ribofuranosyl;
2 '-fluoro-furyl glycosyl; And
3 '-fluoro-furyl xylose base.
5. the benzimidazole nucleoside of the modification of claim 4 is wherein saidly fluoridized the hydroxyl that carbohydrate partly has one or more protection forms.
6. the benzimidazole nucleoside of the modification of claim 1, wherein R
1It is 2 '-fluoro-furyl glycosyl; R
2Be-Cl; R
4Be-H; R
5Be-Cl; R
6Be-Cl; And R
7Be-H.
7. the benzimidazole nucleoside of the modification of claim 1, wherein R
1It is 3 '-fluoro-furyl xylose base; R
2Be-Cl; R
4Be-H; R
5Be-Cl; R
6Be-Cl; And R
7Be-H.
8. the benzimidazole nucleoside of the modification of claim 1, wherein R
1It is 2 '-fluoro-ribofuranosyl; R
2Be-H; R
4Be-H; R
5Be-Cl; R
6Be-Cl; And R
7Be-H.
9. the benzimidazole nucleoside of the modification of claim 1, wherein R
1It is 2 '-fluoro-ribofuranosyl; R
2Be-Br; R
4Be-H; R
5Be-Cl; R
6Be-Cl; And R
7Be-H.
10. the benzimidazole nucleoside of the modification of claim 1, wherein R
1It is 2 '-fluoro-ribofuranosyl; R
2Be-NH (CH (CH
3)
2); R
4Be-H; R
5Be-Cl; R
6Be-Cl; And R
7Be-H.
11. contain with good grounds claim 1-10 in any one compound and the composition of pharmaceutically acceptable carrier.
12., comprise separately or in conjunction with the preparation that is used to suppress or prevent virus infective medicament according to the purposes of the compound of claim 1-10 in any one.
13. the method for virus multiplication in the cell that suppresses virus infection comprises under proper condition the claim 1-10 of said cell and the significant quantity compound in any one is contacted, and virus multiplication is inhibited.
14. a method that suppresses HCMV propagation in the cell that HCMV infects comprises under proper condition the claim 1-10 of said cell and the significant quantity compound in any one is contacted, and HCMV is bred be inhibited.
15. the method for a prophylactic treatment easily infected virus cell comprises under proper condition the claim 1-10 of said cell and the significant quantity compound in any one is contacted, and makes virus infection obtain prevention.
16. the method for a prophylactic treatment easy infection HCMV cell comprises under proper condition the claim 1-10 of said cell and the significant quantity compound in any one is contacted, and HCMV is infected obtain prevention.
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| CN112778388A (en) * | 2021-01-21 | 2021-05-11 | 大连医科大学 | Nucleoside analogue and preparation method and application thereof |
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1997
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| CN112778388A (en) * | 2021-01-21 | 2021-05-11 | 大连医科大学 | Nucleoside analogue and preparation method and application thereof |
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