CN101605457B - P-toluene sulfonic acid salt of 5-amino-3-(2'-o-acetyl-3'-deoxy-ss-d-ribofuranosyl)-3h-thiazole [4, 5-d] pyrimidine-2-one and methods for preparation - Google Patents

P-toluene sulfonic acid salt of 5-amino-3-(2'-o-acetyl-3'-deoxy-ss-d-ribofuranosyl)-3h-thiazole [4, 5-d] pyrimidine-2-one and methods for preparation Download PDF

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CN101605457B
CN101605457B CN200780038464.XA CN200780038464A CN101605457B CN 101605457 B CN101605457 B CN 101605457B CN 200780038464 A CN200780038464 A CN 200780038464A CN 101605457 B CN101605457 B CN 101605457B
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compound
formula
amino
thiazole
pyrimid
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CN101605457A (en
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D·库塞拉
G·J·海力
E·J·鲁登
T·王
F·布拉特
M·维埃特豪斯
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Anadys Pharmaceuticals Inc
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Abstract

The present disclosure relates to p-toluene sulfonic acid salt of 5-amino-3-(2'-O-acetyl-3'-deoxy-beta-D-ribofuranosyl)-3H-thiazolo[4,5-d]pyrimidin-2-one and to its use in treating conditions such as viral infections, tumors, and cancer. Also disclosed is a method of preparing the p-toluene sulfonic acid salt of 5-amino-3-(2'-O-acetyl-3'-deoxy-ss-D-ribofuranosyl)-3H-thiazolo[4,5-d]pyrimidin-2-one and methods for producing furanose compounds which are useful intermediates in the preparation of pharmaceutical compounds such as p-toluene sulfonic acid salt of 5-amino-3-(2'-O-acetyl-3'-deoxy-ss-D-ribofuranosyl)-3H-thiazolo[4,5-d]pyrimidin-2-one and the like.

Description

Tosilate and the preparation method of 5-amino-3-(2'-0-ethanoyl-3'-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5-d] pyrimid-2-one
Invention field
The present invention relates to 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-also tosilate and the application in treatment disease such as virus infection, tumour and cancer thereof of [4,5-d] pyrimid-2-one of 3H-thiazole.Also relate to preparation 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole also [4; 5-d] pyrimid-2-one method and produce such as 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole also can be used as the method for the furanose compound of intermediate in the preparation process of the medicinal compounds such as tosilate of [4,5-d] pyrimid-2-one.
Background technology
Nucleoside analog is the important compound that a class can be used in the therapeutic process of disease.For example, in the treatment of cancer and virus infection, use nucleoside analog.After nucleoside analog entered cell, usually by nucleosides salvage pathway phosphorylation, the analogue phosphorylation formed corresponding single, double and triguaiacyl phosphate.In other born of the same parents in the final result, the nucleoside analog of triphosphoric acid is usually as the substrate of DNA or RNA polymerase and mix among DNA and/or the RNA.If the triphosphoric acid nucleoside analog is strong AG14361, they can induce newborn nucleic acid molecule to cross early stopping.If the triphosphoric acid nucleoside analog is incorporated in nucleic acid replication or the transcript, can cause genetic expression or function to be destroyed.
So some nucleoside analogs are effective because can suppress E.C. 2.7.1.20.E.C. 2.7.1.20 catalysis adenylic acid formation adenosine 5 '-one phosphoric acid (AMP).But the outer level of adenosine born of the same parents in the inhibition Effective Raise human body of E.C. 2.7.1.20, thereby can be used for the treatment of ischemic disease such as apoplexy, inflammation, sacroiliitis, outbreak and epilepsy.
Come in the past few decades, in the treatment of open nucleoside analog is used, carried out a large amount of effort.For example, in the United States Patent (USP) 5,041,542 of authorizing the people such as Robins, disclose some Kui Linpyrimido quinoline [4,5-d] pyrimidine nucleoside and in the BDF1 mouse, can effectively treat L1210.In addition, authorize the United States Patent (USP) 5 of Robins etc., 041,426 and 4,880,784 disclosed 3-β-D-RIBOSE base thiazole also [4,5-d] pyrimidine demonstrate obvious immunocompetence, comprise Muridae splenocyte propagation and to the activity in vivo of Semliki Forest virus (Semliki Forest virus).Many publications also to thiazole also the non-glycosylated derivative of [4,5-d] pyrimidine part be described, referring to for example, United States Patent (USP) 5,994,321 and 5,446,045; The people such as Revankar, J.Het.Chem., 30,1341-49 (1993); The people such as Lewis, J.Het.Chem., 32,547-56 (1995).
Proved 3,5-, two replacement-3H-thiazoles also [4,5-d] pyrimid-2-one compound have immunoregulatory activity.The preparation of this compounds and being applied among the open US2006/0160830 (No. the 11/304th, 691, U. S. application) of U. S. application discloses, and this application is by in full with reference to including this paper in.This application described free alkali compound 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5-d] pyrimid-2-one synthetic also.The purity of this compound depends on the purification process that adopts because of the free alkali amorphous property.The abundant purifying of free alkali is subject to and adopts the unacceptable solvent of some human consumption.In addition, the amorphous forms of this compound (free alkali) tends to moisture absorption, causes compound to be easy to hydrolysis.Therefore, wish very in the pharmaceutical application that preparation innoxious solvent consumption is low, have the method for the crystallization shape compound of high purity and stability.
Summary of the invention
The present invention relates to the 5-amino-3-shown in the formula (1) (2 '-0-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-the thiazole also tosilate of [4,5-d] pyrimid-2-one and the pharmaceutical composition that comprises this salt.
Figure G200780038464XD00021
The compound of formula 1 can use in the treatment of disease or prevention method.For example, the compound of formula 1 can be used for treating or generation and/or the process of prophylaxis of tumours or cancer.Also described the method for the treatment of or prevention pathogenic infection, for example virus infection comprises hepatitis B virus or infection with hepatitis C virus.The compound of formula 1 also can use in the control method of immune cell factor activity.
In another embodiment, the present invention relates to prepare 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole method of the tosilate (1) of [4,5-d] pyrimid-2-one also.
Figure G200780038464XD00031
The method may further comprise the steps:
(i) also [4,5-d] pyrimid-2-one (2) and desoxyribofu-(3) coupling form the compound of formula (4) to make 5-amino-3H-thiazole
Figure G200780038464XD00032
(ii) 5 ' acetic ester on selective splitting formula (4) compound, form 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5-d] pyrimid-2-one (5) also,
(iii) make 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole also [4; 5-d] reaction of pyrimid-2-one (5) and tosic acid form 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole tosilate (1) of [4,5-d] pyrimid-2-one also
Figure G200780038464XD00034
In another embodiment, step (i) comprise make 5-amino-3H-thiazole also the desoxyribofu-coupling of [4,5-d] pyrimid-2-one (2) and formula (3B) form the compound of formula (4)
Figure G200780038464XD00041
Another embodiment relates to the method for preparation formula (3) compound, and the compound of formula (3) can be used as intermediate in the preparation process of formula (1) compound.
Figure G200780038464XD00042
The method comprises:
(i) compound of usefulness sulphonating agent sulfonation formula (6) in the presence of alkali,
Form the compound of the alkylsulfonyl replacement of formula (7),
Figure G200780038464XD00044
Wherein R is the optional alkyl or aryl that replaces;
(ii) compound that replaces with the alkylsulfonyl of reductive agent reduction-type (7) forms the compound of formula (8)
(iii) with the compound of acid hydrolysis formula (8), form the compound of formula (9)
Figure G200780038464XD00052
(iv) with the compound of oxygenant oxidation-type (9), then with the reductive agent reduction, form the compound of formula (10)
Figure G200780038464XD00053
With
(v) in the presence of acid catalyst with the compound of acetylation reagent acetylize formula (10), form the compound of formula (3)
Figure G200780038464XD00054
Another embodiment of the invention relates to the method for the compound of preparation formula (3B), and the compound of formula (3B) can be used as intermediate in the preparation process of formula (1) compound
Figure G200780038464XD00061
The method comprises:
(i) compound or its mixture of usefulness sulphonating agent sulfonation formula (6B), formula (6C) in the presence of alkali,
Figure G200780038464XD00062
Form compound that the alkylsulfonyl of formula (7B), formula (7C) replaces or their mixture
Wherein, R is the optional alkyl or aryl that replaces;
(ii) compound or its mixture that replace with the alkylsulfonyl of reductive agent reduction-type (7B), formula (7C) form the compound of formula 8B
Figure G200780038464XD00064
(iii) with the compound of acid hydrolysis formula (8B), form the compound of formula (9B)
Figure G200780038464XD00071
(iv) with the compound of oxygenant oxidation-type (9B), then with the reductive agent reduction, form the compound of formula (10B)
Figure G200780038464XD00072
With
(v) in the presence of acid catalyst with the compound of acetylation reagent acetylize formula (10B), form the compound of formula (3B)
Figure G200780038464XD00073
In another embodiment, the present invention relates to the compound with the alkylsulfonyl replacement of reductive agent reduction-type (7), form the method for the compound of formula (8),
Figure G200780038464XD00074
Figure G200780038464XD00081
Wherein, R is the optional alkyl or aryl that replaces.In other embodiments, R is the optional C that replaces 1-C 6Alkyl or phenyl.In another embodiment, R is CF 3, CH 3,-C 6H 4CH 3
In another embodiment, the present invention relates to compound or its mixture with the alkylsulfonyl replacement of reductive agent reduction-type (7B), formula (7C), form the method for the compound of formula (8B),
Figure G200780038464XD00082
Wherein R is the optional alkyl or aryl that replaces.
In other embodiments, R is the optional C that replaces 1-C 6Alkyl or phenyl.In another embodiment, R is CF 3, CH 3Or-C 6H 4CH 3
Method of the present invention is applicable to the mass-producing commercial production of compound described herein.The method is easy and simple to handle, sane and effective.Specifically, the method be particularly useful for large-scale production 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole tosilate (1) of [4,5-d] pyrimid-2-one also.
Brief Description Of Drawings
Fig. 1 is the FT-Raman spectrum of formula (1) compound.
Fig. 2 is PXRD (X-ray diffraction) collection of illustrative plates of formula (1) compound.
Detailed Description Of The Invention
Term used herein " comprises " the exclusiveness connotation that comprises connotation rather than " only being made of it " that (and grammatical variants) refers to " containing " or " comprising ".Term used herein " one ", " this " are understood to include odd number and plural form.
Term used herein " halogenide " represent fluoride, muriate, bromide or iodide.Term " halogen " represents fluorine, chlorine, bromine or iodine.
Term used herein " alkyl " except as otherwise noted, comprise have straight chain, the saturated univalence hydrocarbyl of the combination of side chain or circular part (comprising the dicyclo and the volution part that condense with bridging) or aforementioned part.For the alkyl with loop section, this group must contain three carbon atoms at least.
Term used herein " aryl " comprises except as otherwise noted by removing an organic group that hydrogen obtains in the aromatic hydrocarbons, such as phenyl or naphthyl.
" alkyl " and " aryl " optionally is selected from following substituting group by 1-5 and replaces :-OH, halo ,-CN, C 1-C 6Alkyl, arylalkyl, C 1-C 6Alkoxyl group, C 1-C 6Thiazolinyl, C 1-C 6Hydroxyl, C 1-C 6Hydroxyalkyl, amino, C 1-C 6Alkylamine, C 1-C 6Dialkylamine, wherein alkyl also can further be replaced by one or more halogens.
Term " Ac " expression ethanoyl.
The compounds of this invention may be the mixture of single steric isomer, racemic modification and/or various enantiomer and/or diastereomer.The mixture of all this class single stereoisomers, racemic modification and/or various enantiomer and/or diastereomer all comprises within the scope of the invention.
Term used herein " oxygenant " refers to get in the chemical reaction process material of electronics, and term " reductive agent " refers to betatopic material in the chemical reaction process.
Term " immunomodulator " refers to and can or suppress to change normal or unusual immune natural or sintetics by stimulation.
Term " prevention " refers to that compound of the present invention or composition prevent being diagnosed as disease or have the patient's of ill danger the ability of disease.The further developing of patient disease that pre-tetrandra root suffers from or have this class disease symptoms also contained in this term.
Term " patient " or " object " expression animal (such as ox, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, cavy etc.) or Mammals comprise chimeric and transgenic animal and Mammals.
Term " treatment significant quantity " refers to be enough to treat or preventing disease, delay or minimize the symptom relevant with disease or healing or alleviate the consumption of the compounds of this invention of disease or infection or its cause of disease.Particularly, the treatment significant quantity represents to be enough to make the consumption that produces result for the treatment of in the body.Relevant with the use of a certain amount of the compounds of this invention, symptom or the cause of disease of improving total curative effect, reducing or avoid disease preferably contained in this term, perhaps increases the curative effect of another kind of therapeutical agent or produce synergistic avirulent consumption with another kind of therapeutical agent.
Term " prevention significant quantity " refers to be enough to recurrence or the compound of the present invention of propagation or the consumption of other active ingredient of preventing disease, disease.The prevention significant quantity can refer to be enough to prevent the recurrence of primary virus infection or infection or propagation or with the consumption that infects relevant disease.Relevant with the use of a certain amount of the compounds of this invention, this term is preferably contained the total prevention of improvement or is increased the prophylactic effect of another kind of preventive or therapeutical agent or produce synergistic avirulent consumption with another kind of preventive or therapeutical agent.
Term " combination " refers to simultaneously or in succession uses more than one preventive and/or therapeutical agent, and makes its effect adduction that produces separately or collaborative.
Term " treatment " refers to:
(i) preventing disease, imbalance or the state of an illness are being tended to this disease, imbalance or the state of an illness occur but are being occured in the animal that NYD has been suffered from;
(ii) suppress disease, imbalance or the state of an illness, namely stop its development; With
(iii) alleviate disease, imbalance or the state of an illness, or alleviate the symptom of disease, imbalance or the state of an illness and/or disease, imbalance and/or the state of an illness are disappeared.
Substituent specific three-dimensional chemical configuration on the unsymmetrical carbon in the chemical structure that term " R " and " S " refer to describe.
The compounds of this invention can demonstrate tautomerism.Although chemical formula can not demonstrate all possible tautomeric form, should be appreciated that they trend towards representing all tautomeric forms of shown compound, the particular compound form that is not limited only to describe.
Those skilled in the art know, has a chiral centre (namely, a unsymmetrical carbon) optical pure compound is basically by a kind of (being enantiomeric pure) that consists of in two kinds of possible enantiomers, the optically pure compound with an above chiral centre be simultaneously for diastereomer pure with compound enantiomer-pure.Preferably, form when the compounds of this invention uses is at least 90% optical purity, be that it contains at least 90% individual isomer (80% enantiomeric excess (" e.e. ") or diastereomeric excess (" d.e. ")), more preferably at least 95% individual isomer (90%e.e. or d.e.), even more preferably at least 97.5% individual isomer (95%e.e. or d.e.)), at least 99% individual isomer (98%e.e. or d.e.) most preferably.
5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole also the tosilate of [4,5-d] pyrimid-2-one as shown in the formula shown in (1):
5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole also the free alkali of [4,5-d] pyrimid-2-one (5) be amorphous substance.Before the present invention, never obtain crystallized form 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5-d] pyrimid-2-one (5) also.Be surprised to find according to the present invention now; under certain conditions; can by 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole also the tosilate (1) of [4,5-d] pyrimid-2-one obtain the extremely low crystallization shape of residual solvent.Crystallization shape of the present invention have surpass amorphous 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole advantage of [4,5-d] pyrimid-2-one (5) also.For example, dissolvent residual is lower in the final medicine of any form (for example, dissolved state).In addition, improve crystallisation process and can implement extra purifying.This is just so that medicine has higher stability and pharmaceutical factory's processing is easier.
5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole also the free alkali of [4,5-d] pyrimid-2-one (5) be hygroscopic matter.Estimated by chemical structure, 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-also [4,5-d] pyrimid-2-one (5) may be very responsive to hydrolysis for the 3H-thiazole.Be surprised to find according to the present invention now, tosilate crystallization shape is slight moisture absorption only, thereby has preferably storage properties and easier processing.
Found 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole also [4; 5-d] free alkali (5) of pyrimid-2-one contains some related substances (by product between synthesis phase), and shows residual solvent and water.The term according to the present invention " basically pure " represents that by weight the total amount of related substances is less than 1%, preferably less than 0.75%, more preferably less than 0.5%, residual solvent and water are less than 1%, preferably less than 0.75%, more preferably less than 0.5%, even more preferably less than 0.25%.
IR data-Fig. 1 has shown the FT-Raman spectrum of formula (1) compound.The feature of formula (1) compound is, 1356,1130,804,498 and 435cm -1Main IR bands of a spectrum are 1637,1602,1054,1037,609 and 530cm -1Medium bands of a spectrum.
X-ray data-Fig. 2 has shown the X-ray diffracting spectrum of formula (1) compound.In the x-ray spectra, take diffraction angle 2 θ as the x axle, peak intensity is the mapping of y axle.At 5.5 ° ± 0.3 ° the strongest line of observing in the X-ray diffracting spectrum of angle, observe the lower line of intensity at 11.8 °, 12.3 °, 17.9 °, 18.2 °, 19.7 °, 20.2 °, 21.3 °, 21.9 °, 23.8 °, 24.1 ° and 25.9 ° ± 0.3 °.
Pharmaceutical composition
The crystalline compounds of formula (1) can be used for pharmaceutical compositions, and said composition comprises the compound of at least a pharmaceutically acceptable carrier and formula (1).Detailed content with the carrier pharmaceutical compositions is described in U.S. Patent Application Publication 2006/0160830 (No. the 11/304th, 691, U. S. application), and its content is included into this paper as a reference.
The pharmaceutical composition and the single dose formulation that comprise formula 1 compound or its hydrate for medicinal use or solvate also fall within the scope of the present invention.That various formulation of the present invention is fit to is oral, mucosa delivery (comprising hypogloeeis, mouthful cheek, rectum, nose or vagina administration), parenteral (comprise subcutaneous, intramuscular, inject, intra-arterial or intravenously), transdermal or topical.Pharmaceutical composition of the present invention and formulation also comprise one or more pharmaceutically acceptable vehicle usually.Sterile formulation also within the scope of the invention.In an optional embodiment, pharmaceutical composition comprises compound or its pharmaceutically acceptable hydrate or the solvate of formula I of the present invention, and at least a other therapeutical agent.
The composition of formulation of the present invention, shape and type change with its application usually.For example, the formulation that is used for the acute treatment of a kind of disease or relative disease can contain one or more active ingredients larger than chronic treatment same disease consumption.Similarly, parenteral dosage form can contain one or more active ingredients than the oral dosage form less amount that is used for the treatment of same disease or imbalance.The personnel of affiliated technical field can understand very apparently these and be covered by the alternate manner that particular dosage form of the present invention is implemented.Referring to, for example, " Lei Mingdeng pharmaceutical science " (Remington ' s Pharmaceutical Science), the 18th edition, Mack publishing company, pennsylvania, USA Easton (Easton PA) (1990).The example of formulation includes but not limited to: tablet; The capsule sheet; Capsule such as soft elastic gelatin capsule; Flat jelly (cachets); Lozenge; Lozenge; Dispersion agent; Suppository; Ointment; Paste (poutices); Paste; Pulvis; Dressing; Ointment; Plaster; Solution; Patch; Aerosol (such as nasal spray or inhalation); Gel; The liquid dosage form that is fit to or mucosa delivery oral to the patient, comprise suspension agent (as, water-based or non-aqueous liquid suspension agent, oil-in-water emulsion or water-in-oil liquid emulsion), solution and elixir; Be fit to the liquid dosage form to patient's parenteral admin; And can be used to reconstitute the sterile solid that is fit to patient's parenteral admin liquid dosage form (as, crystallization or amorphous solid).
Typical pharmaceutical composition and formulation comprise one or more carriers, vehicle or thinner.Suitable vehicle is known in the pharmaceutical field, and this paper provides the indefiniteness example of suitable vehicle.Whether a kind of specific vehicle is suitable mixes pharmaceutical composition or formulation depends on the known various factors of this technical field, includes but not limited to patient's route of administration.For example, the oral dosage form such as tablet can contain the vehicle that is not suitable for parenteral dosage form.The suitability of particular excipient is also decided according to the concrete activeconstituents in the formulation.
Anhydrous pharmaceutical composition and the formulation that comprises active ingredient further contained in the present invention, because water can accelerate the degraded of some compound.For example, it is generally accepted in the pharmaceutical field adding entry (water such as 5%), and it can be used as the means of simulation long-term storage and measures such as storage life or the stability of preparation in following period of time.For example referring to Carstensen, " medicine stability: principle with put into practice " (DrugStability:Principles﹠amp; Practice), the 2nd edition, Marcel Dekker, New York, United States New York, 1995, the 379-80 pages or leaves.In fact, water and heat can accelerate the decomposition of some compounds.Therefore, owing to generally can run into moisture and/or moisture when making, process, pack, store, transporting and using preparation, water is very huge to the effect of preparation.
Anhydrous pharmaceutical composition of the present invention and formulation can use the component of anhydrous or low humidity and the condition of low humidity or low humidity to be prepared.
Can prepare anhydrous pharmaceutical composition and storage period chien shih its be maintained without aqueous nature.Therefore, anhydrous composition preferably uses known water-proof material to pack, and they can be wrapped in the test kit of suitable regulation.The example of suitable packing includes but not limited to, sealed foil, plastics, unit dosage container (such as phial), Blister Package and band packing.
The present invention also comprises pharmaceutical composition and the formulation of the compound that comprises one or more reduction active ingredient rate of decomposition.This compounds (below be called stablizer) includes but not limited to antioxidant (such as xitix), pH buffer reagent or salt buffer agent.
With the amount of vehicle and class types seemingly, the amount of active ingredient can be different according to various factors with concrete type in the formulation, such as but not limited to, to patient's route of administration.But the typical formulation of the present invention comprises formula 1 compound or its hydrate of 0.1-1500 milligram/unit, so that the dosage of about 0.01 to 200 mg/kg every day to be provided.
Oral dosage form
The pharmaceutical composition of the present invention that is fit to oral administration can be discontinuous formulation, such as but not limited to, tablet (such as chewable tablets), capsule sheet, capsule and liquid (such as the syrup of seasoning).This class formulation contains the active ingredient of predetermined amount, the known method preparation of available pharmaceutical field.Generally referring to " Lei Mingdeng pharmaceutical science ", the 18th edition, Mack publishing company, Pennsylvania, America Easton (EastonPA) (1990).
Prepare the typical oral dosage form of the present invention by following steps: make active ingredient and fully mix according at least a vehicle in the conventional medicine compounding technology.Choose various forms of vehicle according to the formulation of administration.For example, the vehicle that is suitable for liquid oral or aerosol includes but not limited to, water, polyvalent alcohol, oil, alcohol, seasonings, sanitas and tinting material.The vehicle example that is suitable for solid oral dosage form (such as powder, tablet, capsule and capsule sheet) includes but not limited to starch, sugar, Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent and disintegrating agent.
Because the Tablet and Capsula agent is easy to administration, they have represented formulation best in the oral dosage form, have wherein used solid excipient.When needing, the water-based of tablet available standards or non-aqueous technology are carried out dressing.This formulation can be prepared with any method in the pharmacy.In general, pharmaceutical compositions and formulation make active ingredient evenly mix nearly with liquid vehicle, finely divided solid carrier or this two kinds of carriers, as required product are formed afterwards, are made into required shape.
For example, tablet can prepare by compacting or mold pressing.The tablet of compacting can by compacting in suitable machine randomly with the active ingredient of the free-flowing form of mixed with excipients, prepare such as powder or particle.The tablet of mold pressing can make by in suitable machine the mixture of the moistening powdered compound of inert liq vehicle being carried out mold pressing.
The example that can be used for the vehicle of oral dosage form of the present invention includes but not limited to, tackiness agent, weighting agent, disintegrating agent and lubricant.The tackiness agent that is suitable for pharmaceutical composition and formulation includes but not limited to, W-Gum, yam starch or other starch, gelatin, natural and synthetic glue is (such as gum arabic, sodiun alginate, alginic acid, other alginate, the powdered tragacanth, guar gum, Mierocrystalline cellulose and its derivative are (such as ethyl cellulose, rhodia, calcium carboxymethylcellulose, Xylo-Mucine), Polyvinylpyrolidone (PVP), methylcellulose gum, the starch of pre-gelatinization, Vltra tears (as, the 2208th, 2906, No. 2910), Microcrystalline Cellulose and its mixture.
Be suitable for the pharmaceutical composition of this paper and the weighting agent in the formulation and include but not limited to, the Mierocrystalline cellulose of talcum powder, calcium carbonate (such as particle or powder), Microcrystalline Cellulose, powdered, dextrates (dextrates), kaolin, N.F,USP MANNITOL, silicic acid, sorbyl alcohol, starch, the starch of pre-gelatinization and their mixture.Tackiness agent or weighting agent account for about 50-99 % by weight of pharmaceutical composition or formulation usually in the pharmaceutical composition of the present invention.
The suitable form of Microcrystalline Cellulose includes but not limited to, trade(brand)name AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 are (available from FMC Corp. (FMCCorporation), U.S. viscose department (American Viscose Division), Avicel sales department, and their mixture pennsylvania, USA Ma Kusi Hooke (Marcus Hook)).Specific tackiness agent is the mixture of Microcrystalline Cellulose and carboxymethyl cellulose, and commodity are called AVICEL RC-581.Suitable anhydrous or low-moisture vehicle or additive comprise AVICEL-PH-103 TMAnd Starch1500LM.
The disintegrating agent that is used for the present composition makes tablet disintegration when being exposed to water surrounding.The tablet that contains too much disintegrating agent can disintegration when storing, can not be with required speed disintegration or can not disintegration under required condition and contain the tablet of very few disintegrating agent.Therefore, preparing the used disintegrating agent of solid oral dosage form of the present invention can not too much can not be very little, and its consumption should significantly not change the release of active ingredient.The consumption of disintegrating agent can change with the type of preparation, and this those of ordinary skill for described field is apparent.Usually pharmaceutical composition comprises about 0.5-15 % by weight disintegrating agent, the preferably disintegrating agent of about 1-5 % by weight.
The disintegrating agent that can be used for pharmaceutical composition of the present invention and formulation includes but not limited to, starch, other starch, clay, other phycocolloid, other Mierocrystalline cellulose, natural gum and their mixture of agar-agar, alginic acid, calcium carbonate, Microcrystalline Cellulose, croscarmellose sodium, Crospovidone, polacrilin potassium (polacrillin potassium), Explotab, yam starch or tapioca (flour), pre-gelatinization.
The lubricant that can be used for pharmaceutical composition of the present invention and formulation includes but not limited to, calcium stearate, Magnesium Stearate, mineral oil, light mineral oil, glycerine, sorbyl alcohol, N.F,USP MANNITOL, polyoxyethylene glycol, other polyvalent alcohol, stearic acid, Sodium Lauryl Sulphate BP/USP, talcum powder, hydrogenated vegetable oil (such as peanut oil, Oleum Gossypii semen, Trisun Oil R 80, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil), Zinic stearas, ethyl oleate, Laurate ethyl, agar and their mixture.Other lubricant for example comprises, (AEROSIL 200 for silicate silica gel, W.R. Gray company (W.R.Grace Co.) manufacturing by Maryland, USA Baltimore), the coagulated aerosol of synthetic silica is (by the many (TX of Texas, USA Blanc, Plano) goldschmidt chemical corporation (Degussa Co.) sale), CAB-O-SIL (pyrogenic silica product, sold by the card C Compaq (Cabot Co.) in Massachusetts, United States Boston (MA, Boston)) and their mixture.If when needing to use, the consumption of lubricant is less than about 1 % by weight of pharmaceutical composition or formulation.
Delayed release dosage forms
Can give active ingredient of the present invention by the controlled release mode or by the known defeated delivery device of this release field those of ordinary skill.Example can referring to but be not limited to United States Patent (USP) 3,845,770; 3,916,899; 3,536,809; 3,598,123; With 4,008,719,5,674,533,5,059,595,5,591,767,5,120,548,5,073,543,5,639,476,5,354,556 and 5,733,566, these patents are all included this paper in as a reference.This class formulation is one or more active ingredients of slowly-releasing or controlled release by the following material that uses various ratios, described material is for example Vltra tears, other polymeric matrix, gel, permeable membrane, osmosis system, multiple coatings, particulate, liposome, microballoon or its combination, thereby obtains required release profiles.In order to use active ingredient of the present invention, can easily select suitable controlled release preparation known to a person of ordinary skill in the art as herein described.Therefore the unit dosage of suitable oral administration has been contained in the present invention, includes but not limited to, is fit to tablet, capsule, gel capsule (gelcaps) and the capsule sheet (caplets) of controlled release.
The general purpose of all controlled release medicines is to make its curative effect of medication obtain to improve with respect to the corresponding medicine of non-controlled release.It is desirable to, in pharmacological agent, use the controlled release preparation of optimum design to be characterised in that in the shortest time, to be used for and cure or to control the drug dose of the state of an illness minimum.The advantage of controlled release preparation comprises that the activity of medicine prolongs, administration frequency reduces, patient's conformability increases.Therefore in addition, controlled release preparation can be used to affect beginning action time or other characteristic of medicine, such as blood level, and affects the generation of side effect (for example untoward reaction).
Most of controlled release preparations are designed to begin to discharge a certain amount of medicine (active ingredient) with the required therapeutic action of rapid generation, then discharge gradually and constantly the medicine of other amount to keep the level for the treatment of or prophylactic effect in the time of an elongated segment.In order to keep in vivo this stable blood level, medicine must be discharged from formulation by the speed of the medicine of metabolism and drainage with replacement.By various conditions, but include but not limited to the controlled release of pH, temperature, enzyme, water or other physiological condition or compound stimulating activity component.
Parenteral dosage form
Parenteral dosage form is administration by all means, includes but not limited to subcutaneous administration, intravenously (comprise and injecting) administration, intramuscular administration and intra-arterial administration.Because their administration is walked around the patient usually to the natural defence of pollutent, so parenteral dosage form is preferably aseptic, or can carry out disinfection before giving the patient.The example of parenteral dosage form includes but not limited to that instant injection liquid, preparation are dissolved in or are suspended in drying and/or freeze-drying prods (powder that can rebuild), injection suspension and the emulsion of pharmaceutically acceptable injection vehicle.
The suitable vehicle that is used for parenteral dosage form of the present invention is that these those skilled in the art are known.Example includes but not limited to, water for injection USP; The water-based vehicle, such as but not limited to, the ringer's injection of sodium chloride injection, Lin Ge (Ringer) injection liquid, dextrose injection liquid, dextrose and sodium chloride injection and lactic acid; Vehicle that can be miscible with water, such as but not limited to, ethanol, polyoxyethylene glycol and polypropylene glycol; Non-aqueous vehicle, such as but not limited to, Semen Maydis oil, Oleum Gossypii semen, peanut oil, sesame oil, ethyl oleate, Isopropyl myristate and peruscabin.
Also the compound that can increase the solubleness of one or more active ingredients that this paper discloses can be mixed in the parenteral dosage form of the present invention.
The transdermal formulation
The transdermal formulation comprises " reservoir devices " or " matrix type " patch, and it can be used for skin and uses for some time, allows the active ingredient of aequum permeate.
Can be used to provide the appropriate excipients (such as carrier and thinner) of transdermal of the present invention and topical formulations and other material is that technician in the pharmaceutical field is known, can decide according to the particular organization that gives pharmaceutical composition or formulation.Typical vehicle includes but not limited to water, acetone, ethanol, ethylene glycol, propylene glycol, 1,3 butylene glycol, Isopropyl myristate, Wickenol 111, mineral oil and their mixture.
According to the particular organization that is treated, before with active ingredient of the present invention treatment, while or can use other component afterwards.For example, can use penetration enhancer to help active ingredient to the tissue infiltration.Suitable penetration enhancer includes but not limited to: acetone; Various alcohol are such as ethanol, oleyl alcohol and tetrahydrofuran (THF); Alkyl sulfoxide is such as methyl-sulphoxide; N,N-DIMETHYLACETAMIDE; Dimethyl formamide; Polyoxyethylene glycol; Pyrrolidinone compounds is such as polyvinylpyrrolidone; Kollidon (Kollidon) level (pyrrole dimension ketone, polyvidone); Urea and various water-soluble or water-insoluble sugar ester are such as tween 80 (polysorbate80) and sorbester p18 (sorbitan monostearate).
Can the regulating drug composition or the pH value of formulation or give pharmaceutical composition or the pH value of the tissue of formulation is improved the defeated of one or more active ingredients and passed.Similarly, polarity, its ionic strength or the tension force that can regulate solvent carrier improve defeated passing.The compound of stearate and so on also can be added in pharmaceutical composition or the formulation, improves defeated passing with the wetting ability or the lipotropy that advantageously change one or more active ingredients.Thus, stearate can be used as the lipid vehicle of preparation, as emulsifying agent or tensio-active agent, and can be used as defeated pass promotor or penetration enhancer.Different salt, hydrate or the solvate of useful active ingredient further regulated the character of resulting composition.
Topical formulations
Topical formulations of the present invention includes but not limited to, known other formulation of ointment, washing lotion, ointment, gel, solution, emulsion, suspension agent or this those skilled in the art.For example referring to " Lei Mingdeng pharmaceutical science ", the 18th edition, Mike publishing company (Mack Publishing), pennsylvania, USA Easton (1990); " pharmaceutical dosage form introduction " (Introduction to Pharmaceutical DosageForms), the 4th edition, Lea and Febiger, U.S. Philadelphia (1985).
The appropriate excipients that can be used to provide transdermal and topical formulations that the present invention is contained (for example carrier and thinner) and other material are that the pharmaceutical field technician is well-known, and the particular organization that gives according to pharmaceutical composition or formulation decides.Typical vehicle includes but not limited to water, acetone, ethanol, ethylene glycol, propylene glycol, 1,3 butylene glycol, Isopropyl myristate, Wickenol 111, mineral oil and their mixture.
According to the particular organization that is treated, before with active ingredient of the present invention treatment, while or can use other component afterwards.For example, can use penetration enhancer to help active ingredient to send to tissue.Suitable penetration enhancer includes but not limited to: acetone; Various alcohol are such as ethanol, oleyl alcohol and tetrahydrofuran (THF); Alkyl sulfoxide is such as methyl-sulphoxide; N,N-DIMETHYLACETAMIDE; Dimethyl formamide; Polyoxyethylene glycol; Pyrrolidinone compounds is such as polyvinylpyrrolidone; Kollidon (Kollidon) level (pyrrole dimension ketone, polyvidone); Urea and various water-soluble or non-water-soluble sugar ester are such as tween 80 (polysorbate80) and sorbester p18 (sorbitan monostearate).
The mucous membrane formulation
Mucous membrane formulation of the present invention includes but not limited to, ophthalmic solution, sprays and aerosol, or other form well known by persons skilled in the art.For example can be referring to " Lei Mingdeng pharmaceutical science ", the 18th edition, Mike publishing company, pennsylvania, USA Easton (1990); " pharmaceutical dosage form introduction ", the 4th edition, Lea and Febiger, U.S. Philadelphia (1985).The formulation that is fit to treat mucosal tissue in the oral cavity can be mixed with washing liquid of oral cavity or buccal cavity gel.In one embodiment, aerosol comprises carrier.In another embodiment, aerosol does not contain carrier.
The compound of formula (1) also can be by sucking directly to pulmonary administration.For inhalation, formula (1) compound can carry out conventional defeated passing to lung by many different equipment.For example, metered dose inhaler (" MDI ") uses the canister contain suitable lower boiling propelling agent directly with the defeated lung that is delivered to of formula (1) compound, and described propelling agent is for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other other suitable gas.MDI equipment can be buied from many suppliers, replaces this (Aventis), BI company (Boehringer Ingleheim), Forest Laboratories (Forest Laboratories), GlaxoSmithKline PLC (Glaxo-Wellcome), Schering Plough (Schering Plough) and all carat of company (Vectura) such as 3M company (3M Corporation), A Fan.
Perhaps, can use Diskus (DPI) to the compound of lung's giving construction (1) (such as referring to Raleigh etc., american association of cancer research's annual meeting proceedings (Proc.Amer.Assoc.Cancer ResearchAnnual Meeting), 1999,40,397, the document is included this paper in as a reference).DPI equipment uses the smog that produces dry powder such as gas blow-through mechanism in container usually, and then this smog can be the patient and suck.DPI equipment also is well known in the art, can buy from many suppliers, for example comprise Fei Shi (Fisons), GlaxoSmithKline PLC (Glaxo-Wellcome), Inhale Therapeutics Systems, Inc (InhaleTherapeutic Systems), ML laboratory company (ML Laboratories), storehouse all (Qdose) and all carat of company (Vectura).Welcome version is multiple doses DPI (" MDDPI ") system, and it permits the defeated healing potion of passing more than one.MDDPI equipment can be available from for example Aktiebolaget Astra (AstraZeneca), GlaxoSmithKline PLC (Glaxo-Wellcome), IVAX, Schering Plough (ScheringPlough), sky pharmacy (SkyePharma) and all carat of company (Vectura).For example, gelatine capsule and the cartridge for sucker or insufflator can be mixed with the powdered mixture that contains compound and be applicable to the powder binder (such as lactose or starch) of these systems.
Being used for the defeated another kind of equipment that is delivered to lung of formula (1) compound is liquid spray equipment, for example the equipment produced of Aladdin company (Aradigm Corporation).Liquid spray equipment uses minimum nozzle to make liquid pharmaceutical formulation aerosolized, then can directly suck lung.
In one embodiment, use spraying plant with the defeated lung that is delivered to of formula (1) compound.By using, for example ultrasonic energy forms the fine particle that can suck easily, and atomizer is made aerosol by liquid pharmaceutical formulation.(such as referring to Verschoyle etc., British J.Cancer, 1999,80, augment 2,96, the document is included this paper in as a reference).The example of atomizer comprise Shi Fei/systemic lung defeated pass company limited (Sheffield/Systemic Pulmonary Delivery Ltd.) (referring to Armer etc., United States Patent (USP) the 5th, 954, No. 047; Van der Linden etc., United States Patent (USP) the 5th, 950, No. 619; Van der Linden etc., United States Patent (USP) the 5th, 970 No. 974, is included this paper in as a reference); The equipment that A Fantisi (Aventis) and treatment company of Ba Daier lung (Batelle Pulmonary Therapeutics) provide.
In one embodiment, use electrofiuid mechanics (" EHD ") aerosol device to the defeated compound of formula (1) of passing of lung.The EHD aerosol device use electric energy make liquid medicine solution or suspension aerosolized (such as referring to Noakes etc., United States Patent (USP) the 4th, 765, No. 539; Coffee, United States Patent (USP) the 4th, 962, No. 885; Coffee, PCT applies for WO 94/12285; Coffee, PCT applies for WO 94/14543; Coffee, PCT applies for WO 95/26234, Coffee, PCT applies for WO 95/26235, Coffee, PCT applies for WO 95/32807, these documents are included this paper in as a reference).When using the EHD aerosol apparatus to pass this medicine to lung is defeated, the electrochemical properties of formula (1) compound formulation may be important parameters optimization, and this class optimization can be carried out according to routine by those skilled in the art.The defeated technology of passing of the comparable existing lung of EHD aerosol device is more effectively to the defeated drug delivery of lung.The defeated method of passing is well known to a person skilled in the art in other lung of formula (1) compound, also within the scope of the invention.
The liquid pharmaceutical formulation that is fit to the use of atomizer and liquid spray equipment and EHD aerosol apparatus comprises formula (1) compound and pharmaceutically acceptable carrier usually.Preferably, pharmaceutically acceptable carrier is the liquid such as alcohol, water, polyoxyethylene glycol or perfluoro-carbon.Optional is to add the Aerosol Properties that another kind of material comes change formula (1) compound solution or suspension.Preferably, this material is the liquid such as alcohol, glycol, polyglycol or lipid acid.Other method that preparation is suitable for the liquid medicine solution of aerosol apparatus or suspension be this technical field personnel known (for example referring to Biesalski, United States Patent (USP) the 5th, 112, No. 598; Biesalski, the 5th, 556, No. 611, these patents are included this paper in as a reference).Formula (1) compound also can be mixed with rectal compositions or vaginal compositions, such as suppository or delay enema, for example can contain the conventional suppository base such as theobroma oil or other glyceryl ester.
Except aforesaid preparation, formula (1) compound also can be mixed with prolonged action preparation.The preparation of this class long term can be implanted or give by intramuscularly by (for example subcutaneous or intramuscular).Like this, compound can with suitable polymer materials or hydrophobic material (for example, can accept the emulsion in the oil) or ion exchange resin preparation, perhaps be mixed with sl. sol. derivative, for example sl. sol. salt.
Perhaps, can use other drug delivery system.Liposome and emulsion are to can be used to the defeated known defeated example of passing vehicle of passing formula (1) compound.Can use some organic solvent such as methyl-sulphoxide, but this solvent has larger toxicity usually.The compound of formula (1) also can be failed in controlled release system and pass.In one embodiment, can use pump (Sefton, CRC Crit.Ref Biomed Eng, 1987,14,201; Buchwald etc., Surgery, 1980,88,507; Saudek etc., N.Engl.J.Med., 1989,321,574).In another embodiment, can use polymer materials (referring to, the medical use of controlled release (Medical Applications of Controlled Release), Langer and Wise (editor), CRCPres., Boca Raton, Fla. (1974); Controlled drug bioavailability (Controlled DrugBioavailability), " medicine design and performance " (Drug Product Design and Performance), Smolen and Ball (editor), Wiley, N.Y. (1984); Ranger and Peppas, J.Macromol.Sci.Rev.Macromol.Chem., 1983,23,61; Also can be referring to Levy etc., Science, 1985,228,190; During etc., Ann.Neurol., 1989,25,351; Howard etc., 1989, J.Neurosurg.71,105).In another embodiment, controlled release system can place the target of the compounds of this invention, near lung, so just only need to give the part of body dose (for example referring to Goodson, the medical use of controlled release (Medical Applications of Controlled Release), the same, the 2nd volume, 115 pages (1984)).Can also use other controlled release system (for example referring to Langer, Science, 1990,249,1527).
Suitable vehicle (such as carrier and thinner) and to can be used to provide other material of mucous membrane formulation of the present invention be that the pharmaceutical field technician is well-known can be decided according to specific site or method that composition or formulation give.Typical vehicle includes but not limited to that water, ethanol, ethylene glycol, propylene glycol, 1,3 butylene glycol, Isopropyl myristate, Wickenol 111, mineral oil and their mixture, described vehicle are nontoxic and pharmaceutically acceptable.The other component example of this class is well-known in the art.For example referring to, " Lei Mingdeng pharmaceutical science ", the 18th edition, mark publishing company, pennsylvania, USA Easton (1990).
Also can regulate the pH value of pharmaceutical composition or formulation or give pharmaceutical composition or the pH value of the tissue of formulation is improved the defeated of one or more active ingredients and passed.Similarly, can regulate the ionic strength of polarity, solvent carrier of solvent carrier or tension force to improve defeated passing.Also the compound of stearate and so on can be added to wetting ability or the lipotropy advantageously to change one or more active ingredients in pharmaceutical composition or the formulation, thereby improve defeated passing.Thus, stearate can be used as the liquid excipient of preparation, as emulsifying agent or tensio-active agent, and as defeated promotor or the penetration enhancer passed.Different salt, hydrate or the solvate of useful active ingredient further regulated the character of resulting composition.
Medicine box
The invention provides the drug packages or the medicine box that comprise one or more containers, described container comprises and is used for the treatment of or the compound of prophylactic formula (1).In other embodiments, the invention provides the drug packages or the medicine box that comprise one or more containers, described container comprises and is used for the treatment of or the compound of prophylactic formula (1), described drug packages or medicine box also comprise one or more containers, and these containers comprise extra therapeutical agent.
The present invention also provides drug packages or the medicine box that comprises one or more containers, and described container comprises the composition of one or more pharmaceutical compositions of the present invention.These containers randomly are equipped with the book of informing by the medicine of government organs' regulation or biological products production, use or sale prescribed form, and this book of informing has reflected that the described medicine of human or manufacturing, use or the sale of biological products have obtained government organs' license.
The treatment disease
In one embodiment, the compound of use formula (1) in the treatment of disease or prevention process.For example, improved the method that prevention or treatment warm-blooded animal, especially people's pathogenic organisms infect, the method comprises the crystallization shape compound of the formula (1) that gives significant quantity.One preferred embodiment in, pathogenic organisms is on the described bacterium of WO2005/121162, fungi or virus infection, in preferred embodiment, by adenovirus, cytomegalovirus, hepatitis A virus (HAV), hepatitis B virus (HBV), the Flavivirus that comprises yellow fever virus and hepatitis C virus (HCV), 1 type and 2 type herpes simplex viruss, varicella zoster virus, Human herpesviryus 6, human immunodeficiency virus (HIV), human papillomavirus (HPV), influenza A virus, Influenza B virus, Measles virus, parainfluenza virus, poliovirus, poxvirus (comprising smallpox and monkey pox virus), rhinovirus, respiratory syncytial virus (RSV), the multiple Viraceae of the heat that causes bleeding comprises Arenaviridae (LCM, Junin virus, machupo arenavirus, guanarito virus and lassa fever), Bunyaviridae (Hantaan virus and enzootic hepatitis) and Filoviridae (Ebola and marburg virus); Various viral encephalitis viruses comprise west nile virus, La Crosse virus, Gary Fu Niya encephalitis, Venezuelan equine encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, japanese encephalitis virus, kyasanur forest diseae virus,Kyasanur forest virus; The virus infection that causes with tickborne virus such as crimean-Congo hemorrhagic fever virus.Especially preferred HBV and HCV.
Another embodiment provides the method for regulating warm-blooded animal, especially people's immune cell factor activity, and the method comprises formula (1) compound of the crystallized form that gives significant quantity.Crystallization shape compound as the formula (1) of medicine also is provided.Also provide the crystallization shape compound of formula (1) to be used for the treatment of pathogenic infection in manufacturing, especially the application in the medicine of virus (for example HCV or HBV) infection.
Another embodiment provides the method for the treatment of mammal tumor or cancer, and the method comprises the compound of the formula (1) that gives Mammals (patient) treatment significant quantity.Expect that medicable tumour or cancer include but not limited to tumour or cancer that those are caused by virus, these function of chemical compounds relate to and suppress to have infected viral cell transformation is neoplastic state, suppresses virus from the cellular invasion that is converted to other normal cell and/or stops the growth of the cell of virus Transformation.Expect that compound of the present invention can be used for resisting the tumour of wide spectrum, includes but not limited to: cancer, sarcoma and leukemia.This class tumour comprises: mammary cancer, colorectal carcinoma, bladder cancer, lung cancer, prostate cancer, cancer of the stomach and carcinoma of the pancreas and lymphocytoblast leukemia and myelocytic leukemia.
Formula (1) compound or its pharmaceutically acceptable solvate or hydrate in acute or chronically infected treatment or prevention prevention or the size of therapeutic dose, will change with the character that infects and the route of administration of seriousness and activeconstituents.Dosage, and administration frequency in some situation also can be according to age, body weight and the reactions of the disease that will treat, individual patient and different.Suitable dosage can be determined according to these factors at an easy rate by those skilled in the art.
Method of the present invention is particularly suitable for human patients.Particularly, method of the present invention and dosage can be used for immunity and weaken the patient, include but not limited to: cancer patients, HIV infected patient and suffer from the patient of immune degenerative disease.In addition, these methods can be used for being at present the immunity weakening patient of relieved state.Method of the present invention and dosage also can be used for accepting the patient of other antiviral therapy.Prevention method of the present invention is particularly useful for by the patient of risk from viral infection.These patients include but not limited to: health care worker, as, doctor, nurse, the paramedic of collecting post; The military personnel; The teacher; The child-bearing worker; The patient of the third world is particularly lived in travelling or live in abroad, comprises the social helping worker, missionary and diplomatic envoy.At last, these method and compositions comprise the intractable patient for the treatment of or treatment are produced the tolerance patient of (as producing resistance to reversing transcripting enzyme inhibitor, proteinase inhibitor etc.).
Dosage
Toxicity and the drug effect of formula (1) compound can be measured by the standard pharmaceutical procedures of carrying out in cell cultures or laboratory animal, as measuring LD 50(causing the dosage of 50% colony death) and ED 50(to the effective dosage of 50% mass treatment).The dose ratio of toxicity and curative effect is therapeutic index, and it can be expressed as LD 50/ ED 50
The data that obtain from cell culture assays and zooscopy can be used to be identified for the dosage range of the compound of human body.The dosage of this compounds is preferably comprising almost there is not or do not have virose ED 50The circulation composition scope in.Can in this scope, change dosage according to used formulation and route of administration.For any compound that is used for the inventive method, the treatment effective dose can at first estimation from cell culture assays.Dosage in the capable of regulating animal model is to obtain comprising the IC that measures in the cell cultures 50The circulating concentration scope of (that is, reaching the concentration of the test compound of maximum half that suppresses of symptom); Perhaps, the dosage of allocation type in animal model (1) compound is so that the circulating concentration scope of the compound concentration required with being fixed the reaction magnitude is mapped.This category information can be used for determining more accurately the dosage useful to human body.Blood level can pass through, and for example high performance liquid chromatography is measured.
The solution of the present invention and composition preferably carry out in vitro tests to required treatment or prophylactic activity first, and then carry out in vivo test before being used for human body.For example, analyzed in vitro can be used to determine whether to give specific treatment plan, and analyzed in vitro comprises the cell in vitro culture assays, and making has the cell of replying to contact with part to formula (1) compound, and the intensity of replying by suitable commercial measurement.Then assess this compound with regard to the intensity of formula (1) compound.The compound that is used for the inventive method can be tested with suitable animal model before to human trial, and described animal model includes but not limited to: rat, mouse, chicken, ox, monkey, rabbit, hamster etc.Then compound can be used for suitable clinical trial.
The compound of formula of the present invention (1) or its pharmaceutically acceptable solvate or hydrate preventive dose or the value of therapeutic dose in acute or chronic treatment or preventing infection or disease can be different with the route of administration of the character that infects and severity and active ingredient.Dosage, and possible administration frequency also can be different with the disease that will treat, patient's age, body weight and reaction.Those skilled in the art can select suitable dosage at an easy rate according to the consideration to these factors.In some embodiments, dosage is decided according to the specific compound that uses and patient's body weight and the state of an illness.Dosage also can be according to different particular compound of the present invention and difference; Suitable dosage can be predicted according to aforesaid vitro test and zooscopy.In general, the dosage range of every day is about 0.001-100 mg/kg, preferably about 1-25 mg/kg, more preferably from about 5-15 mg/kg., divided to give about 0.1 milligram of dosage to about 15 grams/sky for 1-4 time in one day by the people of infection with hepatitis C virus for treatment, preferably 100 mg/day to 12 gram/sky is more preferably the 100-8000 mg/day.
In addition, the per daily dose of recommendation can following period of time as unitary agent or with other therapeutical agent combined cycle administration.In one embodiment, the every per daily dose that gives is single dose or five equilibrium dosage.In a relevant embodiment, every per daily dose of recommendation can give weekly to give once, weekly twice, weekly give three times, give four times weekly or give weekly five times.
In one embodiment, compound of the present invention can distribute by whole body in patient body through administration.In relevant embodiment, compound of the present invention can produce general action in vivo through administration.
In another embodiment, compound of the present invention is by oral, mucous membrane (comprising hypogloeeis, cheek, rectum, nose or vagina) administration, parenteral (comprise subcutaneous, intramuscular, inject, intra-arterial or intravenously) administration, transdermal administration or topical.In a certain concrete embodiment, compound of the present invention is by mucous membrane (comprising hypogloeeis, cheek, rectum, nose or vagina) administration, parenteral (comprising subcutaneous, intramuscular, intravenous injection, intra-arterial or intravenously) administration, transdermal administration or topical.In another embodiment, compound of the present invention passes through oral administration.In another embodiment, compound of the present invention is not by oral administration.
As those of ordinary skill in the art understand, for the available different treatment significant quantity of different infection.Similar is, is enough to treat or prevents this class to infect but be not enough to cause or the amount that is enough to alleviate the side effect relevant with conventional treatment also is encompassed in above-mentioned dosage range and the administration frequency scheme.
Combination treatment
Concrete grammar of the present invention also comprises the therapeutical agent (that is, the therapeutical agent of non-the compounds of this invention) that gives other.In the concrete embodiment of the present invention, the compounds of this invention can be united use with at least a other therapeutical agent.Described therapeutical agent includes but not limited to: microbiotic, antiemetic, antidepressive and anti-mycotic agent, antiphlogiston, antiviral agent, anticarcinogen, immunomodulator, alpha-interferon, beta-interferon, ribavirin, alkylating agent, hormone, cytokine or toll acceptor sample conditioning agent.
The compound of formula (1) can with Antibiotic combination administration or formulated together.For example, they can be prepared with following microbiotic: Macrolide (as, tobramycin (
Figure G200780038464XD00261
)), cynnematin (as, Cephalexin Monohydrate Micro/Compacted ( ), Cephradine (
Figure G200780038464XD00263
), cephalofruxin (
Figure G200780038464XD00264
), Prozef (
Figure G200780038464XD00265
), cefaclor (
Figure G200780038464XD00266
), Cefixime Micronized (
Figure G200780038464XD00267
) or S 578 (
Figure G200780038464XD00268
)), clarithromycin (as clarithromycin (
Figure G200780038464XD00269
)), erythromycin (as, erythromycin (
Figure G200780038464XD002610
)), penicillin is (such as, penicillin v (V-
Figure G200780038464XD002611
Or Pen
Figure G200780038464XD002612
)) or quinlone (as, Ofloxacine USP 23 ( ), Ciprofloxacin (
Figure G200780038464XD002614
) or norfloxicin (
Figure G200780038464XD002615
)), aminoglycoside antibiotics (as, apramycin, Arbekacin, Moenomycin. Flavophospholopol, butirosin, dibekacin, Liu Suanyan NEOMYCIN SULPHATE, undecylenate (salt), netilmicin, paromycin, ribostamycin, sisomicin and spectinomycin), acid amides alcohol (amphenicol) microbiotic (as, azidoamphenicol, paraxin, florfenicol and thiamphenicol), the ansamycin microbiotic (as, rifamide and Rifampin), carbacephem (as, Loracarbef), carbapenem (as, biapenem and imipenum), cynnematin (as, cefaclor, S 578, Cefamandole, cefatrizine, cefazedone, Cefozopran, U-63196E, cefpiramide and cefpirome), cephamycin-type (as, cefbuperazone, cefmetazole and cefminox), the monobactam class (as, aztreonam, carumonam and tigemonam), oxacephems (as, flomoxef and latamoxef), penicillins (as, nitrogen
Figure G200780038464XD00271
Amidine penicillin, nitrogen
Figure G200780038464XD00272
An amidine penicillin ester (amdinocillinpivoxil); the amoxycilline Trihydrate bp; bacampicillin; benzyl penicillinic acid; benzyl penicillin sodium; epicillin; Fenbenicillin; the Flucloxacillin; Wy-20788; the Pulmo 500 hydriodate; benapen (penicillino-benethamine); penicillin; penicillin v; penicillin V benzathine; abbocillin V; Prestociclina and penicillin-152 (phencihicillin potassium)); lincosamide (as; clindamycin and lincomycin); Ecomytrin; bacitracin; capromycin; Polymyxin E; enramycin; Tuberaction N; tetracyclines (as; Apicycline; duomycin; clomocycline and Demethylchlortetracycline); 2; the 4-diaminopyrimidine (as; brodimoprim); itrofurans (as; levofuraltadone and furazolium chloride); quinolones and its analogue (as; cinoxacin; Clinafloxacin; flumequine and grepafloxacin); sulfamido (as; sulfacetimide methoxy pyrazine; benzylsulfamide; Noprylsulfamide; Phthalylsulfacetamide; sulfachrysoidine and sulfacitine); the sulfone class (as, thymol sulfone; glucosulfone sodium and Solasulfone); seromycin; mupirocin and tuberin (tuberin).
The compound of formula (1) can with antiemetic Combined Preparation or preparation.Suitable antiemetic includes but not limited to: metoclopramide, domperidone, prochlorperazine, promethazine, Torazina, trimethobenzamide, ondansetron, granisetron, hydroxyzine, the N-Acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, umine, diphenidol, dolasetron, Meclozine, Methallatal, metopimazine, nabilone, Oxipendyl, pipamazine, Scopolamine, Sulpiride, tetrahydrocannabinol, Tietylperazine, cephalmin, tropisetron and their mixture.
The compound of formula (1) can with thymoleptic Combined Preparation or formulated together.Suitable thymoleptic include but not limited to: binedaline, caroxazone, citalopram, dimethazan, fencamine, indalpine, Indeloxazine hydrochloride, nefopam, nomifensine, Quietim, oxypertine, paroxetine, Sertraline, Tiazesim, triazolone, benmoxine, iproclozide, iproniazid, Isocarboxazid, nialamide, Ximaol, Phenelzine, cotinine, Rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazapine (mirtazepine), adinazolam, amitriptyline, Amitriptylinoxide, amoxapine, butriptyline, clomipramine, Deparon, Desipramine, the dibenzepin, dimetacrine, the degree coloured glaze is flat, doxepin, Triflupromazine, imipramine, imipramine N-oxide compound, iprindole, Tymelvt, melitracen, metapramine, nortriptyline, noxiptiline, opipramol, Somigran, propizepine, protriptyline, quinupramine, tianeptine, Trimipramine, Adrafinil, benactyzine, Bupropion, Butacetin, dioxadrol, duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine, haematoporphyrin, hypericin, Levophacetoperane, the medifoxamine, Midalcipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, Roxindole, rubidium chloride, Sulpiride, Tandospirone, Tozalinone, tofenacin control-om, Tranylcypromine, L-Trp, Venlafaxine, viloxazine and zimeldine.
The compound of formula (1) can with anti-mycotic agent Combined Preparation or formulated together.Suitable anti-mycotic agent includes but not limited to: amphotericin B, itraconazole, KETOKONAZOL, fluconazole, her Qu Saike (intrathecal), flucytosine, miconazole, butoconazole, clotrimazole, nystatin, Triaconazole, tioconazole, ciclopirox, econazole, haloprogin, naftifungin, Terbinafine, undecylenate (salt) and grisovin.
The compound of formula of the present invention (1) can with antiphlogiston Combined Preparation or formulated together.Useful antiphlogiston includes but not limited to: non-steroidal anti-inflammatory drugs, such as Whitfield's ointment, acetylsalicylic acid, wintergreen oil, diflunisal, salsalate, olsalazine, sulfasalazine, paracetamol, indomethacin, sulindac, R-ETODOLAC, mefenamic acid, Sodium meclophenamate, tolmetin, ketorolac, Diclofenamide, Ibuprofen BP/EP, Naproxen Base, naproxen sodium, fenoprofen, Ketoprofen, U-27182, Taisho), piroxicam, meloxicam, Ampiroxicam, Droxicam, Fu Xikang (pivoxicam), tenoxicam, nabumetone, Phenylbutazone, Tacote, quinizine, pyramidon, Azapropazone and nimesulide; Leukotriene antagonist includes but not limited to: zileuton, Aurothioglucose, Sodium Aurothiomalate and auranofin; Steroid includes but not limited to: Sch-22219, amcinonide, Viarox, Betamethasone Valerate, W-5975, Sch-11460, betamethasone sodium phosphate, Valisone, clobetasol propionate, the PIVALIC ACID CRUDE (25) clocortolone, hydrocortisone, hydrocortisone derivative, Hydroxyprednisolone Acetonide, desoximetasone, dexamethasone, flunisolide, fluorine can hot pine (flucoxinolide), flurrenolone, chlorine fluorine pine, Zpoflogin, methylprednisolone, the acetic acid methylprednisolone, Urbason Solubile, furoic acid momisone, the acetic acid paramethasone, prednisolone, the prednisone acetate dragon, prednisolone phosphate disodium, uncle's Hydeltra T. B. A, prednisone, triamcinolone, Triamcinolone Acetonide, oxalic acid triamcinolone and triamcinolone hexacetonide; And other antiphlogistic drug, include but not limited to: methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone.
The compound of formula (1) can with another kind of antiviral agent Combined Preparation or formulated together.Useful antiviral agent includes but not limited to, proteinase inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and nucleoside analog.Antiviral agent includes but not limited to, zidovudine, acycloguanosine, ganciclovir, vidarabine, iodoxuridine, trifluridine, left Wei Lin (levovirin), ribavirin (viramidine) and ribavirin and FOSCARNET, amantadine, Rimantadine, Saquinavir, Indinavir, amprenavir, rltonavir, ritonavir, alpha-interferon; Beta-interferon; Adefovir, resist to come furan fixed, think for card Wei, pleconaril.
The compound of formula of the present invention (1) can with immunomodulator Combined Preparation or formulated together.Immunomodulator includes but not limited to: methotrexate, leflunomide, endoxan, ciclosporin A, mycophenolate mofetil, SIROLIMUS (sirolimus), mizoribine, Gusperimus, brequinar, malononitrilamide (malononitriloamindes) (such as leflunomide (leflunamide)), φt cell receptor conditioning agent and cytokine receptor conditioning agent, peptide mimics and antibody are (such as the people, humanized, chimeric, mono-clonal, polyclone, Fv, ScFv, Fab or F (ab) 2 fragments or epi-position binding fragment), nucleic acid molecule (such as antisense nucleic acid molecule and triple helical body), small molecules, organic compound and mineral compound.The example of φt cell receptor conditioning agent includes but not limited to: anti--φt cell receptor antibody (such as anti-CD 4 antibodies (such as cM-T412 (Berlin lattice company (Boeringer)), IDEC-CE9.1
Figure G200780038464XD00291
(IDEC and SKB), mAB4162W94, Orthoclone and OKTcdr4a (JC company (Janssen-Cilag)), anti-CD 3 antibodies are (such as Nuvion (product design laboratory (Product Design Labs)), the OKT3 ((Johnson﹠amp of Johson ﹠ Johnson; Johnson)), or Rituximab (IDEC)), anti--CD5 antibody (such as the immune conjugate of anti--CD5 ricin connection), anti--CD7 antibody is (such as CHH-380 (Novartis Co.,Ltd (Novartis)), anti--CD8 antibody, anti-CD 40 title complex monoclonal antibody (such as IDEC-131 (IDEC)), anti-CD 52 antibody (such as CAMPATH 1H (Ilex)), anti--CD2 antibody, anti--CD11a antibody (as, Xanelim (Gene science company (Genentech)), with anti--B7 antibody (such as, IDEC-114 (IDEC)), CTLA4-immunoglobulin (Ig) and Toll acceptor sample (TLR) conditioning agent.The example of cytokine receptor conditioning agent includes but not limited to: soluble cytokine receptor (as, the ectodomain of TNF α acceptor or its fragment, the ectodomain of IL-1 beta receptor or its fragment, ectodomain or its fragment with the IL-6 acceptor), cytokine or its fragment (as, interleukin (IL)-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15, TNF-α, Interferon, rabbit (IFN)-α, IFN-β, IFN-γ, and GM-CSF), the antibacterial agent receptor antibody (as, anti--the IFN receptor antibody, anti--the IL-2 receptor antibody (as, Zenapax (protein design laboratory (Protein Design Labs)), anti--the IL-4 receptor antibody, anti--the IL-6 receptor antibody, anti--the IL-10 receptor antibody, with anti--IL-12 receptor antibody), anti-cytokine antibody (as, anti--IFN antibody, Anti-tnfa antibody, anti--IL-1 β antibody, anti--IL-6 antibody, anti--IL-8 antibody (as, ABX-IL-8 (A Buji Knicks company (Abgenix)) and anti--IL-12 antibody).
The compound of formula (1) can with the medicament Combined Preparation that suppresses viral enzyme or formulated together.Described medicament includes but not limited to: the inhibitor of HCV proteolytic enzyme, such as BILN 2061, SCH-503034, ITMN-191 or VX-950; The inhibitor of NS5b polysaccharase is such as NM107 (and prodrug NM283), R1626, R7078, BILN1941, GSK625433, GILD9128 or HCV-796.
The compound of formula (1) can with such as Wu, Curr Drug Targets Infect Disord., 3, the medicament Combined Preparation of the described inhibition of 207-19 (2003) HCV polysaccharase or formulated together, or with Bretner M, Deng Nucleosides Nucleotides Nucleic Acids., 22, the medicament of the viral spiralization function of 1531 (2003) described inhibition, or with Zhang X.IDrugs., 5 (2): the described HCV particular target of 154-8 (2002) is to the inhibitor Combined Preparation of thing or formulated together.
The compound of formula (1) can with the medicament Combined Preparation that suppresses virus replication or formulated together.
The compound of formula (1) can with cytokine Combined Preparation or formulated together.The example of cytokine includes but not limited to: interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), IL-5 (IL-5), interleukin-6 (IL-6), IL-7 (IL-7), IL-9 (IL-9), interleukin-10 (IL-10), IL-12 (IL-12), interleukin 15 (IL-15), interleukin 18 (IL-18), from hematoblastic somatomedin (PDGF), erythropoietin (Epo), epithelical cell growth factor (EGF), fibroblast growth factor (FGF), granular leukocyte macrophage stimulus factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), prolactin antagonist and Interferon, rabbit (IFN) are such as IFN-α and IFN-γ.
The compound of formula (1) can with hormons administration or formulated together.The example of hormone includes but not limited to: Relefact LH-RH (LHRH), tethelin (GH), growth hormone releasing hormone, ACTH, Somat, tethelin, somatomedin, parathyroid hormone, hypothalamic releasing factor, Regular Insulin, glucagon, enkephalin, antidiuretic hormone, calcitonin, heparin, low molecular weight heparin, heparitin, synthetic and natural opium, Regular Insulin thyrotropin and endorphin.
The compound of formula (1) can with the beta-interferon Combined Preparation that includes but not limited to interferon beta-1a, interferon beta-1b or formulated together.
The compound of formula (1) can with α-disturb plain Combined Preparation or formulated together, α-disturb element to include but not limited to: the alpha-interferon Combined Preparation of Alfacon-1, Intederon Alpha-2a (roferon), Interferon Alpha-2b, intron, Peg-intron, Pegasys, synonym Interferon, rabbit (ingergen) and A Bufenlong (albuferon) or formulated together.
The compound of formula (1) can with absorption enhancer Combined Preparation or formulated together, described absorption enhancer take lymphsystem as target, includes but not limited to specifically, Sodium glycocholate; Sodium decanoic acid; N-lauroyl-β-D-Fructus Hordei Germinatus pyranoside; EDTA; The micella that mixes; And Muranishi Crit.Rev.Ther.Drug Carrier Syst., the material that 7-1-33 reports, it is for reference that the document is incorporated this paper in full into.Also can use other known absorption enhancer.The compound of formula of the present invention (1) can with alkylating agent Combined Preparation or formulated together.The example of alkylating agent includes but not limited to, mustargen, aziridine, methylmelamine, alkyl sulfonate esters, nitrosourea, triazene, chlormethine, endoxan, ifosfamide, melphalan, Chlorambucil, altretamine, tespamin, busulfan, card chlorine mustard, streptozotocin, dacarbazine and Temozolomide.
Formula (1) compound and other therapeutical agent can have adduction, are more preferably synergy.In one embodiment, contain the compounds of this invention composition can with the simultaneously administration of another kind of therapeutical agent, the part that described another kind of therapeutical agent can be said composition or from the composition different from the composition that contains the compounds of this invention.In another embodiment, before or after giving another kind of therapeutical agent, give compound of the present invention.At one independently in the embodiment, to not accepting or do not use at present another kind of therapeutical agent, be that the patient of antiviral agent treatment gives compound of the present invention specifically.
The preparation method
In another embodiment, the invention provides 5-amino-3-shown in preparation following formula (1) (2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole method of [4,5-d] pyrimid-2-one tosilate also:
Figure G200780038464XD00311
The method is easy and simple to handle, sane and effective, can be used for the mass-producing commercial production of this salt.And the method cost is effective, and the efficient and overall productive rate of output is high.
In one embodiment, synthetic 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole also the method for [4,5-d] pyrimid-2-one tosilate (1) may further comprise the steps:
(i) also [4,5-d] pyrimid-2-one (2) and desoxyribofu-(3) coupling form the compound of formula (4) to make 5-amino-3H-thiazole
Figure G200780038464XD00321
(ii) 5 ' acetic ester on selective splitting formula (4) compound, form 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5-d] pyrimid-2-one (5) also,
Figure G200780038464XD00322
With
(iii) make 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole also [4; 5-d] reaction of pyrimid-2-one (5) and tosic acid form 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole tosilate (1) of [4,5-d] pyrimid-2-one also
In another embodiment, step (i) comprise make 5-amino-3H-thiazole also the desoxyribofu-coupling of [4,5-d] pyrimid-2-one (2) and formula (3B) form the compound of formula (4)
Figure G200780038464XD00324
The linked reaction of step (i) can be carried out in high temperature (greater than 130 ℃) " melting " reaction under condition of no solvent, usually adopts 1,3-two (4-nitrophenyl) phosphoric acid ester also sometimes to carry out under vacuum as an acidic catalyst.Perhaps, this reaction can be carried out in solvent such as acetonitrile, toluene, ethylene dichloride, DMF, methylene dichloride or its mixture.Linked reaction usually acid such as trimethylsilyl triflate (" TMSOTf "), AlCl 3, SnCl 4And TiCl 4And silylating reagent (silating reagent) carries out under the existence of two (trimethyl silyl) ethanamides (" BSA ") of O-or trimethylsilyl chloride such as N.Then add water and stop linked reaction, the effect of water is to make excessive acid and silylating reagent quencher.If use TMSOTf and BSA, the water quencher causes forming water-based trifluoromethanesulfonic acid (triflic acid) and hexamethyldisiloxane (CAS#107-46-0).Residual silyl on aqueous peracid solution hydrolysis removal formula (4) the compound heterocyclic moiety.
In another embodiment, the coupling step of step (i) adopts also [4,5-d] pyrimid-2-one (2) of excessive 5-amino-3H-thiazole take the reactive chemistry metering as benchmark with respect to desoxyribofu-(3).For example, 5-amino-3H-thiazole also [4,5-d] pyrimid-2-one (2) can excessive about 5%-50%, about 5%-25%, about 5%-15%.In addition, take the reactive chemistry metering as benchmark, 5-amino-3H-thiazole also [4,5-d] pyrimid-2-one (2) than desoxyribofu-(3) excessive about 10%.In the presence of inert solid, after the linked reaction of step (i) is finished, remove also [4,5-d] pyrimid-2-one (2) of unnecessary 5-amino-3H-thiazole by rising pH, inert solid is through applying and filtering and remove.After (with alkali such as sodium bicarbonate) further neutralizes, add sodium-chlor, three layers of liquid system that generation can be separated.
Excessive 5-amino-3H-thiazole also [4,5-d] pyrimid-2-one (2) separation the difficulty.Yet the pH that has been found that the reaction mixture that rising is finished in the presence of inert solid is conducive to separation method.In the presence of inert solid such as diatomite (celite) filtration adjuvant, with alkali (for example sodium hydroxide and/or yellow soda ash) rising pH to precipitate also [4,5-d] pyrimid-2-one (2) of excessive 5-amino-3H-thiazole.Inert solid filters after applying and removes.After the further neutralization of alkali, in residual filtrate, add extra sodium-chlor, three layers of liquid system that obtain to be separated.Density smallest tier (top layer) is the hexamethyldisiloxane of clarification, can remove by separation of phases, need not distillation (conventional removal method).Middle required nucleosides (4) and the acetonitrile of comprising mutually.The maximum layer of density (bottom) is water, and (4) in the reaction mixture are further reclaimed in available acetonitrile extraction.The compound of this up-to-date style (4) is pure state, and its purity is enough to be used in step (ii) and need not further processing in the time of in solvent mixture.
In step (ii), 5 ' acetic ester on selective splitting formula (4) compound.This can utilize enzyme such as antarctic candida (Candida Antarctica) to realize.Antarctic candida can be available from biocatalysis company limited (Biocatalytics, Inc.).Usually, enzyme covalently bind on the solid phase carrier.It is more effective and the reaction times is shorter to covalently bind in enzyme recirculation on the solid phase carrier.The acetonitrile solution that comprises formula (4) compound that forms in the step (i) is added the enzyme of load and pH to be about in the stirred suspension of 7 buffer reagent.Also it can be added the enzyme of load in the suspension of the water that contains alkali (for example sodium bicarbonate or sodium-acetate).Perhaps, this solution can be added in dehydrated alcohol and sodium bicarbonate and/or the sodium-acetate, with the substantially anhydrous slurries of the enzyme that forms solid supported.After reaction is finished, the enzyme of load is filtered, wash and store for future use.Sodium-chlor can be added in the filtrate and with isopropyl acetate and extract.
Compound such as 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-also the processing of [4,5-d] pyrimid-2-one (5) is difficult for the 3H-thiazole, and this compound usually is unmanageable material.Carry out solvent evaporation or precipitation provides the uncertain method that does not reach optimality criterion product state in this stage.Yet method of the present invention no longer needs to process compound (5), does not need evaporating solvent or makes the product precipitation.5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole also [4,5-d] pyrimid-2-one (5) be pure state, carry out in the solvent mixture of step (iii) being enough to.
Step (iii) comprise make 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole also [4; 5-d] pyrimid-2-one (5) and tosic acid in solvent, react formation 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole tosilate (1) of [4,5-d] pyrimid-2-one also.Usually at-20 ℃ to about 40 ℃ approximately, about 0 ℃ to about 30 ℃, about 15 ℃ are carried out under about 30 ℃ temperature in this reaction.The solvent that is applicable to this reaction for example comprises: ethanol, methyl alcohol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, ethyl acetate, acetonitrile, isopropyl acetate, THF and their mixture.For example, solvent can comprise the mixture of isopropyl acetate and acetonitrile.In one embodiment, the mixture of isopropyl acetate and acetonitrile produces in step (ii), and the method also comprises interpolation ethanol.Usually, take the chemical reaction metering as benchmark, the consumption of sulfonic acid is about equimolar amount to excessive about 10 % by mole in the step (iii).
The reaction of step (iii) can reactant any concentration carry out.For example, reactant concn is about the 1-1000 mmole.In addition, concentration is about 50-500 mmole or about 100-250 mmole.
5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole also solution and the tosic acid solution reaction of [4,5-d] pyrimid-2-one (5).Two kinds of solution are mixed about 5 minutes to about 2 hours, or about 5 minutes to about 1 hour.In addition, tosic acid solution can be added in the reaction mixture, by this reaction mixture synthesis type (1) compound, such as No. 2006/0160830 (sequence number 11/304 of U.S. Patent Application Publication, 691) described, its content is included into this paper as a reference.
The reaction of step (iii) is at-20 ℃ to about 40 ℃ approximately, and about 0 ℃ to about 30 ℃, about 15 ℃ are carried out under about 30 ℃ temperature.The solvent that is applicable to this reaction comprises: ethanol, methyl alcohol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, ethyl acetate, acetonitrile, isopropyl acetate, THF and their mixture.In one embodiment, mixture comprises isopropyl acetate and the acetonitrile that produces in the step (ii), and the method also comprises ethanol is added in the mixture.Usually, take the chemical reaction metering as benchmark, the consumption of sulfonic acid is about equimolar amount to excessive about 25 % by mole in the step (iii), or is about equimolar amount to excessive about 10 % by mole.
With 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole also [4; 5-d] solution of pyrimid-2-one (5) is with after tosic acid solution mixes; 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-also tosilate (1) precipitation or the crystallization of [4,5-d] pyrimid-2-one of 3H-thiazole.Then reaction product is passed through filtering separation, washing is also dry.Reaction product also can be come separated product from other solvent systems precipitation or crystallization by from the reaction mixture evaporating solvent, perhaps precipitates by reaction mixture or crystallized product separates.The product 5-amino-3-that separates (2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole also [4; 5-d] the usually washing of tosilate (1) of pyrimid-2-one, then about 40 ℃ to about 70 ℃ or about 50 ℃ dry under about 60 ℃ temperature.Drying means can carry out at normal atmosphere or under decompression (vacuum).Pressure relief ranges is about 0.1 to about 10 inches of mercury.
Methods described herein also comprise separate 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole also [4; 5-d] step of pyrimid-2-one tosilate (1), the purity of the salt that wherein separates is at least 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.
The present invention also provides the method for preparation formula (3) and formula (3B) compound.These methods below schematically are described.
In the first reaction process (flow process 1), in the presence of alkali, with the compound of sulphonating agent sulfonation formula (6), form the compound of the alkylsulfonyl replacement of formula (7).This reaction process (flow process 1) is as follows:
Figure G200780038464XD00351
Flow process 1
To sulphonating agent, alkali and solvent and unrestricted, as long as they can implementing procedure 1 described chemical reaction.R group in the flow process 1 can be the optional alkyl or aryl that replaces.
Nonrestrictive sulphonating agent comprises: alkylsulphonic acid acid anhydride, heteroaryl-alkylsulfonyl halides (sulfonic halide), aromatic sulfonic acid acid anhydride, aromatics sulfonic acid halide and their mixture.Sulphonating agent comprises: the Phenylsulfonic acid acid anhydride of the benzene sulfonyl halogen of trifluoromethanesulfanhydride anhydride, toluene sulfonyl chloride, methanesulfonic acid anhydride, sulfonyl methane halogen, benzene sulfonyl halogen, replacement, Phenylsulfonic acid acid anhydride, replacement and their mixture.
Alkali to use in the flow process 1 is also unrestricted, can be organic or inorganic alkali, such as triethylamine, diisopropylethylamine, imidazoles or pyridine.
The solvent that adopts in the reaction process 1 is also unrestricted.Can use halogen-containing solvent such as methylene dichloride, ethylene dichloride and composition thereof.Usually, can use aprotic solvent such as tetrahydrofuran (THF) or acetonitrile.
Reaction process in the flow process 1 can be carried out under about 25 ℃ temperature at about-40 ℃.In addition, reaction can be carried out under about 0 ℃ temperature at about-20 ℃.
In next process (flow process 2), use the compound of the alkylsulfonyl replacement of the formula (7) that forms in the reductive agent reduction reaction flow process 1, form the compound of formula (8).Reaction process (flow process 2) is as follows:
Figure G200780038464XD00361
The reductive agent that adopts in the reaction process 2 is also unrestricted, as long as reductive agent can be realized required reduction reaction.Reductive agent can be borohydride.Borohydride can be hydrogen boronation tetra-allkylammonium, hydrogen boronation TBuA, sodium borohydride, cyano group sodium borohydride, lithium borohydride, potassium borohydrid, hydrogen boronation magnesium, hydrogen calcium boride, triacetoxyl group sodium borohydride and their mixture.
The solvent that adopts in the reaction process 2 is also unrestricted.Can use the mixture of aromatic solvent or aromatic solvent.Can use the benzene compound of solvent such as toluene, benzene, dimethylbenzene, other replacements and their mixture.In addition, also can use aprotic solvent such as diox, ethylene dichloride, tetrahydrofuran (THF) and their mixture.
Reaction process in the flow process 2 can be carried out under about 100 ℃ temperature at about 25 ℃.In addition, also can under about 80 ℃ temperature, carry out at about 60 ℃.
In next reaction process (flow process 3), in the presence of acid, the compound of the formula (8) that forms in the water hydrolysis reaction flow process 2 forms the compound of formula (9).This reaction process (flow process 3) is as follows:
Figure G200780038464XD00371
Also unrestricted to the acid of using in the reaction process 3, can use organic acid or mineral acid.Reaction can be carried out in aqueous solvent.Reaction also can be carried out with 50% aqueous acetic acid or aqueous hydrochloric acid.
The reaction process of flow process 3 is carried out under about 50 ℃ temperature at about 0 ℃.The reaction process of flow process 3 also can be carried out under about 30 ℃ temperature at about 20 ℃.
In next reaction process (flow process 4), the compound of the formula (9) that forms in the reaction process 3 forms the compound of formula (10) with the oxygenant oxidation, then with the reductive agent reduction.This reaction process (flow process 4) is as follows:
Figure G200780038464XD00372
Oxygenant to use in the reaction process 4 is also unrestricted, as long as oxygenant can be realized required oxidizing reaction.Oxygenant comprises sodium periodate, plumbic acetate and their mixture.
Reductive agent to use in the reaction process 4 is also unrestricted, comprises the reductive agent of listing in the reaction process 2.
Solvent to use in the reaction process 4 is also unrestricted.Solvent comprises: the combination of the combination of methyl alcohol, methylene dichloride, methylene dichloride and methyl alcohol or methyl alcohol and water.
The reaction process of flow process 4 is carried out under about 50 ℃ temperature at about 0 ℃.In addition, the reaction process of flow process 4 also can be carried out under about 30 ℃ temperature at about 20 ℃.
In end reaction process (flow process 5), in the presence of acid catalyst, make the compound acetylize of the formula (10) that forms in the reaction process 4 with acetylation reagent such as diacetyl oxide or Acetyl Chloride 98Min., form the compound of formula (3).Reaction process (flow process 5) is as follows:
Figure G200780038464XD00381
The acid catalyst that uses in the reaction process of flow process 5 is also unrestricted, comprises mineral acid, organic acid or mineral acid and organic acid are arranged simultaneously.Acid comprises nitric acid, hydrochloric acid, sulfuric acid, sulfonic acid, trifluoroacetic acid, alkylsulphonic acid, aryl sulfonic acid and immobilization form thereof and their mixture.
Reaction process in the flow process 5 is carried out in containing the organic solvent of above-mentioned acid catalyst usually.Solvent also can be acetic acid.
The reaction process of flow process 5 is carried out under about 5 ℃ temperature at about 0 ℃.In addition, the reaction process of flow process 5 also can be carried out under about 30 ℃ temperature at about 20 ℃.
In yet another embodiment of the present invention; above-mentioned general reaction process (flow process 1-5) can carry out with the initial reactant of the glucofuranose compound of formula (6B); form ethanoyl-deoxidation of formula (3B)-furan type wood sugar compound, shown in following reaction process 6:
Flow process 6
Reaction reagent among the above-mentioned flow process 1-5 and reaction conditions can be used in the reaction process 6.
In yet another embodiment of the present invention; above-mentioned general reaction process (flow process 1-5) can carry out with the initial reactant of furan type allose (allofuranose) compound of formula (6C); form ethanoyl-deoxidation of formula (3C)-furan type wood sugar (xylofuranso) compound, shown in following reaction process 7:
Figure G200780038464XD00392
Flow process 7
Reaction reagent among the above-mentioned flow process 1-5 and reaction conditions can be used in the reaction process 7.
The present invention also comprises and adopts the general reaction process of listing among the flow process 1-5, with formula (6B) and (6C) mixture of compound form the embodiment of the final product of formula (3B) as raw material.
According to following reaction process 8 preparation ethanoyl-deoxidation-furan type wood sugar compounds, 1,2,5-, three-O-ethanoyl-3-deoxidation-D-furan type wood sugar (3B):
Figure G200780038464XD00401
Flow process 8
The reaction reagent of above-mentioned flow process 1-5 and reaction conditions also are used for flow process 8.
Another embodiment of the invention comprises the compound of the formula (7) that replaces with reductive agent reduction alkylsulfonyl, with the method for the compound that forms formula (8),
Figure G200780038464XD00402
Wherein, the optional alkyl or aryl that replaces of R representative.
In a concrete embodiment of the present invention, R is CF 3, CH 3Or-C 6H 4CH 3The compound of formula (7) can be the furan type allose isomer of the glucofuranose isomer of above-mentioned formula (7B) or formula (7C) or formula (7B) and (7C) mixture of compound
Or both mixtures.
Reductive agent can be hydroborate.Borohydride can be hydrogen boronation tetra-allkylammonium, hydrogen boronation TBuA, sodium borohydride, cyano group hydrogen sodium hydride, lithium borohydride, potassium borohydrid, hydrogen boronation magnesium, hydrogen calcium boride, triacetoxyl group sodium borohydride and their mixture.
Embodiment
The following examples only are exemplary purposes, do not limit the scope of claims.
In following synthesis flow, unless otherwise indicated, all temperature are degree centigrade that all umbers and percentage ratio are take weight as benchmark.
Reaction reagent can be available from synthesizing the suppliers such as company limited (Lancaster Synthesis Ltd.) such as aldrich chemical company (Aldrich Chemical Company) or Lancaster, unless otherwise indicated, described reagent need not to be further purified and can use.All solvents are available from also can directly using such as aldrich EMD chemical company (Aldrich, EMD Chemicals) or Fei Shi company (Fisher).
General under the positive pressure and envrionment temperature of argon gas or nitrogen (unless otherwise indicated), in anhydrous solvent, carry out following reaction, reaction flask is furnished with rubber septum, is used for introducing substrate and reaction reagent through syringe.Glassware oven drying and/or heat drying.
Reaction is analyzed with TLC and/or LC-MS, judges the termination of reaction by consumption of raw materials.The thin-layer chromatography (TLC) of analyzing usefulness is coated with silica gel 60 F in advance 2540.25 carry out on the glass plate (EMD chemical company) of millimeter plate, carry out visual inspection and/or heat with TLC developer such as ethanol phospho-molybdic acid processed, ninhydrin solution, potassium permanganate solution or ceric sulfate solution carrying out visual inspection with the iodine on UV light (254nm) and/or the silica gel.Preparative thin-layer chromatography (preparation type TLC) applies silica gel 60 F in advance 2540.5 carry out on the sheet glass (20 * 20 centimetres, available from thomson apparatus company (ThomsonInstrument Company)) of millimeter sheet, (254nm) carries out visual inspection with UV light.
Use Varian Mercury-VX400 instrument, operating record under 400MHz 1H-NMR spectrum and 13C-NMR.NMR spectrum is from CDCl 3Obtain in the solution (ppm of unit), in appropriate circumstances, with chloroform as reference standard thing (be 7.27ppm to proton, carbon is 77.00ppm), CD 3OD (proton is 3.4 and 4.8ppm, and carbon is 49.3ppm), DMSO-d 6(proton is 2.49ppm), or interior mark tetramethylsilane (0.00ppm).Other NMR solvent can use as required.When if the peak multiplicity is arranged, use following abbreviation: s (unimodal), d (bimodal), t (triplet), q (quartet), m (multiplet), br (peak of widening), bs (wide is unimodal), dd (double doublet), dt (two triplet).The unit of coupling constant record is hertz (Hz).
At infrared (IR) spectrum of ATR FT-IR spectrometer record net phase oil or solid, with wave number (cm -1) expression.Mass spectrum is recorded as (+)-ES or APCI (+) LC/MS, is undertaken by the analytical chemistry section (Analytical ChemistryDepartment) of Anadys Pharmaceuticals Inc. (Anadys Pharmaceuticals, Inc).Ultimate analysis is by (the Atlantic Microlab of Atlantic Ocean Microscopy laboratory company limited of Georgia State Norcross, Inc., Norcross, GA) or the NMR laboratory company limited (NuMega Resonance Labs, Inc.) in San Diego, California carry out.Fusing point (mp) is measured at open capillaries equipment, not calibration.
Described route of synthesis and experimentation use many common chemical abbreviations: 2; 2-DMP (2; the 2-Propanal dimethyl acetal); Ac (ethanoyl); ACN (acetonitrile); Bn (benzyl); BOC (tert-butoxycarbonyl); Bz (benzoyl); DBU (1; 8-diazabicyclo [5; 4; 0] 11 carbon-7-alkene); DCC (N; N '-dicyclohexylcarbodiimide); DCE (1; the 2-ethylene dichloride); DCM (methylene dichloride); DEAD (azoethane dicarboxylic ester); DIEA (diisopropylethylamine); DMA (N; the N-N,N-DIMETHYLACETAMIDE); DMAP (4-(N; the N-dimethylamino) pyridine); DMF (N; dinethylformamide); DMSO (methyl-sulphoxide); EDC (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride); Et (ethyl); EtOAc (ethyl acetate); EtOH (ethanol); HATU (phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-1; 1; 3; the 3-tetramethyl-urea); HBTU (phosphofluoric acid O-benzotriazole-1-base-N; N; N ', N '-tetramethyl-urea); HF (hydrogen fluoride); HOBT (I-hydroxybenzotriazole hydrate); HPLC (high performance liquid chromatography); IPA (Virahol); KO tBu (tert.-butoxy potassium), LDA (LDA), MCPBA (3-chlorine peroxybenzoic acid), Me (methyl), MeCN (acetonitrile), MeOH (methyl alcohol), NaH (sodium hydride), NaOAc (sodium acetate), NaOEt (sodium ethylate), Phe (phenylalanine), PPTS (tosic acid pyridine), PS (polymkeric substance of load), Py (pyridine), pyBOP (phosphofluoric acid benzotriazole-1-base oxygen base) tripyrrole Wan Ji Phosphonium), TEA (triethylamine), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran (THF)), TLC (thin-layer chromatography), Tol (toluoyl), Val (α-amino-isovaleric acid) etc.
Embodiment 1
Synthetic 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5] pyrimid-2-one also) tosilate
Step (i)-linked reaction
In the three-necked flask that is equipped with hygrosensor, condenser and nitrogen inlet, add 5-amino-3H-thiazole also [4,5-d] pyrimid-2-one (2) is [according to Wolfe etc., J.Org.Chem.1997,62, the described method preparation of 1754-1759] (22 grams, 130.9 mmoles) and acetonitrile (198 milliliters).Slowly under the nitrogen purging, when stirring, add BSA (79.86 milliliters, 327.8 mmoles) by funnel, will be warming up to 40 ℃ at this mixture under the nitrogen atmosphere and keep 90 minutes.Make the solution of black, homogeneous be cooled to 5 ℃ with ice bath, be added in 1,2 in 66 milliliters of acetonitriles, 5-three-O-ethanoyl-β-D-RIBOSE (3) (35.42 grams, 111.32 mmoles).Add TMSOTf (23.54 milliliters, 130.9 mmoles) by transfer pipet when under nitrogen, stirring, cause thermopositive reaction to 15 ℃.Then this mixture is warming up to 75 ℃, kept this temperature 10 hours, then with the ice-water bath cooling, at first be cooled to envrionment temperature, be cooled to again 15 ℃.1 milliliter every part in water ground is added in the reaction solution, make thermopositive reaction reach the peak between the water adding at every turn.After adding for six times, add again 1 ml water and do not cause heat release, then add 38 ml waters by funnel, this mixture was stirred 15 minutes at ambient temperature.Diatomite (Celite, 44 grams) is added in the reaction solution that stirs, then in about 30 seconds, add 22 ml water solution of sodium hydroxide (15.7 gram 50%NaOH, 196.35 mmoles).Stirred 90 minutes reacting liquid filtering under the envrionment temperature.In the filtrate of stirring, add the sodium bicarbonate (16.5 grams, 196.35 mmoles) that is dissolved in 200 ml waters.When no longer including Bubble formation, add 50 gram solid sodium chloride, stir the mixture until all solids dissolving.This mixture is transferred to separating funnel, the three-phase liquid system that obtains is separated.Extracting once with 50 milliliters of acetonitriles mutually of density maximum merges its centre with initial separation mutually.In the liquid of this merging, add 11 gram diatomite, filtering mixt after 5 minutes when stirring.Filtrate comprises required coupled product (4); It is identified and purity can utilize known substance to be measured by HPLC.
Step (ii)-enzymic hydrolysis
To sodium bicarbonate (9.34 grams that are dissolved in 278 ml waters, 111.32 mmole, be equivalent to the sugar (3) in the step (i)) solution add the lipase of the in advance covalency load of the humidity of washing [washing process: the covalently bound Type B antarctic candida (biological catalyst catalog number (Cat.No.) IMB-111) that 23.21 grams are done be suspended in the solution of 1: 1 acetonitrile and water, stirred 4 hours, filter, with 60 milliliters of acetonitrile-waters (1: 1) washing].The acetonitrile solution that adds (4) that step (i) produces in the solution of this stirring.With this suspension agitation 36 hours, filtering catalyst, with acetonitrile-water (1: 1) washing, 0 ℃ stores for future use.Filtrate extracts with 222 milliliters of isopropyl acetates, stirs water and 30 gram sodium-chlor until then all solids dissolving uses again extracting twice of 111 milliliters of isopropyl acetates.Merge organic phase, use MgSO 4Drying stirred 90 minutes with 2.5 gram Norit 211, filtered by the diatomite filtration auxiliary agent.Filtrate comprises required alcohol (5); It is identified and purity can utilize known substance to be measured by HPLC as standard substance.
Step (iii)-with the tosic acid salify
Comprise the filtrate that is dissolved in (5) in isopropyl acetate and the acetonitrile with what 100 milliliter of 200 standard earthquake intensity ethanol (proof ethanol) dilution step (ii) obtained.When stirring, dropwise be added in the hydration tosic acid (15.89 grams, 83.49 mmoles) in the ethanol of 50 milliliter of 200 standard earthquake intensity in 30 minutes.Go out pale solid from the reaction mixture crystallization.Stir after 16 hours, solid collected by filtration is with 100 milliliters of isopropyl acetate washed twice, with the washing with alcohol of 50 milliliter of 200 standard earthquake intensity once.Solid is dry in vacuum drying oven, obtain 30.55 gram 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5] pyrimid-2-one tosilate also, HPLC measures its purity＞98%.
Embodiment 2
Do not add in the enzymolysis process of step (ii) water carry out 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5] pyrimid-2-one also) tosilate synthetic
Step (i)-linked reaction
In the three-necked flask that is equipped with hygrosensor, condenser and nitrogen inlet, add 5-amino-3H-thiazole also [4,5-d] pyrimid-2-one (2) (22 grams, 130.9 mmoles) and acetonitrile (198 milliliters).Slowly under the nitrogen purging, when stirring, add BSA (79.86 milliliters, 327.8 mmoles) from funnel, under nitrogen atmosphere, this mixture is warming up to 40 ℃ and kept 90 minutes.Make the solution of black, homogeneous be cooled to 5 ℃ with ice bath, be added in 1,2 in 66 milliliters of acetonitriles, 5-three-O-ethanoyl-β-D-RIBOSE (3) (35.42 grams, 111.32 mmoles).Add TMSOTf (23.54 milliliters, 130.9 mmoles) by transfer pipet when under nitrogen, stirring, cause thermopositive reaction to 15 ℃.Then this mixture is warming up to 75 ℃, kept this temperature 10 hours, then with the ice-water bath cooling, at first be cooled to envrionment temperature, be cooled to again 15 ℃.1 milliliter every part in water ground is added in the reaction solution, make thermopositive reaction reach the peak between the water adding at every turn.After adding for six times, add again 1 ml water and do not cause heat release, then add 38 ml waters by funnel, this mixture was stirred 15 minutes at ambient temperature.Diatomite (Celite, 44 grams) is added in the reaction solution that stirs, then in about 30 seconds, add 22 ml water solution of sodium hydroxide (15.7 gram 50%NaOH, 196.35 mmoles).Stirred 90 minutes reacting liquid filtering under the envrionment temperature.In the filtrate of stirring, add the sodium bicarbonate (16.5 grams, 196.35 mmoles) that is dissolved in 200 ml waters.When no longer including Bubble formation, add 50 gram solid sodium chloride, stir the mixture until all solids dissolving.This mixture is transferred to separating funnel, will obtains the three-phase liquid system and separate.Extracting once with 50 milliliters of acetonitriles mutually of density maximum merges its centre with initial separation mutually.In the liquid of this merging, add 11 gram diatomite, filtering mixt after 5 minutes when stirring.Filtrate comprises required coupled product (4); It is identified and purity can utilize known substance to be measured by HPLC.
Step (ii) does not add enzymolysis under any water condition
In 500 milliliters of round-bottomed flasks, add the fixing antarctic candida (Novozyme 435, biological catalyst catalog number (Cat.No.) 1MB-102) of 15.0 grams, add again dehydrated alcohol (60 milliliters).Add the acetonitrile solution of (4) that step (i) produces in this liquid, with flask and atmospheric sealing, stir under the envrionment temperature.After 72 hours, add 17.5 gram diatomite 545, stirred 10 minutes, then cross filter solid, with 80 milliliters of washing with alcohol.Filtrate comprises required alcohol (5); It is identified and purifying can utilize known substance to be measured by HPLC as standard substance.
Step (iii)-with the tosic acid salify
Comprise the filtrate that is dissolved in (5) in ethanol and the acetonitrile with the alcohol dilution of 100 milliliter of 200 normal intensity what step (ii) obtained.When stirring, dropwise be added in the hydration tosic acid (15.89 grams, 83.49 mmoles) in the ethanol of 50 milliliter of 200 standard earthquake intensity in 30 minutes.Go out pale solid from the reaction mixture crystallization.Stir after 16 hours, solid collected by filtration is with 100 milliliters of isopropyl acetate washed twice, with the washing with alcohol of 50 milliliter of 200 standard earthquake intensity once.Solid is dry in vacuum drying oven, obtain 30.55 gram 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5] pyrimid-2-one tosilate also, HPLC measures its purity＞98%.
Embodiment 3
Mass-producing synthesize 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5-d] pyrimid-2-one tosilate also
Step (i)-linked reaction
In the reactor that is equipped with hygrosensor, condenser and nitrogen inlet, add 5-amino-3H-thiazole also [4,5-d] pyrimid-2-one (2) (1.45 kilograms, 8.6 moles) and acetonitrile (1.29 liters).Slowly under the nitrogen purging, when stirring, add BSA (5.23 liters, 21.5 moles) by funnel, under nitrogen atmosphere, this mixture is warming up to 40 ℃ and kept 90 minutes.Make the solution of black, homogeneous be cooled to 5 ℃ with ice bath, be added in 1,2 in 4.3 liters of acetonitriles, 5-three-O-ethanoyl-β-D-RIBOSE (3) (2.33 kilograms, 7.32 moles).Dropwise add TMSOTf (1.54 liters, 8.6 moles) when stirring under the nitrogen, cause thermopositive reaction to 15 ℃.Then this mixture is warming up to 75 ℃, kept this temperature 10 hours, then cooling at first is cooled to envrionment temperature, is cooled to 15 ℃ again.
To add every part by 100 milliliters in the reaction solutions, make thermopositive reaction reach the peak between the water adding at every turn in water.Add last 100 ml waters when no longer causing heat release, add 1.9 premium on currency by funnel, this mixture was stirred 15 minutes at ambient temperature.Diatomite (2.47 kilograms) is added in the reaction solution that stirs, then add 14.5 premium on currency solution of sodium hydroxide (516.8 grams, 12.92 moles).Stirred 90 minutes reacting liquid filtering under the envrionment temperature.In the filtrate of stirring, add the sodium bicarbonate (1.08 kilograms, 12.92 moles) that is dissolved in 14.5 premium on currency.When no longer including Bubble formation, add 3.3 kilograms of solid sodium chloride, stir the mixture until all solids dissolving.Gained three-phase liquid system is separated.Extracting once with 3.3 liters of acetonitriles mutually of density maximum merges its centre with initial separation mutually.What merge comprises required coupled product (4) mutually; It is identified and purity can utilize known substance to be measured by HPLC as standard substance.
Step (ii)-enzymic hydrolysis
To sodium bicarbonate (615 grams that are dissolved in 21.5 premium on currency, 7.32 mole, be equivalent to the sugar (3) in the step (i)) covalently bound Type B antarctic candida (1.59 kilograms, biological catalyst catalog number (Cat.No.) IMB-111) that add to do of solution.The acetonitrile solution that adds (4) that step (i) produces in the solution of this stirring.With this suspension agitation 36 hours, filtering catalyst, with acetonitrile-water (1: 1) washing, 0 ℃ stores for future use.Filtrate extracts with 17.5 liters of isopropyl acetates, and water stirs with 3.3 kilograms of sodium-chlor until then all solids dissolving uses again extracting twice of 9 liters of isopropyl acetates.Merge organic moiety, use MgSO 4Drying stirred 90 minutes with 117 gram Norit 211, filtered by the diatomite filtration auxiliary agent.Filtrate comprises required alcohol (5); It is identified and purity can utilize known substance to be measured by HPLC as standard substance.
Step (iii)-with the tosic acid salify
The filtrate that is dissolved in (5) in isopropyl acetate and the acetonitrile that comprises with alcohol dilution step (ii) gained of 5.5 liter of 200 standard earthquake intensity.When stirring, dropwise be added in the hydration tosic acid (1.04 kilograms, 5.49 moles) in the ethanol of 3.3 liter of 200 standard earthquake intensity in 30 minutes.Go out pale solid from the reaction mixture crystallization.Stir after 16 hours, solid collected by filtration is with 7.5 liters of isopropyl acetate washed twice, with the washing with alcohol of 3.5 liter of 200 standard earthquake intensity once.Solid is dry in vacuum drying oven, obtain 2.38 kilograms of 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5] pyrimid-2-one tosilate also, HPLC measures its purity＞98%.
Embodiment 4
Crystallization 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole [4,5-dl pyrimid-2-one tosilate also
With 5-amino-3-(2 '-O-ethanoyl-3 '-deoxidation-β-D-RIBOSE base)-the 3H-thiazole also [4,5-d] pyrimid-2-one [50.0 grams, (take CoA as benchmark, 43.85 grams, 134 mmoles are effective)] add in the three-necked flask that 2-rises.Add dehydrated alcohol (840 milliliters), with mixture stir about 10 minutes at ambient temperature, obtain yellow solution.Tosic acid (pTsOH) (26.2 grams, 138 mmoles) is added in another flask, be dissolved under the envrionment temperature in the dehydrated alcohol (220 milliliters).The p-TsOH/ ethanolic soln is added in the addition funnel, then at ambient temperature, dropwise be added drop-wise in the stirred solution of formula (5) in 40 minutes time.(3 * 20mL) drip washing are for the preparation of flask and the addition funnel of p-TsOH/ ethanolic soln, and each leacheate adds in the reaction suspension with dehydrated alcohol.Reaction solution stirs spend the night (18 hours) under envrionment temperature, nitrogen, then use Büchner funnel and the vacuum filtration of Whatman#1 filter paper.Solid remaining in the flask is transferred in the filter with dehydrated alcohol (2 * 50 milliliters), then uses dehydrated alcohol (4 * 150 milliliters) washing leaching cake.In filter behind the simple dry cake of suction, with the white solid of humidity in 50-55 ℃, the vacuum chamber of 28-29 inch vacuum, nitrogen purging dry 54 hours.After being cooled to envrionment temperature under the vacuum, obtaining 62.9 grams (productive rate 93.8%) and be the formula of white crystals (1) compound, it is 99.1% that HPLC measures purity.
The separation of second batch formula (1) compound: the supernatant liquor of above-mentioned merging and washings are concentrated into volume on rotatory evaporator (45-50 ℃ of water-bath, 28-29 inch vacuum) be 470 milliliters.Under stirring, the solution that gained is contained crystalline particle is cooled to envrionment temperature.In 5 minutes, form crystal suspension.With this suspension stir about 48 hours at ambient temperature, then use Büchner funnel and the vacuum filtration of Whatman#1 filter paper.Filter cake is with dehydrated alcohol (4 * 6 milliliters) washing, then with solid in 50-55 ℃, the vacuum chamber of 28-29 inch vacuum, nitrogen purging dry 48 hours.After being cooled to envrionment temperature under the vacuum, obtain the compound of 2.8 gram (productive rate 4.2%) formulas (1) as the compound of second batch formula (1), it is 96% that HPLC measures purity.
Embodiment 5
1,2:5,6-two-O-isopropylidene-3-O-trifyl-α-D-glucofuranose (7a)
Trifluoromethanesulfanhydride anhydride (10.9 milliliters, 64.9 mmoles) is dropwise added 1,2:5,6-two-O-isopropylidene-α-D-glucofuranose (13.0 grams, 50.0 mmoles), pyridine (10.0 milliliters, 124 mmoles) and CH 2Cl 2(300 milliliters)-20 ℃ in-10 ℃ stirred solution, keep simultaneously internal temperature to be lower than-10 ℃.Gained solution stirs between-10 ℃ to 0 ℃, simultaneously by TLC monitoring consumption of raw materials (requiring about 1 hour).Reaction solution H 2Then O (2 * 100 milliliters) washing uses the saturated NaCl aqueous solution (50 milliliters) washing.Organic phase Na 2SO 4Then drying filters.Filtrate is concentrated into dried (about 30 ℃) at rotatory evaporator, obtains 20.4 gram (100%) white waxy solid 1,2:5,6-two-O-isopropylidene-3-O-trifyl-α-D-glucofuranose (7a).This material can need not to be further purified and can be directly used in next step. 1HNMR(400MHz，CDCl 3)δ5.99(d，1H)，5.26(d，1H)，4.76(d，1H)，4.14-4.25(m，3H)，3.96-3.99(dd，1H)，1.53(s，3H)，1.44(s，3H)，1.35(s，3H)，1.34(s，3H)。
Embodiment 6
3-deoxidation-1,2:5,6-two-O-isopropylidene-α-D-glucofuranose (8B)
With 1,2:5,6-two-O-isopropylidene-3-O-trifyl-α-D-glucofuranose (7a) (20.4 grams, 52.0 mmoles) and n-Bu 4NBH 4(40.0 grams, 155 mmoles) mixture in toluene (500 milliliters) is used degassed 20 minutes of nitrogen bubble.With mixture 80 ℃ of heating under nitrogen, simultaneously by TLC monitoring consumption of raw materials (requiring about 6 hours).Reaction solution is cooled to envrionment temperature, then carefully adds entry (200 milliliters).The gained mixture stirs at ambient temperature until no longer include the hydrogen effusion.Separate two-phase, organic phase is water (2 * 200 milliliters) and the saturated NaCl aqueous solution (100 milliliters) washing successively.Organic phase is at the concentrated 3-deoxidation-1 that obtains 9.5 gram (78%) clarification oily matter of rotatory evaporator (40-50 ℃), 2:5,6-two-O-isopropylidene-α-D-glucofuranose (8a).This material need not to be further purified and namely can be used for next step (annotating 5): 1HNMR (400MHz, CDCl 3) δ 5.8 (d, 1H), 4.75 (t, 1H), (4.08-4.19 m, 3H), 3.79-3.85 (m, 1H), (2.17-2.21 dd, 1H), 1.73-1.80 (m, 1H), 1.51 (s, 3H), (1.43 s, 3H), 1.36 (s, 3H), 1.32 (s, 3H).
Embodiment 7
3-deoxidation-1,2-O-isopropylidene-α-D-glucofuranose (9a)
With 3-deoxidation-1,2:5,6-two-O-isopropylidene-α-D-glucofuranose (8a) (9.50 grams, 38.9 mmoles) is dissolved in the acetic acid (60 milliliters).Add water (60 milliliters), gained solution stirs at ambient temperature and spends the night, simultaneously by TLC monitoring consumption of raw materials.Solution obtains the 3-deoxidation-1 of the clarification oily matter of 7.9 gram (100%) thickness, 2-O-isopropylidene-α-D-glucofuranose (9a) at rotatory evaporator concentrated (about 50 ℃).This material need not to be further purified and namely can be used for next step: 1H NMR (400MHz, CDCl 3) δ 5.72 (d, 1H), 4.67 (t, 1H), (4.11 m, 1H), 3.78 (m, 1H+2OH), (3.75-3.79 m, 1H), 3.44-3.49 (m, 1H), 1.97-2.02 (m, 1H), (1.74-1.81 m, 1H), 1.44 (s, 3H), 1.25 (s, 3H).
Embodiment 8
3-deoxidation-1,2-O-isopropylidene-α-D-furan type wood sugar (10a)
With 3-deoxidation-1,2-O-isopropylidene-α-D-glucofuranose (9a) is dissolved in CH 3Among the OH (50.0 milliliters), add CH 2Cl 2In (50.0 milliliters).Under the envrionment temperature, with NaIO 4In (10.0 grams, 46.7 mmoles) this solution of disposable adding.Gained suspension stirs at ambient temperature and spends the night, simultaneously by TLC monitoring consumption of raw materials.Filtering suspension liquid, salt CH 2Cl 2Washing (20 milliliters).Filtrate is transferred in the dry flask.With NaBH 4(4.0 grams, 106 mmoles) slowly add in the stirring filtrate that merges in batches.After suspension stirred 2 hours at ambient temperature, TLC showed that intermediate aldehydes is converted into 3-deoxidation-1,2-O-isopropylidene-α-D-furan type wood sugar (10a) fully.(about 40 ℃) desolventizing on the rotatory evaporator, residue distribute between the 10%NaCl aqueous solution (50 milliliters) and EtOAc (50 milliliters).Two-phase is acutely mixed, then separate.Water extracts with EtOAc (3 * 50 milliliters).The organic extract that merges is used Na with the saturated NaCl aqueous solution (30 milliliters) washing 2SO 4Then drying filters.Filtrate is concentrated at rotatory evaporator (about 40 ℃), obtains 4.7 grams (70%) and is the 3-deoxidation-1 of white solid, 2-O-isopropylidene-α-D-furan type wood sugar (10a). 1H?NMR(400MHz，CDCl 3)δ5.82(d，1H)，4.76(t，1H)，4.34-4.37(m，1H)，3.90(dd，1H)，3.56(q，1H)，1.99-2.04(m，1H)，1.82-1.89(m，1H)，1.76(br?s，1H)，1.53(s，3H)，1.34(s，3H)。
Embodiment 9
3-deoxidation-1,2,5-three-O-ethanoyl-α-D-furan type wood sugar (3B)
With H 2SO 4The aqueous solution (the solution of 0.1 milliliter of 1M, 0.1 mmole) slowly join 3-deoxidation-1, in the solution of 2-O-isopropylidene-α-D-furan type wood sugar (10a) (0.26 gram, 1.5 mmoles), Glacial acetic acid (3 milliliters) and diacetyl oxide (0.6 milliliter).Gained solution stirs at ambient temperature and spends the night, and then is evaporated to dried.Residue distributes between water and EtOAc.Phase mixture is fully jolted, then separate.Water extracts with EtOAc.The organic moiety Na that merges 2SO 4Drying is filtered, and is evaporated to driedly, obtains the rough 3-deoxidation-1,2 of α and β anomer form of mixtures, 5-three-O-ethanoyl-α-D-furan type wood sugar (3B).The β anomer 1HNMR:(400MHz, CDCl 3) δ 6.17 (s, 1H), 5.19 (d, 1H), 4.55-4.61 (m, 1H), 4.22 (d, 0.5H), 4.20 (d, 0.5H), 4.07-4.12 (m, 1H), 2.04-2.18 (m, 11H).
Embodiment 10
3-deoxidation-1,2,5-three-O-ethanoyl-α-D-furan type wood sugar (3B)
With 3-deoxidation-1,2-O-isopropylidene-α-D-furan type wood sugar (10a) (1.0 grams, 5.7 mmoles), CH 2Cl 2The solution of (5 milliliters), diacetyl oxide (2 milliliters) and pyridine (0.3 milliliter) stirs at ambient temperature and spends the night.Vacuum evaporated solution is to remove CH 2Cl 20 ℃ adds acetic acid (18 milliliters), diacetyl oxide (1 milliliter) and the vitriol oil (1.2 milliliters) in surplus solution.Gained solution is warming up to envrionment temperature and stirred 24 hours from 0 ℃.Solution is cooled to 0 ℃, adds 10% aqueous sodium acetate solution (150 milliliters).Gained solution extracts (2 * 100 milliliters) with methyl tertiary butyl ether (MTBE).The MTBE extract that merges is used 5%NaHCO successively 3(2 * 40 milliliters), water and the saturated NaCl aqueous solution (50 milliliters) washing.MTBE is evaporated to dried mutually, obtains the 3-deoxidation-1,2 of 0.9 gram α and β anomer form of mixtures, 5-three-O-ethanoyl-α-D-furan type wood sugar (3B). 1H NMR analyzes identical with embodiment 9 acquired results.
Importantly, the structure of the method shown in the illustrative embodiments and step and arrangement only are illustrative.Although this paper only describes some embodiments of the present invention in detail, those skilled in the art will understand easily, many improved forms also be possible and not essence deviate from novel teachings and the advantage of purport described in claims.Therefore, all these improved forms are intended to be included in the scope of the present invention that appended claims limits.According to optional embodiment, the order of any means or method steps or sequence can change or reset.The design of embodiment, operational condition and arrangement can be carried out other and substitute, improve, change or omit and do not deviate from the expressed spirit of the present invention of appended claims.
Described all publications of this specification sheets, patent and patent application are included this paper in as a reference, and for any and all purposes, specifically and separately are included into this paper as a reference as each publication, patent or patent application.In inconsistent situation, the present invention is preferential.

Claims (18)

1. the compound of formula (1):
Figure FDA00003490984500011
Described compound is crystallized form, and its X-ray diffraction (2-θ) as shown in Figure 2.
2. compound as claimed in claim 1, wherein, described crystallization has FT-Raman spectrum as shown in Figure 1.
3. pharmaceutical composition, it comprises claim 1 or 2 described compounds and pharmaceutically acceptable carrier.
4. the application in the medicine of compound as claimed in claim 1 or 2, infection with hepatitis C virus hepatitis b virus infected in preparation treatment, tumour or cancer.
5. the method for the crystallized form of synthetic following formula as claimed in claim 1 (a 1) compound,
Figure FDA00003490984500012
Said method comprising the steps of:
(i) also [4,5-d] pyrimid-2-one (2) and desoxyribofu-(3) coupling form the compound of formula (4) to make 5-amino-3H-thiazole
(ii) with the 5' acetic ester on enzyme selectivity cracking type (4) compound, form also [4,5-d] pyrimid-2-one (5) of 5-amino-3-(2'-O-ethanoyl-3'-deoxidation-β-D-RIBOSE base)-3H-thiazole,
Figure FDA00003490984500021
(iii) make 5-amino-3-(2'-O-ethanoyl-3'-deoxidation-β-D-RIBOSE base)-3H-thiazole also [4; 5-d] reaction of pyrimid-2-one (5) and tosic acid forms the also tosilate (1) of [4,5-d] pyrimid-2-one of 5-amino-3-(2'-O-ethanoyl-3'-deoxidation-β-D-RIBOSE base)-3H-thiazole
Wherein, step solvent (iii) is the mixture of isopropyl acetate and acetonitrile.
6. method as claimed in claim 5 is characterized in that, step (i) comprise make 5-amino-3H-thiazole also the desoxyribofu-coupling of [4,5-d] pyrimid-2-one (2) and formula (3B) form the compound of formula (4)
Figure FDA00003490984500023
7. method as claimed in claim 5 is characterized in that, the linked reaction of described step (i) is carried out under condition of no solvent.
8. method as claimed in claim 5 is characterized in that, the linked reaction of described step (i) is carried out in acetonitrile.
9. method as claimed in claim 5 is characterized in that, the linked reaction of described step (i) is carried out in the presence of acid.
10. method as claimed in claim 9 is characterized in that, described acid is TMSOTf.
11. method as claimed in claim 5 is characterized in that, the linked reaction of described step (i) is carried out in the presence of silylating reagent.
12. method as claimed in claim 11 is characterized in that, described silylating reagent is N, O-two (trimethyl silyl) ethanamide.
13. method as claimed in claim 5 is characterized in that, the linked reaction of described step (i), is carried out in acetonitrile under the existence of O-two (trimethyl silyl) ethanamide at TMSOTf and N.
14. method as claimed in claim 13 is characterized in that, adds entry after linked reaction is finished with quencher excessive TMSOTf and BSA, to form water-based triflate and hexamethyldisiloxane.
15. method as claimed in claim 5, it is characterized in that, take the chemical reaction metering as benchmark, the linked reaction of described step (i) adopts also [4,5-d] pyrimid-2-one (2) of the 5-amino excessive with respect to desoxyribofu-(3)-3H-thiazole.
16. method as claimed in claim 5 is characterized in that, described enzyme is antarctic candida.
17. also comprising, method as claimed in claim 5, described method separate also [4,5-d] pyrimid-2-one tosilate (1) of 5-amino-3-(2'-O-ethanoyl-3'-deoxidation-β-D-RIBOSE base)-3H-thiazole.
18. method as claimed in claim 17; it is characterized in that; 5-amino-the 3-of described separation (2'-O-ethanoyl-3'-deoxidation-β-D-RIBOSE the base)-3H-thiazole also purity of [4,5-d] pyrimid-2-one tosilate (1) is at least 95%.
CN200780038464.XA 2006-10-17 2007-10-16 P-toluene sulfonic acid salt of 5-amino-3-(2'-o-acetyl-3'-deoxy-ss-d-ribofuranosyl)-3h-thiazole [4, 5-d] pyrimidine-2-one and methods for preparation Expired - Fee Related CN101605457B (en)

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PCT/US2007/081526 WO2008140549A1 (en) 2006-10-17 2007-10-16 P-TOLUENE SULFONIC ACID SALT OF 5-AMINO-3-(2'-O-ACETYL-3'-DEOXY-β-D-RIBOFURANOSYL)-3H-THIAZOLE [4, 5-D] PYRIMIDINE-2-ONE AND METHODS FOR PREPARATION

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