CN101605457A - P-toluenesulfonate of 5-amino-3-(2'-0-acetyl-3'-deoxy-beta-D-ribofuranosyl)-3H-thiazole [4,5-D] pyrimidin-2-one and method of preparation - Google Patents
P-toluenesulfonate of 5-amino-3-(2'-0-acetyl-3'-deoxy-beta-D-ribofuranosyl)-3H-thiazole [4,5-D] pyrimidin-2-one and method of preparation Download PDFInfo
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Abstract
The present invention relates to 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-also [4,5-d] pyrimid-2-one tosilate and the application in treatment disease such as virus infections, tumour and cancer thereof of 3H-thiazole.Also relate to preparation 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole also [4; 5-d] pyrimid-2-one method and produce such as 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the 3H-thiazole also can be used as the method for the furanose compound of intermediate in the preparation process of medicinal compound such as [4,5-d] pyrimid-2-one tosilate.
Description
Invention field
The present invention relates to 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the also tosilate and the application in treatment disease such as virus infections, tumour and cancer thereof of [4,5-d] pyrimid-2-one of 3H-thiazole.Also relate to preparation 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole also [4; 5-d] pyrimid-2-one method and produce such as 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-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 treatment of diseases process.For example, in the treatment of cancer and virus infections, use nucleoside analog.After nucleoside analog entered cell, usually by nucleosides remedial pathway phosphorylation, the analog phosphorylation formed corresponding single, double and triguaiacyl phosphate.In other born of the same parents in the final result, the nucleoside analog of triphosphoric acidization 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 molecules to cross early stopping.If the triphosphoric acid nucleoside analog is incorporated in nucleic acid replication or the transcript, can cause gene expression or function to be destroyed.
So some nucleoside analogs are effective because can suppress adenosine kinase.Adenosine kinase catalysis adenylic acid formation adenosine 5 '-one phosphoric acid (AMP).The inhibition of adenosine kinase can effectively improve the outer level of adenosine born of the same parents in the human body, thereby can be used for the treatment of ischemic disease such as apoplexy, inflammation, arthritis, 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 people such as Robins, disclose some pyrimido [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-ribofuranosyl thiazole also [4,5-d] pyrimidine demonstrate tangible immunocompetence, comprise Muridae splenocyte propagation and to the activity in vivo of Semliki Forest virus (Semliki Forestvirus).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; People such as Revankar, J.Het.Chem., 30,1341-49 (1993); 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-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-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 applications 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-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-the thiazole also tosilate of [4,5-d] pyrimid-2-one and the pharmaceutical composition that comprises this salt.
The compound of formula 1 can use in treatment of diseases or prevention method.For example, the compound of formula 1 can be used for treating or the generation and/or the process of pre-preventing tumor or cancer.Also described the method for treatment or prevention pathogenic infection, for example virus infections comprises hepatitis type 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-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the 3H-thiazole method of the tosilate (1) of [4,5-d] pyrimid-2-one also.
This method may further comprise the steps:
(i) make the also compound of [4,5-d] pyrimid-2-ones (2) and desoxyribofuranose (3) coupling formation formula (4) of 5-amino-3H-thiazole
(ii) 5 ' acetic acid esters on selective splitting formula (4) compound, form 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5-d] pyrimid-2-ones (5) also,
(iii) make 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole also [4; 5-d] reaction of pyrimid-2-one (5) and p-methyl benzenesulfonic acid form 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-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 desoxyribofuranose coupling of [4,5-d] pyrimid-2-ones (2) and formula (3B) form the compound of formula (4)
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.
This method comprises:
(i) compound of usefulness sulfonating agent sulfonation formula (6) in the presence of alkali,
Form the compound of the sulfonyl replacement of formula (7),
Wherein R is the optional alkyl or aryl that replaces;
(ii) use the compound of the sulfonyl replacement of reductant reduction-type (7), form the compound of formula (8)
(iii) use the compound of acid hydrolysis formula (8), form the compound of formula (9)
(iv) use the compound of oxidant oxidation formula (9),, form the compound of formula (10) then with the reductant reduction
With
(v) in the presence of acid catalyst, use the compound of acetylation reagent acetylization formula (10), form the compound of formula (3)
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
This method comprises:
(i) compound or its mixture of usefulness sulfonating agent sulfonation formula (6B), formula (6C) in the presence of alkali,
Form compound that the sulfonyl of formula (7B), formula (7C) replaces or their mixture
Wherein, R is the optional alkyl or aryl that replaces;
(ii) use compound or its mixture of the sulfonyl replacement of reductant reduction-type (7B), formula (7C), form the compound of formula 8B
(iii) use the compound of acid hydrolysis formula (8B), form the compound of formula (9B)
(iv) use the compound of oxidant oxidation formula (9B),, form the compound of formula (10B) then with the reductant reduction
(v) in the presence of acid catalyst, use the compound of acetylation reagent acetylization formula (10B), form the compound of formula (3B)
In another embodiment, the present invention relates to compound, form the method for the compound of formula (8) with the sulfonyl replacement of reductant reduction-type (7),
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, form the method for the compound of formula (8B) with the sulfonyl replacement of reductant reduction-type (7B), formula (7C),
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 scale commodity production of compound described herein.This method is easy and simple to handle, sane and effective.Specifically, this method be particularly useful for large-scale production 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-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 " halide " represent fluoride, chloride, 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 annulus (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, C1-C
6Alkyl, aryl alkyl, C1-C
6Alkoxyl, C1-C
6Thiazolinyl, C1-C
6Hydroxyl, C1-C
6Hydroxy alkyl, amino, C1-C
6Alkylamine, C1-C
6Dialkylamine, wherein alkyl also can further be replaced by one or more halogens.
Term " Ac " expression acetyl group.
The compounds of this invention may be the mixture of single stereoisomer, racemic modification and/or various enantiomter and/or diastereoisomer. The mixture of all this class single stereoisomers, racemic modification and/or various enantiomter and/or diastereoisomer all comprises within the scope of the invention.
Term used herein " oxidant " refers to get in the chemical reaction process material of electronics, and term " reducing 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 mammal comprise chimeric and transgenic animals and mammal.
Term " treatment effective dose " refers to be enough to treat or prevent disease, delay or minimize the symptom relevant with disease or healing or alleviate the consumption of the The compounds of this invention of disease or infection or its cause of disease. Particularly, the treatment effective dose 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 therapeutic agent or produce synergistic avirulent consumption with another kind of therapeutic agent.
Term " prevention effective dose " refers to be enough to recurrence or the compound of the present invention of propagation or the consumption of other active component of prevent disease, disease. The prevention effective dose can refer to be enough to prevent the recurrence of primary virus infections 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 prophylactic or therapeutic agent or produce synergistic avirulent consumption with another kind of prophylactic or therapeutic agent.
Term " combination " refers to simultaneously or in succession uses more than one prophylactic and/or therapeutic agent, and makes its effect adduction that produces separately or collaborative.
Term " treatment " refers to:
(i) prevent disease, imbalance or the state of an illness are being tended to this disease, imbalance or the state of an illness take place but are being taken place in the animal that NYD 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 asymmetric carbon atom in the chemical constitution 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, an asymmetric carbon atom) optical pure compound is basically by a kind of (being enantiomeric pure) that consists of in two kinds of possible enantiomters, 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 voidness, 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-acetyl group-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-acetyl group-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 crystal form 5-amino-3-(2 '-O-acetyl group-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-acetyl group-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-acetyl group-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 crystallization 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-acetyl group-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 constitution, 5-amino-3-(2 '-O-acetyl group-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-acetyl group-3 '-deoxidation-β-D-RIBOSE base)-3H-thiazole also [4; 5-d] free alkali (5) of pyrimid-2-one contains some related substances (accessory substance 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 the angle of diffraction 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), stomach and intestine outer (comprise in subcutaneous, the muscle, inject, in the artery or intravenous), transdermal or topical. Pharmaceutical composition of the present invention and formulation also comprise one or more pharmaceutically acceptable excipient 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 therapeutic 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 relevant disease can contain one or more active components bigger than chronic treatment same disease consumption. Similarly, parenteral dosage form can contain one or more active components than the peroral 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; Dispersant; Suppository; Ointment; Opoultice (poutices); Paste; Pulvis; Dressing; Cream; Plaster; Solution; Patch; Aerosol (such as nasal spray or inhalant); Gel; The liquid dosage form that is fit to or mucosa delivery oral to the patient, comprise suspending agent (as, water-based or non-aqueous liquid suspending 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; And can be used to reconstitute the sterile solid that is fit to patient's parenteral liquid dosage form (as, crystallization or amorphous solid).
Typical pharmaceutical composition and formulation comprise one or more carriers, excipient or diluent. Suitable excipient is known in the pharmaceutical field, and this paper provides the non-limiting example of suitable excipient. Whether a kind of specific excipient is suitable mixes pharmaceutical composition or formulation depends on the known various factors of this technical field, includes but not limited to patient's method of administration. For example, the peroral dosage form such as tablet can contain the excipient that is not suitable for parenteral dosage form. The suitability of particular excipient is also decided according to the concrete active component in the formulation.
Anhydrous pharmaceutical composition and the formulation that comprises active component 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﹠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 its no aqueous nature of chien shih be maintained. Therefore, anhydrous composition preferably uses known waterproof material to pack, and they can be wrapped in the kit of suitable regulation. The example of suitable packing includes but not limited to, sealed foil, plastics, unit dosage forms 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 component decomposition rates. This compounds (below be called stabilizing agent) includes but not limited to antioxidant (such as ascorbic acid), pH buffer or salt buffer agent.
With the amount of excipient and class types seemingly, the amount of active component can be different according to various factors with concrete type in the formulation, such as but not limited to, to patient's method 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.
Peroral 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 component of scheduled volume, 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 peroral dosage form of the present invention by following steps: make active component and fully mix according at least a excipient in the conventional medicine complex technique. Choose various forms of excipient according to the formulation of administration. For example, the excipient that is suitable for liquid oral or aerosol includes but not limited to, water, polyalcohol, oil, alcohol, flavor enhancement, anticorrisive agent and colouring agent. The excipient 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, diluent, granulating agent, lubricant, adhesive and disintegrant.
Because the Tablet and Capsula agent is easy to administration, they have represented formulation best in the peroral 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 component evenly mix nearly with liquid-carrier, 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 component 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 fluid excipient being carried out mold pressing.
The example that can be used for the excipient of peroral dosage form of the present invention includes but not limited to, adhesive, filler, disintegrant and lubricant. The adhesive that is suitable for pharmaceutical composition and formulation includes but not limited to, cornstarch, farina or other starch, gelatin, natural and synthetic glue is (such as Arabic gum, mosanom, alginic acid, other alginates, the powdered tragacanth, guar gum, cellulose and its derivative are (such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), PVP, methylcellulose, the starch of pre-gelatinization, hydroxypropyl methylcellulose (as, the 2208th, 2906, No. 2910), microcrystalline cellulose and its mixture.
Be suitable for the pharmaceutical composition of this paper and the filler in the formulation and include but not limited to, the cellulose of talcum powder, calcium carbonate (such as particle or powder), microcrystalline cellulose, powdered, dextrates (dextrates), kaolin, sweet mellow wine, silicic acid, sorbierite, starch, the starch of pre-gelatinization and their mixture. Adhesive or filler 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 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 adhesive is the mixture of microcrystalline cellulose and carboxymethyl cellulose, and commodity are called AVICEL RC-581. Suitable anhydrous or low-moisture excipient or additive comprise AVICEL-PH-103TMAnd Starch1500LM.
The disintegrant that is used for the present composition makes tablet disintegration when being exposed to water environment. The tablet that contains too much disintegrant 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 disintegrant. Therefore, preparing the used disintegrant 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 component. The consumption of disintegrant 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 disintegrant, the preferably disintegrant of about 1-5 % by weight.
The disintegrant 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 cellulose, natural gum and their mixture of agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, Ac-Di-Sol, Crospovidone, polacrilin potassium (polacrillin potassium), Explotab, farina or tapioca, pre-gelatinization.
The lubricant that can be used for pharmaceutical composition of the present invention and formulation includes but not limited to, calcium stearate, dolomol, mineral oil, light mineral oil, glycerine, sorbierite, sweet mellow wine, polyethylene glycol, other polyalcohol, stearic acid, NaLS, talcum powder, hydrogenated vegetable oil (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soya-bean oil), zinc stearate, ethyl oleate, ethyl laurate, 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 component 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 components of slowly-releasing or controlled release by the following material that uses various ratios, described material is for example hydroxypropyl methylcellulose, other polymer substrate, gel, permeable membrane, osmosis system, multiple coatings, particulate, liposome, microballoon or its combination, thereby obtains required release profiles. In order to use active component 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 forms 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 drug therapy, use the controlled release preparation of optimal 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 compliance 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 bad reaction).
Most of controlled release preparations are designed to begin to discharge a certain amount of medicine (active component) with the required therapeutic action of rapid generation, discharge gradually and constantly then the medicine of other amount to keep the level for the treatment of or prevention 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 administration in subcutaneous administration, intravenous (comprise and injecting) administration, intramuscular administration and the artery. Because their administration is walked around the patient usually to the natural defence of pollutant, 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 parenteral solution, 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 carrier.
The suitable excipient 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 excipient, such as but not limited to, the ringer's injection of sodium chloride injection, Lin Ge (Ringer) parenteral solution, dextrose parenteral solution, dextrose and sodium chloride injection and lactic acidization; Excipient that can be miscible with water, such as but not limited to, ethanol, polyethylene glycol and polypropylene glycol; Non-aqueous excipient, such as but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and Ergol.
Also the compound that can increase the solvability of one or more active components 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 a period of time, allows the active component of aequum permeate.
Can be used to provide the appropriate excipients (as carrier and thinner) of transdermal of the present invention and topical formulations and other material is that technical staff in the pharmaceutical field is known, can decide according to the particular organization that gives pharmaceutical composition or formulation.Typical excipient includes but not limited to water, acetone, ethanol, ethylene glycol, propane diols, 1,3-butanediol, isopropyl myristate, isopropyl palmitate, mineral oil and their mixture.
According to by the particular organization of being treated, before with active component treatment of the present invention, while or can use other component afterwards.For example, can use penetration enhancer to help active component to the tissue infiltration.Suitable penetration enhancer includes but not limited to: acetone; Various alcohol are as ethanol, oleyl alcohol and oxolane; Alkyl sulfoxide is as methyl-sulfoxide; Dimethylacetylamide; Dimethyl formamide; Polyethylene glycol; Pyrrolidinone compounds is as polyvinylpyrrolidone; Kollidon (Kollidon) level (pyrrole dimension ketone, polyvidone); Urea and various water-soluble or water-insoluble sugar ester are as Tween 80 (polysorbate80) and sorbester p18 (sorbitan monostearate).
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 components and passed.Similarly, polarity, its ion strength or the tension force that can regulate solvent carrier improves defeated passing.The compound of stearate and so on also can be added in pharmaceutical composition or the formulation, improves defeated passing with the hydrophily or the lipophilicity that advantageously change one or more active components.Thus, stearate can be used as the lipid excipient of preparation, as emulsifier or surfactant, and can be used as defeated pass promoter or penetration enhancer.The character that can use different salt, hydrate or the solvate of active component further to regulate resulting composition.
Topical formulations
Topical formulations of the present invention includes but not limited to, known other formulation of cream, washing lotion, ointment, gel, solution, emulsion, suspending 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 technical staff is well-known, and the particular organization that gives according to pharmaceutical composition or formulation decides.Typical excipient includes but not limited to water, acetone, ethanol, ethylene glycol, propane diols, 1,3-butanediol, isopropyl myristate, isopropyl palmitate, mineral oil and their mixture.
According to by the particular organization of being treated, before with active component treatment of the present invention, while or can use other component afterwards.For example, can use penetration enhancer to help active component to send to tissue.Suitable penetration enhancer includes but not limited to: acetone; Various alcohol are as ethanol, oleyl alcohol and oxolane; Alkyl sulfoxide is as methyl-sulfoxide; Dimethylacetylamide; Dimethyl formamide; Polyethylene glycol; Pyrrolidinone compounds is as polyvinylpyrrolidone; Kollidon (Kollidon) level (pyrrole dimension ketone, polyvidone); Urea and various water-soluble or non-water-soluble sugar ester are 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, spray 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 be used for treating 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 propellant directly with the defeated lung that is delivered to of formula (1) compound, and described propellant is for example dicholorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, 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) as 3M company (3M Corporation), A Fan.
Perhaps, can use Diskus (DPI) to the compound of pulmonary administration formula (1) (for example 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 this smog can be the patient then and sucks.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 dose 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 that is used for inhalator or insufflator can be mixed with the mixture of powders that contains compound and be applicable to the powder binder (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, can directly suck lung then.
In one embodiment, use sprayer unit 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 sprayer is made aerosol by liquid pharmaceutical formulation.(for example 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 sprayer comprise Shi Fei/systemic lung defeated pass Co., Ltd (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 Electrofluid 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 (for example 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 lung is defeated when passing this medicine, the electrochemical properties of formula (1) compound formulation may be important optimization parameter, 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 sprayer 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, polyethylene glycol or perfluocarbon.Optional is to add the aerosol character that another kind of material comes change formula (1) compound solution or suspension.Preferably, this material is the liquid such as alcohol, glycol, polyglycols or fatty 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, as suppository or delay enema, for example can contain the conventional suppository base such as cupu oil or other glyceride.
Except aforesaid preparation, formula (1) compound also can be mixed with durative action preparation.The preparation of this class long term can be implanted or give by intramuscular injection by (for example subcutaneous or intramuscular).Like this, compound can perhaps be mixed with sl. sol. derivative, for example sl. sol. salt with suitable polymers material or hydrophobic material (for example, can accept the emulsion in the oil) or ion exchange resin preparation.
Perhaps, can use other drug delivery system.Liposome and emulsion are to can be used to the defeated known defeated example of passing excipient of passing formula (1) compound.Can use some organic solvent, but this solvent has bigger toxicity usually such as methyl-sulfoxide.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 polymeric material (referring to, the medical application 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 give the part of whole-body dose (for example referring to Goodson, the medical application 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 excipient (as carrier and thinner) and to can be used to other material of mucous membrane formulation of the present invention is provided be that the pharmaceutical field technical staff is well-known can be decided according to specific site or method that composition or formulation give.Typical excipient includes but not limited to, water, ethanol, ethylene glycol, propane diols, 1, and 3-butanediol, isopropyl myristate, isopropyl palmitate, mineral oil and their mixture, described excipient 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 components and passed.Similarly, can regulate the ion 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 hydrophily or the lipophilicity advantageously to change one or more active components in pharmaceutical composition or the formulation, thereby improve defeated passing.Thus, stearate can be used as the liquid excipient of preparation, as emulsifier or surfactant, and as defeated promoter or the penetration enhancer passed.The character that can use different salt, hydrate or the solvate of active component further to regulate 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), and described drug packages or medicine box also comprise one or more containers, and these containers comprise extra therapeutic 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' permission.
The treatment disease
In one embodiment, the compound of use formula (1) in treatment of diseases or prevention process.For example, improved the method that prevention or treatment warm blooded animal, especially people's pathogenic organisms infect, this method comprises the crystallization shape compound of the formula (1) that gives effective dose.One preferred embodiment in, pathogenic organisms is on the described bacterium of WO2005/121162, fungi or virus infections, in preferred embodiment, be by adenovirus, cytomegalovirus, hepatitis A virus (HAV), hepatitis type B virus (HBV), the Flavivirus that comprises flavivirus and hepatitis C virus (HCV), 1 type and 2 type herpes simplex viruss, herpes zoster virus, the herpes virus hominis 6, human immunodeficiency virus (HIV), human papilloma virus (HPV), influenza A virus, influenza B virus, measles virus, parainfluenza virus, polyovirus, poxvirus (comprising smallpox and monkey pox virus), rhinovirus, respiratory syncytial virus (RSV) (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 viruses, Venezuelan equine encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Japanese encephalitis virus, kyasanur forest diseae virus,Kyasanur forest virus; The virus infections 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 this method comprises formula (1) compound of the crystal form that gives effective dose.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, especially the application in the medicine of virus (for example HCV or HBV) infection in manufacturing.
Another embodiment provides treatment mammal tumor or method for cancer, and this method comprises the compound of the formula (1) that gives mammal (patient) treatment effective dose.Expect that medicable tumour or cancer include but not limited to tumour or cancer that those are caused by virus, the effect of these compounds relates to and suppresses to have infected viral cell transformation is neoplastic state, suppresses virus from being diffused into other normal cell by cell transformed and/or stoping the growth of viral cell transformed.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: breast cancer, colon cancer, carcinoma of urinary bladder, lung cancer, prostate cancer, cancer of the stomach and cancer of pancreas and lymphoblast leukemia and granulocytic 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 method for administration of seriousness and active component.Dosage, and administration frequency under some situation also can be according to age, body weight and the reactions of the disease that will treat, individual patient and different.The proper dosage scheme 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 patient, 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 nursing staff of collecting post; The army 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 of treatment or treatment are produced the tolerance patient of (as producing drug resistance to reversing transcripting enzyme inhibitor, protease inhibitors etc.).
Dosage
The toxicity and the drug effect of formula (1) compound can be measured by the standard pharmaceutical procedures of carrying out in cell culture 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 dosage of toxicity and curative effect is than being 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 the ED that does not almost have or do not have toxicity
50The circulation composition scope in.Can in this scope, change dosage according to used formulation and method of administration.For any compound that is used for the inventive method, the treatment effective dose can estimation at first from cell culture assays.Can adjust dosage in the animal model to obtain comprising the IC that measures in the cell culture
50The circulation blood concentration scope of (that is, reaching the concentration of the test compound of maximum half that suppresses of symptom); Perhaps, the dosage of allotment formula (1) compound in animal model is so that the circulation blood concentration scope of the compound concentration required with being fixed the reaction magnitude is mapped.This category information can be used for more accurately determining 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 are before being used for human body, and preferred elder generation carries out in vitro test to required treatment or prophylactic activity, and then carries out in vivo studies.For example, analyzed in vitro can be used to determine whether to give specific therapeutic scheme, 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 the suitable technique measurement.Assess this compound with regard to the intensity of formula (1) compound then.The compound that is used for the inventive method can be tested with suitable animal model before giving human trial, and described animal model includes but not limited to: rat, mouse, chicken, ox, monkey, rabbit, hamster etc.Compound can be used for suitable clinical testing then.
The compound of formula of the present invention (1) or its pharmaceutically acceptable solvate or the hydrate preventive dose or the value of therapeutic dose in acute or chronic treatment or prevention infection or disease can be different with the method for administration of the character that infects and the order of severity and active component.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 the proper dosage scheme 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 the body weight and the state of an illness.Dosage also can be according to different particular compound of the present invention and difference; Proper dosage can be predicted according to aforesaid testing in vitro 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 gram/skies 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/skies are more preferably the 100-8000 mg/day.
In addition, the daily dose of recommendation can following period of time as unitary agent or with other therapeutic agent combined cycle administration.In one embodiment, dosage every day that gives is single agent or five equilibrium dosage.In a relevant embodiment, dosage every day 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's 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, stomach and intestine outer (comprise subcutaneous, intramuscular, inject, intra-arterial or intravenous) administration, cutaneous penetration or topical.In a certain concrete embodiment, compound of the present invention is by mucous membrane (comprising hypogloeeis, cheek, rectum, nose or vagina) administration, stomach and intestine outer (comprising subcutaneous, intramuscular, intravenous injection, intra-arterial or intravenous) administration, cutaneous penetration 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 understood, for the available different treatment effective dose 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 therapy also is encompassed in above-mentioned dosage range and the administration frequency scheme.
Combination treatment
Concrete grammar of the present invention also comprises the therapeutic agent (that is the therapeutic 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 therapeutic agent.Described therapeutic agent includes but not limited to: antibiotic, antiemetic, antidepressant and antifungal agent, antiinflammatory agent, antivirotic, anticarcinogen, immunomodulator, alpha-interferon, beta-interferon, Ribavirin, alkylating agent, hormone, cell factor or toll acceptor sample conditioning agent.
The compound of formula (1) can with antibiotic administering drug combinations or formulated together.For example, they can be prepared with following antibiotic: macrolides (as, tobramycin (
)), cynnematin (as, cefalexin (
), Cefradine (
), cefuroxime (
), Cefprozil (
), Cefaclor (
), Cefixime (
) or cefadroxil (
)), clarithromycin (as Clarithromycin (
)), erythromycin (as, erythromycin (
)), penicillin is (as, ospen (V-
Or Pen
)) or quinolione (as, Ofloxacin (
), Ciprofloxacin (
) or Norfloxacin (
)), aminoglycoside antibiotics (as, apramycin, Arbekacin, bambermycin, Butirosin, dibekacin, neomycin, undecylenate (salt), Netilmicin, paromomycin, ribostamycin, sisomycin and spectinomycin), acid amides alcohol (amphenicol) antibiotic (as, azidamfenicol, chloramphenicol, Florfenicol and Thiamphenicol), the ansamycin antibiotic (as, Rifamide and rifampin), carbacephem (as, Loracarbef), carbapenem (as, Biapenem and Imipenem), cynnematin (as, Cefaclor, cefadroxil, Cefamandole, cefatrizine, Cefazedone, Cefozopran, Cefpimizole, cefpiramide and Cefpirome), cephamycin-type (as, cefbuperazone, cefmetazole and Cefminox), the monobactam class (as, aztreonam, carumonan and Tigemonam), oxacephems (as, Flomoxef and latamoxef), penicillins (as, nitrogen
Amidine penicillin, nitrogen
An amidine penicillin ester (amdinocillinpivoxil); the Amoxicillin; Bacampicillin; benzyl penicillinic acid; benzyl penicillin sodium; Epicillin; fenbenicillin; the flucloxacillin; penamecillin; the penethacillin hydriodate; benapen (penicillino-benethamine); penicillin; ospen; penicillin V benzathine; abbocillin V; penimepicycline and penicillin-152 (phencihicillin potassium)); lincosamide (as; clindamycin and lincomycin); amfomycin; bacitracin; capreomycin; polymyxin e; enramycin; Enviomycin; Tetracyclines (as; apicycline; aureomycin; clomocycline and demeclocycline); 2; the 4-diaminopyrimidine (as; brodimoprim); itrofurans (as; Levofuraltadone and furazolium chloride); quinolones and its analog (as; cinoxacin; Clinafloxacin; flumequine and Grepafloxacin); sulfamido (as; sulfacetamide methoxy pyrazine; benzylsulfamide; noprylsulfamide; sterathal; sulfachrysoidine and sulfacitine); the sulfone class (as, Diathymosulfone; glucosulfone sodium and solasulfone); seromycin; mupirocin and tuberin (tuberin).
The compound of formula (1) can with antemetic administering drug combinations or preparation.Suitable antemetic includes but not limited to: Metoclopramide, domperidone, prochlorperazine, fenazil, chlorpromazine hydrochloride, Trimethobenzamide, Ondansetron, Granisetron, hydroxyzine, the Acetylleucine MEA, alizapride, Azasetron, benzene quinoline amine, bietanautine, Bromopride, Buclizine, clebopride, Cyclizine, dramamine, difenidol, Dolasetron, meclozine, methallatal, metopimazine, nabilone, Oxipendyl, Pipamazine, hyoscine, Sulpiride, tetrahydrocannabinol, tietylperazine, cephalmin, Tropisetron and their mixture.
The compound of formula (1) can with antidepressants administering drug combinations or formulated together.Suitable antidepressants include but not limited to: Binedaline, caroxazone, Citalopram, dimethazan, fencamine, Indalpine, the hydrochloric acid Indeloxazine, nefopam, Nomifensine, hydroxytryptophane, Oxypertine, Paxil, Sertraline, thiazesim, triazolone, benmoxine, iproclozide, iproniazid, Isocarboxazid, Nialamide, octamoxin, nardil, cotinine, rolicyprine, rolipram, maprotiline, metralindole, Mianserin, Mirtazapine (mirtazepine), Adinazolam, amitriptyline, Amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline, desipramine, the dibenzepine, dimetacrine, the degree coloured glaze is flat, doxepin, padil, imipramine, imipramine N-oxide, Iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxiptiline, Opipramol, pizotifen, propizepine, protriptyline, Quinupramine, Tianeptine, trimipramine, adrafinil, benactyzine, Bupropion, butacetin, Dioxadrol, Duloxetine, etoperidone, febarbamate, femoxetine, fenpentadiol, Prozac, Fluvoxamine, haematoporphyrin, hypericin, acetopherane, the medifoxamine, Milnacipran, minaprine, Moclobemide, Nefazodone, Oxaflozane, Piberaline, prolintane, pyrisuccideanol, ritanserin, Roxindole, rubidium chloride, Sulpiride, Tandospirone, thozalinone, Tofenacin control-om, parnitene, the L-tryptophan, Venlafaxine, Viloxazine and Zimeldine.
The compound of formula (1) can with antifungal agent administering drug combinations or formulated together.Suitable antifungal agent includes but not limited to: amphotericin B, Itraconazole, ketoconazole, Fluconazole, her Qu Saike (intrathecal), Flucytosine, Miconazole, butoconazole, clotrimazole, nystatin, terconazole, tioconazole, Ciclopirox, econazole, haloprogin, Naftifine, Terbinafine, undecylenate (salt) and griseofulvin.
The compound of formula of the present invention (1) can with antiinflammatory agent administering drug combinations or formulated together.Useful antiinflammatory agent includes but not limited to: non-steroid anti-inflammatory drug, as salicylic acid, acetylsalicylic acid, gaultherolin, Diflunisal, salsalate, Olsalazine, Sulfasalazine, paracetamol, Indomethacin, sulindac, Etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, diclofenamide, brufen, naproxen, naproxen sodium, fenoprofen, Ketoprofen, BTS-18322, olsapozine, piroxicam, Meloxicam, Ampiroxicam, Droxicam, Fu Xikang (pivoxicam), tenoxicam, Nabumetone, phenylbutazone, Oxyphenbutazone, antipyrine, aminopyrine, apazone and aulin; Leukotriene antagonist includes but not limited to: Zileuton, aurothioglucose, sodium aurothiomalate and Anranofin; The steroidal class includes but not limited to: alclometasone diproionate, Amcinonide, beclomethasone dipropionate, betamethasone, betamethasone benzoate, BDP, betamethasone sodium phosphate, betamethasone valerate, clobetasol propionate, the neopentanoic acid clocortolone, hydrocortisone, hydrocortisone derivative, desonide, Desoximetasone, dexamethasone, flunisolide, fluorine can hot pine (flucoxinolide), fludroxycortide, chlorine fluorine pine, medrysone, methylprednisolone, the acetate methylprednisolone, Urbason Solubile, momestasone furoate, the acetate paramethasone, prednisolone, the prednisone acetate dragon, Inflamase, uncle's Hydeltra T. B. A, metacortandracin, fluoxyprednisolone, Triamcinolone acetonide, oxalic acid fluoxyprednisolone and Triamcinolone Hexacetonide; And other antiphlogistic, include but not limited to: methotrexate (MTX), colchicin, Allopurinol, probenecid, Sulfinpyrazone and Benzbromarone.
The compound of formula (1) can with another kind of antivirotic administering drug combinations or formulated together.Useful antivirotic includes but not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and nucleoside analog.Antivirotic includes but not limited to, Zidovudine, acyclovir, Ganciclovir, arabinosy ladenosine, iodoxuridine, Trifluridine, left Wei Lin (levovirin), ribavirin (viramidine) and Ribavirin and phosphine formic acid, amantadine, Rimantadine, inverase, indinavir, amprenavir, Lopinavir, Ritonavir, alpha-interferon; Beta-interferon; Adefovirdipivoxil, resist to come furan fixed, think for card Wei, pleconaril.
The compound of formula of the present invention (1) can with immunomodulator administering drug combinations or formulated together.Immunomodulator includes but not limited to: methotrexate (MTX), leflunomide, cyclophosphamide, ciclosporin A, mycophenolate mofetil, thunder primycin (sirolimus), mizoribine, deoxyspergualin, the cloth quinoline that, malononitrilamide (malononitriloamindes) (as leflunomide (leflunamide)), TXi Baoshouti conditioning agent and cytokine receptor conditioning agent, peptide mimics and antibody are (as the people, humanized, chimeric, monoclonal, polyclone, Fv, ScFv, Fab or F (ab) 2 fragments or epi-position binding fragment), nucleic acid molecules (as antisense nucleic acid molecule and triple helical body), little molecule, organic compound and inorganic compound.The example of TXi Baoshouti conditioning agent includes but not limited to: anti--TXi Baoshouti antibody (as anti-CD 4 antibodies (as cM-T412 (Berlin lattice company (Boeringer)), IDEC-CE9.1
(IDEC and SKB), mAB4162W94, Orthoclone and OKTcdr4a (JC company (Janssen-Cilag)), anti-CD 3 antibodies are (as Nuvion (product design laboratory (Product Design Labs)), the OKT3 ((Johnson﹠amp of Johson ﹠ Johnson; Johnson)), or rituximab (IDEC)), anti--CD5 antibody (as the immune conjugate of anti--CD5 ricin connection), anti--CD7 antibody is (as CHH-380 (Novartis Co.,Ltd (Novartis)), anti--CD8 antibody, anti-CD 40 complex monoclone antibody (as IDEC-131 (IDEC)), anti-CD 52 antibody (as CAMPATH 1H (Ilex)), anti--CD2 antibody, anti--CD11a antibody (as, Xanelim (Gene science company (Genentech)), with anti--B7 antibody (as, IDEC-114 (IDEC)), CTLA4-immunoglobulin 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), cell factor 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 (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-TNF alpha 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 administering drug combinations that suppresses viral enzyme or formulated together.Described medicament includes but not limited to: the inhibitor of HCV protease, as BILN 2061, SCH-503034, ITMN-191 or VX-950; The inhibitor of NS5b polymerase is as NM107 (and prodrug NM283), R1626, R7078, BILN1941, GSK625433, GILD9128 or HCV-796.
The compound of formula (1) can with as Wu, Curr Drug Targets Infect Disord., 3, the medicament administering drug combinations of the described inhibition of 207-19 (2003) HCV polymerase 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 administering drug combinations of thing or formulated together.
The compound of formula (1) can with the medicament administering drug combinations that suppresses virus replication or formulated together.
The compound of formula (1) can with cell factor administering drug combinations or formulated together.The example of cell factor includes but not limited to: proleulzin (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-9 (IL-9), interleukin-10 (IL-10), il-1 2 (IL-12), interleukin 15 (IL-15), interleukin 18 (IL-18), from hematoblastic growth factor (PDGF), hematopoietin (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 stimulatory factor (M-CSF), prolactin and interferon (IFN) are 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), somatotropin (GH), growth hormone releasing hormone, ACTH, Somat, somatotropin, somatomedin, parathormone, hypothalamic releasing factor, insulin, glucagon, enkephalins, anti diuretic hormone, calcitonin, heparin, low molecular weight heparin, heparan, synthetic and natural opium, insulin thyroid-stimulating hormone (TSH) and endorphin.
The compound of formula (1) can with the beta-interferon administering drug combinations 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 administering drug combinations or formulated together, α-disturb element to include but not limited to: the alpha-interferon administering drug combinations of Alfacon-1, Intederon Alpha-2a (roferon), Interferon Alpha-2b, intron, Peg-intron, Pegasys, synonym interferon (ingergen) and A Bufenlong (albuferon) or formulated together.
The compound of formula (1) can with sorbefacient administering drug combinations or formulated together, described sorbefacient is target with the lymphatic system specifically, includes but not limited to sodium glycocholate; Sodium caprate; 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 reported, it is for reference that the document is incorporated this paper in full into.Also can use other known absorption promoter.The compound of formula of the present invention (1) can with alkylating agent administering drug combinations or formulated together.The example of alkylating agent includes but not limited to, mustargen, aziridine, methylmelamine, alkyl sulfonate esters, nitroso ureas, triazenes, chlormethine, cyclophosphamide, ifosfamide, melphalan, Chlorambucil, hemel, tespamin, busulfan, card chlorine mustard, streptozotocin, dacarbazine and Temozolomide.
Formula (1) compound and other therapeutic agent can have adduction, are more preferably synergy.In one embodiment, contain The compounds of this invention composition can with the administration simultaneously of another kind of therapeutic agent, the part that described another kind of therapeutic agent can be a said composition or from the composition different with the composition that contains The compounds of this invention.In another embodiment, before or after giving another kind of therapeutic agent, give compound of the present invention.At one independently in the embodiment,, be that the patient of antivirotic treatment gives compound of the present invention specifically to not accepting or do not use at present another kind of therapeutic agent.
The preparation method
In another embodiment, the invention provides 5-amino-3-shown in preparation following formula (1) (2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the 3H-thiazole method of [4,5-d] pyrimid-2-one tosilate also:
This method is easy and simple to handle, sane and effective, can be used for the scale commodity production of this salt.And this method cost is effective, the efficient and overall productive rate height of output.
In one embodiment, synthetic 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the 3H-thiazole also the method for [4,5-d] pyrimid-2-one tosilate (1) may further comprise the steps:
(i) make the also compound of [4,5-d] pyrimid-2-ones (2) and desoxyribofuranose (3) coupling formation formula (4) of 5-amino-3H-thiazole
(ii) 5 ' acetic acid esters on selective splitting formula (4) compound, form 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5-d] pyrimid-2-ones (5) also,
(iii) make 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole also [4; 5-d] reaction of pyrimid-2-one (5) and p-methyl benzenesulfonic acid form 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-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 desoxyribofuranose coupling of [4,5-d] pyrimid-2-ones (2) and formula (3B) form the compound of formula (4)
The coupling reaction of step (i) can be carried out in high temperature (greater than 130 ℃) " fusion " reaction under condition of no solvent, adopts 1 usually, and 3-two (4-nitrobenzophenone) phosphate also carries out under vacuum sometimes as acidic catalyst.Perhaps, this reaction can be carried out in solvent such as acetonitrile, toluene, dichloroethane, DMF, carrene or its mixture.Coupling reaction usually acid as trimethylsilyl triflate (" TMSOTf "), AlCl
3, SnCl
4And TiCl
4And silylating reagent (silating reagent) carries out under the existence of two (trimethyl silyl) acetamides (" BSA ") of O-or trimethylsilyl chloride as N.Add water then and stop coupling 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 silicyl on formula (4) the compound heterocyclic moiety is removed in the aqueous peracid solution hydrolysis.
In another embodiment, the coupling step of step (i) is a benchmark with the reactive chemistry metering, adopts also [4,5-d] pyrimid-2-ones (2) of excessive 5-amino-3H-thiazole with respect to desoxyribofuranose (3).For example, 5-amino-3H-thiazole also [4,5-d] pyrimid-2-ones (2) can excessive about 5%-50%, about 5%-25%, about 5%-15%.In addition, be benchmark with the reactive chemistry metering, 5-amino-3H-thiazole also [4,5-d] pyrimid-2-ones (2) than desoxyribofuranose (3) excessive about 10%.In the presence of inert solid, after the coupling reaction of step (i) is finished, remove also [4,5-d] pyrimid-2-ones (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 chloride, three layers of liquid system that generation can be separated.
Excessive 5-amino-3H-thiazole also [4,5-d] pyrimid-2-ones (2) separation the difficulty.Yet the pH that has been found that the reactant mixture that rising is finished in the presence of inert solid helps separating method.In the presence of inert solid such as diatomite (celite) filtration adjuvant, with alkali (for example sodium hydroxide and/or sodium carbonate) rising pH to precipitate also [4,5-d] pyrimid-2-ones (2) of excessive 5-amino-3H-thiazole.Inert solid filters removal after applying.After the further neutralization of alkali, in residual filtrate, add extra sodium chloride, three layers of liquid system that obtain to be separated.Density smallest tier (top layer) is the hexamethyldisiloxane of clarification, can remove mutually by separating each, need not distillation (conventional removal method).Middle required nucleosides (4) and the acetonitrile of comprising mutually.The maximum layer of density (bottom) is a water, and (4) in the reactant 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 and (ii) need not further processing in the time of in solvent mixture.
Step (ii) in, 5 ' acetic acid esters on selective splitting formula (4) compound.This can utilize enzyme such as antarctic candida (Candida Antarctica) to realize.Antarctic candida can available from living things catalysis Co., Ltd (Biocatalytics, Inc.).Usually, enzyme covalently bind on the solid phase carrier.It is more effective and the reaction time is shorter to covalently bind in enzyme recycle 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.The enzyme that also it can be added load is in the suspension of the water that contains alkali (for example sodium bicarbonate or sodium acetate).Perhaps, this solution can be added in absolute ethyl 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 chloride can be added in the filtrate and with isopropyl acetate and extract.
Compound such as 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-also the processing of [4,5-d] pyrimid-2-ones (5) is difficult for the 3H-thiazole, and this compound usually is unmanageable material.Carry out the solvent evaporation or precipitate the uncertain method that does not reach optimality criterion product state that provides in this stage.Yet method of the present invention no longer needs to handle compound (5), does not need evaporating solvent or makes the product precipitation.5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the 3H-thiazole also [4,5-d] pyrimid-2-ones (5) be pure state, carry out in the step solvent mixture (iii) being enough to.
Step (iii) comprise make 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole also [4; 5-d] pyrimid-2-one (5) and p-methyl benzenesulfonic acid in solvent, react formation 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-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, normal propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, 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 (ii) in step, and this method also comprises interpolation ethanol.Usually, be benchmark with the chemical reaction metering, the step (iii) consumption of middle sulfonic acid is about equimolar amounts to excessive about 10 moles of %.
Step reaction (iii) can reactant any concentration carry out.For example, reactant concentration is about the 1-1000 mM.In addition, concentration is about 50-500 mM or about 100-250 mM.
5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-the thiazole also solution and the p-methyl benzenesulfonic acid solution reaction of [4,5-d] pyrimid-2-ones (5).Two kinds of solution are mixed about 5 minutes to about 2 hours, or about 5 minutes to about 1 hour.In addition, p-methyl benzenesulfonic acid solution can be added in the reactant mixture, by this reactant mixture synthesis type (1) compound, of U.S. Patent Application Publication No. 2006/0160830 (sequence number 11/304,691), its content is included into this paper as a reference.
Step (iii) be reflected at-20 ℃ to about 40 ℃ approximately, 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, normal propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, ethyl acetate, acetonitrile, isopropyl acetate, THF and their mixture.In one embodiment, mixture comprises (ii) middle isopropyl acetate and the acetonitrile that produces of step, and this method also comprises ethanol is added in the mixture.Usually, be benchmark with the chemical reaction metering, the step (iii) consumption of middle sulfonic acid is about equimolar amounts to excessive about 25 moles of %, or is about equimolar amounts to excessive about 10 moles of %.
With 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole also [4; 5-d] solution of pyrimid-2-one (5) is with after p-methyl benzenesulfonic acid solution mixes; 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-also tosilate (1) precipitation or the crystallization of [4,5-d] pyrimid-2-one of 3H-thiazole.Then product is passed through isolated by filtration, washing is also dry.Product also can be come separated product from other solvent system precipitation or crystallization by from the reactant mixture evaporating solvent, perhaps precipitates by reaction mixture or crystallized product separates.The product 5-amino-3-that separates (2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-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 atmospheric pressure 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-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole also [4; 5-d] step of pyrimid-2-one tosilate (1), wherein the purity of the salt of Fen Liing 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 first kind of course of reaction (flow process 1), in the presence of alkali,, form the compound of the sulfonyl replacement of formula (7) with the compound of sulfonating agent sulfonation formula (6).This course of reaction (flow process 1) is as follows:
Flow process 1
To sulfonating 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 sulfonating agent comprises: alkyl sulfonic acid acid anhydride, heteroaryl-alkylsulfonyl halides (sulfonic halide), aromatic sulfonic acid acid anhydride, aromatics sulfonic acid halide and their mixture.Sulfonating agent comprises: the benzene sulfonic acid acid anhydride of the benzene sulfonyl halogen of trifluoromethanesulfanhydride anhydride, toluene sulfochloride, Loprazolam acid anhydride, sulfonyl methane halogen, benzene sulfonyl halogen, replacement, benzene sulfonic acid acid anhydride, replacement and their mixture.
Alkali to use in the flow process 1 is also unrestricted, can be organic or inorganic alkali, 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 carrene, dichloroethane and composition thereof.Usually, can use aprotic solvent such as oxolane or acetonitrile.
Course of reaction 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 sulfonyl replacement of the formula (7) that forms in the reductant reduction reaction flow process 1, form the compound of formula (8).Course of reaction (flow process 2) is as follows:
The reductant that adopts in the reaction process 2 is also unrestricted, as long as reductant can be realized required reduction reaction.Reductant can be a borohydrides.Borohydrides can be a hydrogen boronation tetra-allkylammonium, hydrogen boronation TBuA, borohydride sodium, cyano group borohydride sodium, lithium borohydride, potassium borohydrid, hydrogen boronation magnesium, hydrogen calcium boride, triacetyl oxygen base borohydride sodium and their mixture.
The solvent that adopts in the reaction process 2 is also unrestricted.Can use the mixture of arsol or arsol.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, dichloroethane, oxolane and their mixture.
Course of reaction 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 course of reaction (flow process 3), in the presence of acid, the compound of the formula (8) that forms in the water hydrolysis flow process 2 forms the compound of formula (9).This course of reaction (flow process 3) is as follows:
Also unrestricted to the acid of using in the reaction process 3, can use organic acid or inorganic acid.Reaction can be carried out in aqueous solvent.Reaction also can be carried out with 50% aqueous acetic acid or aqueous hydrochloric acid solution.
The course of reaction of flow process 3 is carried out under about 50 ℃ temperature at about 0 ℃.The course of reaction of flow process 3 also can be carried out under about 30 ℃ temperature at about 20 ℃.
In next course of reaction (flow process 4), the compound of the formula (9) that forms in the reaction process 3 forms the compound of formula (10) with the oxidant oxidation, then with the reductant reduction.This course of reaction (flow process 4) is as follows:
Oxidant to use in the reaction process 4 is also unrestricted, as long as oxidant can be realized required oxidation reaction.Oxidant comprises sodium metaperiodate, lead acetate and their mixture.
Reductant to use in the reaction process 4 is also unrestricted, comprises the reductant 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, carrene, carrene and methyl alcohol or methyl alcohol and water.
The course of reaction of flow process 4 is carried out under about 50 ℃ temperature at about 0 ℃.In addition, the course of reaction 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 acetylization of the formula (10) that forms in the reaction process 4 with acetylation reagent such as acetic anhydride or chloroacetic chloride, form the compound of formula (3).Course of reaction (flow process 5) is as follows:
The acid catalyst that uses in the course of reaction of flow process 5 is also unrestricted, comprises inorganic acid, organic acid or inorganic acid and organic acid are arranged simultaneously.Acid comprises nitric acid, hydrochloric acid, sulfuric acid, sulfonic acid, trifluoroacetic acid, alkyl sulfonic acid, aryl sulfonic acid and immobilization form thereof and their mixture.
Course of reaction in the flow process 5 is carried out in containing the organic solvent of above-mentioned acid catalyst usually.Solvent also can be an acetate.
The course of reaction of flow process 5 is carried out under about 5 ℃ temperature at about 0 ℃.In addition, the course of reaction 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 acetyl group-deoxidation-furan type wood sugar compound of formula (3B), shown in following reaction process 6:
Flow process 6
Reaction reagent among the above-mentioned flow process 1-5 and reaction condition 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 acetyl group-deoxidation-furan type wood sugar (xylofuranso) compound of formula (3C), shown in following reaction process 7:
Flow process 7
Reaction reagent among the above-mentioned flow process 1-5 and reaction condition 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 end product of formula (3B) as raw material.
According to following reaction process 8 preparation acetyl group-deoxidation-furan type wood sugar compounds, 1,2,5-three-O-acetyl group-3-deoxidation-D-furan type wood sugar (3B):
The reaction reagent of above-mentioned flow process 1-5 and reaction condition also are used for flow process 8.
Another embodiment of the invention comprises the compound of the formula (7) that replaces with reductant reduction sulfonyl, with the method for the compound that forms formula (8),
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.
Reductant can be a boron hydride.Borohydrides can be hydrogen boronation tetra-allkylammonium, hydrogen boronation TBuA, borohydride sodium, cyano group hydrogen sodium hydride, lithium borohydride, potassium borohydrid, hydrogen boronation magnesium, hydrogen calcium boride, triacetyl oxygen base borohydride sodium 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 are benchmark with weight.
Reaction reagent can be available from synthesizing the suppliers such as (Lancaster Synthesis Ltd.) of Co., Ltd 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 as aldrich EMD chemical company (Aldrich, EMD Chemicals) or Fei Shi company (Fisher).
General under the normal pressure and environmental 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 perusal and/or heat carrying out perusal with TLC developer such as ethanol system phosphomolybdic acid, ninhydrin solution, liquor potassic permanganate or ceric sulfate solution 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 glass plate (20 * 20 centimetres, available from thomson apparatus company (ThomsonInstrument Company)) of millimeter sheet, (254nm) carries out perusal with UV light.
Use Varian Mercury-VX400 instrument, operation note 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 (to proton is 7.27ppm, and 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.If when 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).
Infrared (IR) spectrum of record net phase oil or solid on ATR FT-IR spectrometer is with wave number (cm
-1) expression.Mass spectrum is recorded as (+)-ES or APCI (+) LC/MS, and (Anadys Pharmaceuticals, analytical chemistry portion Inc) (Analytical ChemistryDepartment) carries out by Anadys Pharmaceuticals Inc..Elementary analysis by microscope experiment chamber, the Atlantic Ocean Co., Ltd of Georgia State Norcross (Atlantic Microlab, Inc., Norcross, GA) or the NMR laboratory Co., Ltd in Santiago, California (NuMega Resonance Labs Inc.) carries out.Fusing point (mp) is measured on open capillaries equipment, not calibration.
Described route of synthesis and experimentation use many common chemical abbreviations: 2; 2-DMP (2; the 2-dimethoxy propane); Ac (acetyl group); 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-dichloroethane); DCM (carrene); DEAD (azoethane dicarboxylic ester); DIEA (diisopropylethylamine); DMA (N; the N-dimethylacetylamide); DMAP (4-(N; the N-dimethylamino) pyridine); DMF (N; dinethylformamide); DMSO (methyl-sulfoxide); EDC (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride); Et (ethyl); EtOAc (ethyl acetate); EtOH (ethanol); HATU (hexafluorophosphoric acid O-(7-azepine benzo triazol-1-yl)-1; 1; 3; the 3-tetramethylurea); HBTU (hexafluorophosphoric acid O-BTA-1-base-N; N; N ', N '-tetramethylurea); HF (hydrogen fluoride); HOBT (I-hydroxybenzotriazole hydrate); HPLC (high performance liquid chromatography); IPA (isopropyl alcohol); KO
tBu (tert-butoxy potassium), LDA (LDA), MCPBA (3-chlorine benzylhydroperoxide), Me (methyl), MeCN (acetonitrile), MeOH (methyl alcohol), NaH (sodium hydride), NaOAc (sodium acetate), NaOEt (caustic alcohol), Phe (phenyl alanine), PPTS (p-methyl benzenesulfonic acid pyridine), PS (polymer of load), Py (pyridine), pyBOP (hexafluorophosphoric acid BTA-1-base oxygen base) tripyrrole Wan Ji Phosphonium), TEA (triethylamine), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (oxolane), TLC (thin layer chromatography), Tol (toluoyl), Val (valine) etc.
Embodiment 1
Synthetic 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5] pyrimid-2-one also) tosilate
Step (i)-coupling reaction
In the three-neck 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 mMs) and acetonitrile (198 milliliters).Slowly nitrogen purges down, adds BSA (79.86 milliliters, 327.8 mMs) by funnel when stirring, and will be warming up to 40 ℃ at this mixture under the blanket of nitrogen 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-acetyl group-β-D-ribofuranose (3) (35.42 grams, 111.32 mMs).Add TMSOTf (23.54 milliliters, 130.9 mMs) by pipette when under nitrogen, stirring, cause exothermic reaction to 15 ℃.Then this mixture is warming up to 75 ℃, kept this temperature 10 hours, with the ice-water bath cooling, at first be cooled to environmental temperature then, be cooled to 15 ℃ again.1 milliliter every part in water ground is added in the reactant liquor, make exothermic reaction reach the peak between the water adding at every turn.After adding for six times, add 1 ml water again and do not cause heat release, add 38 ml waters by funnel then, this mixture was stirred 15 minutes at ambient temperature.Diatomite (Celite, 44 grams) is added in the reactant liquor that stirs, in about 30 seconds, add 22 ml water solution of sodium hydroxide (15.7 gram 50%NaOH, 196.35 mMs) then.Stirred 90 minutes reacting liquid filtering under the environmental temperature.In the filtrate of stirring, add the sodium bicarbonate (16.5 grams, 196.35 mMs) that is dissolved in 200 ml waters.When no longer including the bubble generation, add 50 gram solid sodium chloride, stir the mixture and dissolve up to all solids.This mixture is transferred to separatory funnel, the three-phase liquid system that obtains is separated.Extracting once with 50 milliliters of acetonitriles mutually of density maximum merges it mutually with the centre of initial separation.In the liquid of this merging, add 11 gram diatomite when stirring, filtering mixt after 5 minutes.Filtrate comprises required coupled product (4); It is identified and purity can utilize known substance to be measured by HPLC.
Step (ii)-enzymatic hydrolysis
Sodium bicarbonate in being dissolved in 278 ml waters (9.34 grams, 111.32 mM, be equivalent to the sugar (3) in the step (i)) solution add the lipase of the covalency load of the humidity of washing in advance [washing process: the covalently bound Type B antarctic candida (biocatalyst 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 in the solution of this stirring, adds (4) of step (i) generation.This suspension was stirred 36 hours, filtering catalyst, with acetonitrile-water (1: 1) washing, 0 ℃ stores for future use.Filtrate extracts with 222 milliliters of isopropyl acetates, and stirring water and 30 gram sodium chloride dissolve up to all solids, use 111 milliliters of isopropyl acetates extracting twice more then.Merge organic facies, 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 reference material.
Step (iii)-with the p-methyl benzenesulfonic 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 p-methyl benzenesulfonic acid (15.89 grams, 83.49 mMs) in the ethanol of 50 milliliter of 200 standard earthquake intensity in 30 minutes.Go out pale solid from the reactant 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-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5] pyrimid-2-one tosilate also, HPLC measures its purity＞98%.
Embodiment 2
Do not add in the step enzymolysis process (ii) water carry out 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5] pyrimid-2-one also) tosilate synthetic
Step (i)-coupling reaction
In the three-neck flask that is equipped with hygrosensor, condenser and nitrogen inlet, add 5-amino-3H-thiazole also [4,5-d] pyrimid-2-ones (2) (22 grams, 130.9 mMs) and acetonitrile (198 milliliters).Slowly nitrogen purges down, adds BSA (79.86 milliliters, 327.8 mMs) from funnel when stirring, and under blanket of nitrogen this mixture is warming up to 40 ℃ and keeps 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-acetyl group-β-D-ribofuranose (3) (35.42 grams, 111.32 mMs).Add TMSOTf (23.54 milliliters, 130.9 mMs) by pipette when under nitrogen, stirring, cause exothermic reaction to 15 ℃.Then this mixture is warming up to 75 ℃, kept this temperature 10 hours, with the ice-water bath cooling, at first be cooled to environmental temperature then, be cooled to 15 ℃ again.1 milliliter every part in water ground is added in the reactant liquor, make exothermic reaction reach the peak between the water adding at every turn.After adding for six times, add 1 ml water again and do not cause heat release, add 38 ml waters by funnel then, this mixture was stirred 15 minutes at ambient temperature.Diatomite (Celite, 44 grams) is added in the reactant liquor that stirs, in about 30 seconds, add 22 ml water solution of sodium hydroxide (15.7 gram 50%NaOH, 196.35 mMs) then.Stirred 90 minutes reacting liquid filtering under the environmental temperature.In the filtrate of stirring, add the sodium bicarbonate (16.5 grams, 196.35 mMs) that is dissolved in 200 ml waters.When no longer including the bubble generation, add 50 gram solid sodium chloride, stir the mixture and dissolve up to all solids.This mixture is transferred to separatory funnel, will obtains the three-phase liquid system and separate.Extracting once with 50 milliliters of acetonitriles mutually of density maximum merges it mutually with the centre of initial separation.In the liquid of this merging, add 11 gram diatomite when stirring, filtering mixt after 5 minutes.Filtrate comprises required coupled product (4); It is identified and purity can utilize known substance to be measured by HPLC.
Step does not (ii) add enzymolysis under any water condition
In 500 milliliters of round-bottomed flasks, add the fixing antarctic candida (Novozyme 435, biocatalyst catalog number (Cat.No.) 1MB-102) of 15.0 grams, add absolute ethyl alcohol (60 milliliters) again.In this liquid, add the acetonitrile solution of (4) of step (i) generation,, stir under the environmental temperature flask and atmospheric sealing.After 72 hours, add 17.5 gram diatomite 545, stirred 10 minutes, cross filter solid then, 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 reference material.
Step (iii)-with the p-methyl benzenesulfonic acid salify
Comprise the filtrate that is dissolved in (5) in ethanol and the acetonitrile with the ethanol dilution of 100 milliliter of 200 normal intensity what step (ii) obtained.When stirring, dropwise be added in the hydration p-methyl benzenesulfonic acid (15.89 grams, 83.49 mMs) in the ethanol of 50 milliliter of 200 standard earthquake intensity in 30 minutes.Go out pale solid from the reactant 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-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5] pyrimid-2-one tosilate also, HPLC measures its purity＞98%.
Embodiment 3
Scale synthesize 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5-d] pyrimid-2-one tosilate also
Step (i)-coupling reaction
In the reactor that is equipped with hygrosensor, condenser and nitrogen inlet, add 5-amino-3H-thiazole also [4,5-d] pyrimid-2-ones (2) (1.45 kilograms, 8.6 moles) and acetonitrile (1.29 liters).Slowly nitrogen purges down, adds BSA (5.23 liters, 21.5 moles) by funnel when stirring, and under blanket of nitrogen this mixture is warming up to 40 ℃ and keeps 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-acetyl group-β-D-ribofuranose (3) (2.33 kilograms, 7.32 moles).Nitrogen dropwise adds TMSOTf (1.54 liters, 8.6 moles) when stirring down, causes exothermic reaction to 15 ℃.Then this mixture is warming up to 75 ℃, kept this temperature 10 hours, cooling at first is cooled to environmental temperature then, is cooled to 15 ℃ again.
To add every part by 100 milliliters in the reactant liquors, make exothermic 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, this mixture was stirred 15 minutes at ambient temperature by funnel.Diatomite (2.47 kilograms) is added in the reactant liquor that stirs, add 14.5 premium on currency solution of sodium hydroxide (516.8 grams, 12.92 moles) then.Stirred 90 minutes reacting liquid filtering under the environmental 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 the bubble generation, add 3.3 kilograms of solid sodium chloride, stir the mixture and dissolve up to all solids.Gained three-phase liquid system is separated.Extracting once with 3.3 liters of acetonitriles mutually of density maximum merges it mutually with the centre of initial separation.What merge comprises required coupled product (4) mutually; It is identified and purity can utilize known substance to be measured by HPLC as reference material.
Step (ii)-enzymatic hydrolysis
The solution of the sodium bicarbonate in being dissolved in 21.5 premium on currency (615 grams, are equivalent to the sugar (3) in the step (i) by 7.32 moles) adds the covalently bound Type B antarctic candida of doing (1.59 kilograms, biocatalyst catalog number (Cat.No.) IMB-111).The acetonitrile solution that in the solution of this stirring, adds (4) of step (i) generation.This suspension was stirred 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 up to all solids dissolving with 3.3 kilograms of sodium chloride, uses 9 liters of isopropyl acetates extracting twice more then.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 reference material.
Step (iii)-with the p-methyl benzenesulfonic acid salify
With the ethanol dilution step of 5.5 liter of 200 standard earthquake intensity (ii) gained comprise the filtrate that is dissolved in (5) in isopropyl acetate and the acetonitrile.When stirring, dropwise be added in the hydration p-methyl benzenesulfonic 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 reactant 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-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5] pyrimid-2-one tosilate also, HPLC measures its purity＞98%.
Embodiment 4
Crystallization 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the 3H-thiazole also [4,5-dl pyrimid-2-one tosilate
With 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the 3H-thiazole also [4,5-d] pyrimid-2-one [50.0 grams, (is benchmark with CoA, 43.85 grams, 134 mMs are effective)] add in the three-neck flask that 2-rises.Add absolute ethyl alcohol (840 milliliters),, obtain yellow solution mixture stir about 10 minutes at ambient temperature.P-methyl benzenesulfonic acid (pTsOH) (26.2 grams, 138 mMs) is added in another flask, be dissolved under the environmental temperature in the absolute ethyl alcohol (220 milliliters).The p-TsOH/ ethanolic solution is added in the addition funnel, then at ambient temperature, dropwise be added drop-wise in the agitating solution of formula (5) in 40 minutes time.(3 * 20mL) drip washing are used to prepare the flask and the addition funnel of p-TsOH/ ethanolic solution, and each leacheate adds in the reaction suspension with absolute ethyl alcohol.Reactant liquor stirs spend the night (18 hours) under environmental temperature, nitrogen, use Buchner funnel and the vacuum filtration of Whatman#1 filter paper then.Solid remaining in the flask is transferred in the filter with absolute ethyl alcohol (2 * 50 milliliters), uses absolute ethyl alcohol (4 * 150 milliliters) washing leaching cake then.In filter behind the simple dry cake of suction, with the white solid of humidity in the vacuum tank that 50-55 ℃, 28-29 inch vacuum, nitrogen purge dry 54 hours.After being cooled to environmental 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 of formula (1) compound: the supernatant of above-mentioned merging and cleaning solution are concentrated into volume on rotary evaporator (45-50 ℃ of water-bath, 28-29 inch vacuum) be 470 milliliters.Stir down, the solution that gained is contained crystalline particle is cooled to environmental temperature.In 5 minutes, form crystal suspension.With this suspension stir about 48 hours at ambient temperature, use Buchner funnel and the vacuum filtration of Whatman#1 filter paper then.Filter cake is with absolute ethyl alcohol (4 * 6 milliliters) washing, then with solid in the vacuum tank that 50-55 ℃, 28-29 inch vacuum, nitrogen purge dry 48 hours.After being cooled to environmental temperature under the vacuum, obtain the compound of the compound of 2.8 gram (productive rate 4.2%) formulas (1) as second batch of 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 mMs) is dropwise added 1,2:5,6-two-O-isopropylidene-α-D-glucofuranose (13.0 grams, 50.0 mMs), pyridine (10.0 milliliters, 124 mMs) and CH
2Cl
2(300 milliliters)-20 ℃ in-10 ℃ agitating solution, keep internal temperature to be lower than-10 ℃ simultaneously.Gained solution stirs between-10 ℃ to 0 ℃, simultaneously by TLC monitoring consumption of raw materials (requiring about 1 hour).Reactant liquor H
2The saturated NaCl aqueous solution (50 milliliters) washing is used in O (2 * 100 milliliters) washing then.Organic facies Na
2SO
4Drying is filtered then.Filtrate is concentrated on rotary evaporator dried (about 30 ℃), 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 mMs) and n-Bu
4NBH
4(40.0 grams, 155 mMs) mixture in toluene (500 milliliters) outgased 20 minutes with nitrogen bubble.With mixture 80 ℃ of heating under nitrogen, simultaneously by TLC monitoring consumption of raw materials (requiring about 6 hours).Reactant liquor is cooled to environmental temperature, carefully adds entry (200 milliliters) then.The gained mixture stirs at ambient temperature up to no longer including hydrogen and overflows.Separate two-phase, organic facies is water (2 * 200 milliliters) and the saturated NaCl aqueous solution (100 milliliters) washing successively.Organic facies goes up at rotary evaporator (40-50 ℃) and concentrates the 3-deoxidation-1 that obtains 9.5 gram (78%) clarification grease, 2:5,6-two-O-isopropylidene-α-D-glucofuranose (8a).This material need not to be further purified and promptly 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 mMs) is dissolved in the acetate (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 concentrates (about 50 ℃) on rotary evaporator, obtain the 3-deoxidation-1 of the clarification grease of 7.9 gram (100%) thickness, 2-O-isopropylidene-α-D-glucofuranose (9a).This material need not to be further purified and promptly 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).
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 environmental temperature, with NaIO
4In (10.0 grams, 46.7 mMs) 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 mMs) 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 ℃) remove and desolvate on the rotary evaporator, and residue distributes between the 10%NaCl aqueous solution (50 milliliters) and EtOAc (50 milliliters).Two-phase is acutely mixed, separate then.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
4Drying is filtered then.Filter liquor goes up at rotary evaporator (about 40 ℃) and concentrates, and 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-acetyl group-α-D-furan type wood sugar (3B)
With H
2SO
4The aqueous solution (solution of 0.1 milliliter of 1M, 0.1 mM) slowly joins 3-deoxidation-1, in the solution of 2-O-isopropylidene-α-D-furan type wood sugar (10a) (0.26 gram, 1.5 mMs), glacial acetic acid (3 milliliters) and acetic anhydride (0.6 milliliter).Gained solution stirs at ambient temperature and spends the night, and is evaporated to dried then.Residue distributes between water and EtOAc.Phase mixture is fully jolted, separate then.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-acetyl group-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-acetyl group-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 mMs), CH
2Cl
2The solution of (5 milliliters), acetic anhydride (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 acetate (18 milliliters), acetic anhydride (1 milliliter) and the concentrated sulfuric acid (1.2 milliliters) in surplus solution.Gained solution is warming up to environmental 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) (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-acetyl group-α-D-furan type wood sugar (3B).
1H NMR analyzes with embodiment 9 gained and comes to the same thing.
Importantly, the structure of method shown in the illustrative embodiments and step and arrangement only are illustrative.Though 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 the 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 step or sequence can change or reset.The design of embodiment, operating 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, 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.Under inconsistent situation, the present invention is preferential.
Claims (50)
1. the compound of formula (1):
2. compound as claimed in claim 1, described compound are pure basically form.
3. compound as claimed in claim 1 is characterized in that, described compound is gone up substantially and do not contained residual solvent.
4. compound as claimed in claim 1, described compound are crystal form.
5. compound as claimed in claim 4 is characterized in that, described crystal form has following character:
In the X-ray diffraction (2-θ), observe the strongest line for 5.5 ° ± 0.3 ° in 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 °; With
1356,1130,804,498 and 435cm
-1Has the IR characteristic absorption band, 1637,1602,1054,1037,609 and 530cm
-1Have medium bands of a spectrum.
6. pharmaceutical composition, it comprises the compound and the pharmaceutically acceptable carrier of formula (1).
7. treat or prophylactic method for one kind, described method comprises the compound of the formula (1) of the patient treatment effective dose that needs:
8. method as claimed in claim 7 is characterized in that described disease is a virus infections.
9. method as claimed in claim 7 is characterized in that described virus infections is hepatitis b virus infected or infection with hepatitis C virus.
10. method as claimed in claim 7 is characterized in that, described disease is tumour or cancer.
11. a synthetic 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the 3H-thiazole method of [4,5-d] pyrimid-2-ones (1) tosilate also, said method comprising the steps of:
(i) make the also compound of [4,5-d] pyrimid-2-ones (2) and desoxyribofuranose (3) coupling formation formula (4) of 5-amino-3H-thiazole
(ii) 5 ' acetic acid esters on selective splitting formula (4) compound, form 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5-d] pyrimid-2-ones (5) also,
(iii) make 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole also [4; 5-d] reaction of pyrimid-2-one (5) and p-methyl benzenesulfonic acid form 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the 3H-thiazole tosilate (1) of [4,5-d] pyrimid-2-one also
12. method as claimed in claim 11 is characterized in that, step (i) comprise make 5-amino-3H-thiazole also the desoxyribofuranose coupling of [4,5-d] pyrimid-2-ones (2) and formula (3B) form the compound of formula (4)
13. method as claimed in claim 11 is characterized in that, the coupling reaction of described step (i) is carried out under condition of no solvent.
14. method as claimed in claim 11 is characterized in that, the coupling reaction of described step (i) is carried out in acetonitrile.
15. method as claimed in claim 11 is characterized in that, the coupling reaction of described step (i) is carried out in the presence of acid.
16. method as claimed in claim 15 is characterized in that, described acid is TMSOTf.
17. method as claimed in claim 11 is characterized in that, the coupling reaction of described step (i) is carried out in the presence of silylating reagent.
18. method as claimed in claim 17 is characterized in that, described silylating reagent is N, O-two (trimethyl silyl) acetamide.
19. method as claimed in claim 11 is characterized in that, the coupling reaction of described step (i), is carried out in acetonitrile under the existence of O-two (trimethyl silyl) acetamide at TMSOTf and N.
20. method as claimed in claim 19 is characterized in that, adds entry after coupling reaction is finished with quencher excessive TMSOTf and BSA, to form water-based triflate and hexamethyldisiloxane.
21. method as claimed in claim 11 is characterized in that, is benchmark with the chemical reaction metering, the coupling reaction of described step (i) adopts with respect to the excessive 5-amino-3H-thiazole of desoxyribofuranose (3) [4,5-d] pyrimid-2-ones (2) also.
22. method as claimed in claim 11 is characterized in that, with (ii) 5 ' acetic acid esters on Chinese style (4) compound of enzyme selectivity ground cleavage step.
23. method as claimed in claim 22 is characterized in that, described enzyme is an antarctic candida.
24. method as claimed in claim 11; it is characterized in that; step (iii) comprises: make 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole also [4; 5-d] pyrimid-2-one (5) and p-methyl benzenesulfonic acid react in solvent; form 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5-d] pyrimid-2-one tosilate (1) also.
25. method as claimed in claim 24 is characterized in that, described solvent is selected from: ethanol, methyl alcohol, normal propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, ethyl acetate, acetonitrile, isopropyl acetate, THF and their mixture.
26. method as claimed in claim 25 is characterized in that, described solvent comprises the mixture of isopropyl acetate and acetonitrile.
27. method as claimed in claim 11, described method also comprise separate 5-amino-3-(2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-3H-thiazole [4,5-d] pyrimid-2-one tosilate (1) also.
28. method as claimed in claim 27 is characterized in that, the 5-amino-3-of described separation (2 '-O-acetyl group-3 '-deoxidation-β-D-ribofuranosyl)-the 3H-thiazole also the purity of [4,5-d] pyrimid-2-one tosilate (1) be at least 95%.
29. the method for a preparation formula (3) compound
Described method comprises:
(i) make the compound sulfonation of formula (6) with sulfonating agent and alkali, form the compound that the sulfonyl of formula (7) replaces,
Wherein R is the optional alkyl or aryl that replaces;
(ii) use the compound of the sulfonyl replacement of reductant reduction-type (7), form the compound of formula (8)
(iii) use the compound of acid hydrolysis formula (8), form the compound of formula (9)
(iv) use the compound of oxidant oxidation formula (9),, form the compound of formula (10) then with the reductant reduction
With
(v) in the presence of acid catalyst, make the compound acetylization of formula (10), form the compound of formula (3) with acetylation reagent
30. the method for the compound of a preparation formula (3B),
Described method comprises:
(i) make the compound of formula (6B), formula (6C) or their mixture sulfonation with sulfonating agent and alkali, form compound or its mixture of the sulfonyl replacement of formula (7B), formula (7C)
Wherein, R is the optional alkyl or aryl that replaces;
(ii) use compound or its mixture of the sulfonyl replacement of reductant reduction-type (7B), formula (7C), form the compound of formula 8B
(iii) use the compound of acid hydrolysis formula (8B), form the compound of formula (9B)
(iv) use the compound of oxidant oxidation formula (9B),, form the compound of formula (10B) then with the reductant reduction
(v) in the presence of acid catalyst, make the compound acetylization of formula (10B), form the compound of formula (3B) with acetylation reagent
31. method as claimed in claim 29 is characterized in that, described sulfonating agent is selected from: alkyl sulfonic acid acid anhydride, heteroaryl-alkylsulfonyl halides, aromatic sulfonic acid acid anhydride, aromatics sulfonic acid halide and their mixture.
32. method as claimed in claim 29 is characterized in that, described sulfonating agent is selected from: trifluoromethanesulfanhydride anhydride, toluene sulfochloride, methanesulfonic acid acid anhydride and methylsulfonyl halogen and their mixture.
33. method as claimed in claim 29 is characterized in that, described sulfonating agent is a trifluoromethanesulfanhydride anhydride.
34. method as claimed in claim 29 is characterized in that, described reductant is borohydrides or aluminum hydride compound.
35. method as claimed in claim 46, it is characterized in that described reductant is selected from: hydrogen boronation TBuA, hydrogen boronation tetra-allkylammonium, borohydride sodium, lithium borohydride, potassium borohydrid, cyano group borohydride sodium, hydrogen boronation magnesium, hydrogen calcium boride, triacetyl oxygen base borohydride sodium and their mixture.
36. method as claimed in claim 29 is characterized in that, the acid (iii) of described course of reaction is the inorganic acid or the organic acid of randomly dilute with water.
37. method as claimed in claim 29 is characterized in that, described oxidant is selected from: sodium metaperiodate and lead acetate.
38. method as claimed in claim 29 is characterized in that, described acid catalyst is selected from: nitric acid, hydrochloric acid, sulfuric acid, sulfurous acid, acetate, trifluoroacetic acid, alkyl sulfonic acid, aryl sulfonic acid and their mixture.
39. method as claimed in claim 29 is characterized in that, R is CF
3, CH
3Or-C
6H
4CH
3
40. method as claimed in claim 29 is characterized in that, the alkali of course of reaction (i) be selected from following at least a: pyridine, triethylamine, imidazoles and diisopropylethylamine.
41. method as claimed in claim 29 is characterized in that, adopts carrene in the course of reaction (i).
42. method as claimed in claim 29 is characterized in that, the (ii) middle arsol that adopts of course of reaction.
43. method as claimed in claim 29 is characterized in that, course of reaction is (iv) carried out in methanol solvate, dichloromethane solvent, ethanol/methylene solvent or methanol solvent.
44. method as claimed in claim 29 is characterized in that, course of reaction (is v) carried out in acetic acid solvent, acetate/organic solvent or acetic acid/water solvent.
45. the method for the compound that the sulfonyl of a reduction-type (7) replaces
Described method comprises: with the compound that borohydrides reductant reduction sulfonyl replaces, form the compound of formula (8),
46. method as claimed in claim 45 is characterized in that, the compound of described formula (7) is the glucofuranose compound of formula 7B
The furan type allose compound of formula 7C
Or their mixture.
47. method as claimed in claim 45 is characterized in that, the compound that described sulfonyl replaces is the compound that triflate replaces.
48. method as claimed in claim 45 is characterized in that, described borohydrides reductant is a hydrogen boronation TBuA.
49. method as claimed in claim 47 is characterized in that, reduces the furanose that described triflate replaces with hydrogen boronation TBuA.
50. method as claimed in claim 45 is characterized in that, described acetylation reagent is acetic anhydride or chloroacetic chloride.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US85200206P | 2006-10-17 | 2006-10-17 | |
| US60/852,002 | 2006-10-17 | ||
| US89940507P | 2007-02-05 | 2007-02-05 | |
| US60/899,405 | 2007-02-05 | ||
| US95359707P | 2007-08-02 | 2007-08-02 | |
| US60/953,597 | 2007-08-02 | ||
| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101605457A true CN101605457A (en) | 2009-12-16 |
| CN101605457B CN101605457B (en) | 2013-10-30 |
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|---|---|---|---|
| CN200780038464.XA Expired - Fee Related CN101605457B (en) | 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 |
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| Country | Link |
|---|---|
| CN (1) | CN101605457B (en) |
| SI (1) | SI2076132T1 (en) |
| ZA (1) | ZA200903372B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107108655A (en) * | 2014-12-23 | 2017-08-29 | 豪夫迈·罗氏有限公司 | The cocrystallization and its preparation and application of the oxothiazoiium of the 5 amino 2 simultaneously yl acetate of 5 hydroxymethyl tetrahydrofuran of [4,5 D] pyrimidine 3 (2H) base 3 |
| CN114213263A (en) * | 2021-11-24 | 2022-03-22 | 江苏宝众宝达药业股份有限公司 | Purification method of chlophedianol hydrochloride |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060160830A1 (en) * | 2004-12-17 | 2006-07-20 | Anadys Pharmaceuticals, Inc. | 3,5-Disubsitituted and 3,5,7-trisubstituted-3H-oxazolo and 3H-thiazolo[4,5-d]pyrimidin-2-one compounds and prodrugs thereof |
-
2007
- 2007-10-16 CN CN200780038464.XA patent/CN101605457B/en not_active Expired - Fee Related
- 2007-10-16 SI SI200731032T patent/SI2076132T1/en unknown
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060160830A1 (en) * | 2004-12-17 | 2006-07-20 | Anadys Pharmaceuticals, Inc. | 3,5-Disubsitituted and 3,5,7-trisubstituted-3H-oxazolo and 3H-thiazolo[4,5-d]pyrimidin-2-one compounds and prodrugs thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107108655A (en) * | 2014-12-23 | 2017-08-29 | 豪夫迈·罗氏有限公司 | The cocrystallization and its preparation and application of the oxothiazoiium of the 5 amino 2 simultaneously yl acetate of 5 hydroxymethyl tetrahydrofuran of [4,5 D] pyrimidine 3 (2H) base 3 |
| CN114213263A (en) * | 2021-11-24 | 2022-03-22 | 江苏宝众宝达药业股份有限公司 | Purification method of chlophedianol hydrochloride |
| CN114213263B (en) * | 2021-11-24 | 2024-04-26 | 江苏宝众宝达药业股份有限公司 | Method for purifying chlorphenideno hydrochloride |
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| Publication number | Publication date |
|---|---|
| SI2076132T1 (en) | 2012-11-30 |
| CN101605457B (en) | 2013-10-30 |
| ZA200903372B (en) | 2010-10-27 |
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