TWI355270B - Compositions and methods for combination antiviral - Google Patents

Description

1355270 (1) 发明, invention description This case is a non-provisional application, the application for the provisional application (the case number 60/440, 246 and 60/440, 3 08) applied for on January 14, 2003, the provisional application The case was referred to the case as a reference. TECHNICAL FIELD OF THE INVENTION The present invention generally relates to a combination of compounds having antiviral activity (more precisely, antiviral activity with anti-HIV properties). In particular, the invention relates to a chemically stable combination of structurally distinct antiviral agents. [Prior Art] Human immunodeficiency virus (HIV) infection and related diseases are major public health problems throughout the world. Human immunodeficiency virus type 1 (HI V-1 ) encodes the enzymes required for at least three viral replications: reverse transcriptase (RT) 'protease (Prt), and integrase (Int). Although reverse transcriptase and protease have been widely used as drugs and have proven effective, especially when used in combination, the production of toxic and resistant strains limits their utility (Palella et al., N. Engl. Med. (1998) 338:8 53-860; Richman, DD Nature (200 1 ) 4 1 0 : 995-1001). The human immunodeficiency virus type 1 (HIV-1) protease (Prt) is required for viral replication and is a valid target for licensed antiviral agents. HIV Prt cleaves the Gag and Gag-P〇l polyproteins, producing viral structural proteins (p]7, p24, p7 and ρ6) and tris-5-(2) (2) 1355270 viral enzymes. Combination therapies using RT inhibitors have been shown to be highly effective in inhibiting viral replication to an unmeasurable extent and for a period of time. Combination therapy with RT and Prt inhibitor (PI) has also been shown to inhibit the replication of HIV replication. Unfortunately, due to the development of drug resistance, incompatibility with complex drug regimens, pharmacokinetic interactions, toxicity, and ineffectiveness, a high proportion of patients (typically 30 to 50%) currently fail to combine therapy. Therefore, the novel HI V-1 inhibitors can be effectively used to have a differential drug resistance quantitative curve and less side effects on anti-HIV mutant strains; less complicated drug schedules and oral administration. In particular, it is pleading for a less troublesome medication regimen, such as oral medication, once a day, and the best medicines that are used are as few as possible. Using a combination of compounds, a reduction in toxicity can be achieved, but the antiviral efficacy is equal, or the potency of the drug is enhanced. Lower total drug doses reduce the chances of developing HIV-resistant variants. Many different methods have been used to detect the combined effects of compounds functioning under different analytical systems (Furman WO 02/06805 8 ). When reducing the burden of the drug nine, simplifying the medication schedule, sometimes, if the compounding between the compounds can be produced, the lower dose can expect the patient to cooperate better (Loveday, C. "Nucleoside reverse transcriptase inhibitor resistance&quot (2001) JAIDS Journal of Acquired Immune Deficiency Syndromes 26 : S10-S24). AZT [zidovudineTM, azido, 3'-deoxythymidine) combined with a drug, confirmed in vitro antiviral multiplication activity' This agent acts on HIV-1 replication in addition to reverse transcription The steps include recombinant soluble CD4 (Kaitan Boming, castanospermine (3) (3) 1355270) and recombinant interferon-cx. However, it must be noted that the combination of compounds will increase the previously increased cytotoxicity. For example, AZT and recombinant interferon-α have an increased cytotoxic effect on normal human bone progenitor cells. The chemical stability of the combination of antiviral agents is an important issue in the success of co-formulation, and the present invention provides examples of such combinations. Prefer for a novel combination of oral active drugs to treat patients infected with certain viruses (eg, HIV); this combination provides improved therapeutic safety and efficacy, results in lower drug resistance, and is expected to have higher patient compliance degree. SUMMARY OF THE INVENTION The present invention provides a combination of antiviral compounds, particularly compositions and methods for inhibiting HIV. In an exemplary aspect, the invention includes a composition having anti-HIV activity comprising a fumarate of tenofovir disoproxil and an extract of Tabin ( Emtricitabine ). The composition consisting of Cyclosporin DF and the octopine is both chemically stable, multiplicative and/or reduces the side effects of either Navnovir DF and ampazine. . Patient fit can be increased in terms of less drug burden and simplified medication schedule. The present invention relates to [2-(6-amino-indol-9.yl)-1-methyl-ethoxymethyl]-phosphonic acid·diisopropoxycarbonyloxymethyl ester (Dinovir dioxime) Propionate of propoxycarbonyloxymethyl acetonate, DF, DF, TDF, Viread® and (2R, 5S, cis)-4 -amino-5-fluoro-1-(2 -Methyl-(4) (4)1355270 I-thromidin-5-yl)·(1H)-pyrimidin-2-one (Attaching Tabin, Empriva TM ' ( - ) · Shun a combination of treatments consisting of FTC; and the use of the combination in the treatment of HIV infection, including infection with HIV mutants, which are resistant to nucleoside inhibitors and/or non-nucleoside inhibitors. A pharmaceutical composition and formulation of the combination consisting of fenoflavin diisopropoxy oxymethyl gg fumarate and ampam. Another aspect of the invention is a pharmaceutical formulation containing days a physiologically functional derivative of fumarate of norfovir diisopropoxycarbonyloxymethyl ester or a physiologically functional derivative of tabin. The therapeutic combination, pharmaceutical composition, and formulation of the present invention, including PMEA or PMPA (天诺弗维) And with or without Tabin or (2R,5S,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiane-5-yl)-(1H)- a combination of 2-ketone [3TC, lamivudine, EpivirTM] and the use thereof to treat HIV infection. One aspect of the invention is a method of treating or preventing HIV in an infected animal. A method of infecting a condition or effect comprising administering (i.e., treating) a combination of a therapeutically effective amount to the animal, the combination comprising [2 ·(6-amino-indol-9-yl)--methyl-ethoxymethyl -phosphonic acid. Diisopropoxycarbonyloxymethyl fumarate (Dinovir DF, TDF) or a physiologically functional derivative thereof; and (2R, 5S, cis)-4-amino-5 -Fluoro-1-(2-hydroxymethyl-1,3-oxathiazin-5-yl)-(1H)-pyrimidin-2-one (Tabatin) or a physiologically functional derivative thereof. Another aspect is a unit of the composition consisting of a therapeutic combination - 8 - (5) 1355270 - This combination contains fenoflavin diisopropoxy oxyoxymethyl oxymethyl ester and the stagnation of Tabin, or their physiology Functional derivative. The single is formulated as oral or via other routes. Application, and in terms of the nature of the structure, the unit dosage form has unanticipated chemical stability. Another aspect of the invention is directed to a chemically stable combination of products containing 'nanovir diisopropoxycarbonyl The oxymethyl ester is enriched in tabin. In another aspect of the invention, the chemistry consisting of the fumarate of fenoflavin and the octopine further comprises a third antiviral agent. This combination of three components is capable of being combined with a third antiviral agent, utilizing the unique chemical stability of the teno acid salt and the octopine. By way of example, a particularly useful third agent includes the one listed in Table A. 'This third component is a licensed anti-viral agent. It is preferably an NNRTI or a protease inhibitor (PI NNRTI is preferred). In a particularly preferred embodiment, the invention consists of a combination of chemically stable mixtures which are synthesized from the isopropoxycarbonyloxymethyl fumarate with ampazine and (Efavirenz). A further aspect of the invention is a kit for a patient, comprising a kit comprising at least one (generally two, having a sputum component, and the other antiviral agent is selected from the group of genus Di-g-methyl ester of fumarate and the addition of Tabin; and the data said that the sun and the moon {party _ contains the anti-diisooxycarbonyl methoxy vinegar of the stomach | Indications. The fumarate dosage form may be characterized by a different composition. In the antiviral group and the diisopropoxylate composition, it is a non-limiting agent of Vervifima. A preferred agent, ) In order to target a kind of Norfolk II method, a kind of disease) Carbonyl Oxide, the Monomaleate and An (6) (6) 1355270 Another aspect of the invention is a method of preparing the above combination, the method comprising the steps of: combining the combination of the Tenofovir DF with the Antalization Tower The guest is mixed together in the drug to provide antiviral efficacy. In still another aspect of the invention, there is provided the use of a combination of the invention for the preparation of a medicament for the treatment of a viral infection or disorder as described above. DETAILED DESCRIPTION OF THE INVENTION The present invention will be described with respect to the number of patent applications, and it is to be understood that the invention is not intended to limit the invention. On the contrary, the invention is intended to cover all modifications, modifications, and equivalents of the invention as defined by the scope of the invention. DEFINITIONS Unless otherwise stated, the following terms and expressions used herein have the following meanings: When using a trade name, the applicant intends to indiscriminately include the product with the trade name and the product with the trade name. The active pharmaceutical component 〇 ''chemical stability' 诃 indicates that the two major antiviral agents in a combination are substantially stable in chemical degradation. Preferably, the antiviral agents are sufficiently stable during the physical combination process, This makes it possible to obtain a commercially practical shelf life of the combination product. In general, the term "chemically stable" means the first group of the mixture when the two components are physically combined to form a pharmaceutical dosage form. The fraction does not act to degrade the second component. More commonly, the -10-(7) 1355270 ' ” chemical stability H word indicates that the acidity of the first component does not induce acid decomposition of the second component. In one aspect of the invention, where "Chemical stability" is a word indicating that the fumarate of fenoflavin is not substantially represented by the 'substantial' word in the acidity of Tabin. When the product is in the form of a pharmaceutical, diisopropyloxy The fumarate of the carbopol oxymethylate has a shape of at least about 10%, preferably less than 1%, more preferably less than 0.01% over a 24-hour period. The word "additionality" The multiplied '' indicates that the efficacy of Compound I is greater than the effect of using the compounds separately. It is generally expected to be administered separately according to the two active ingredients. When 1) co-formulated and applied simultaneously in a combined formulation Alternately administered in separate formulations, or in parallel; or (in the case of other regimens, a synergistic effect), the compounds are administered sequentially, such as in separately packaged lozenges, Nine doses or capsules, or different injections through a split syringe The effect of multiplication. During the therapy, the effective dose of each active ingredient is administered continuously; however, in combination therapy, the effective doses of the two or sexual components are administered together. The disease-to-antiviral efficacy is greater than the simple expectation that the individual components of the combination, 6 "physiological functional derivatives,", when used in combination with the pharmaceutically active compounds of the present invention, have a paradigm with Limited to isopropoxycarbonyl degradation. This is said, the acid degradation of fenoflavin. I %, and the use of the combination, that is, the large compound is (K administration; (2:3) via some. In alternating (or administration, for example The open-packed note is usually alternately or alternatively (ie, two or more viable efficacies indicate an additive combination of efficiencies in another dimension DF or An-11 - (8) (8) 1355270. Pharmaceutically active compound. As used herein, "physiologically functional derivative" includes any physiologically acceptable salts, ethers, esters, prodrugs, solvates, stereoisomers (including enantiomers, a diastereomer, or a mixture of stereoisomers or racemic mixtures) and, once administered to a recipient, can provide (directly or indirectly) such a compound, or an antiviral active metabolite thereof, or a group thereof Any other compound. "Bioavailability" is the degree to which a pharmaceutical agent becomes available to the target tissue after it has been introduced into the body. Increasing the bioavailability of the pharmaceutically active agent provides a more effective treatment for the patient. More The treatment used, because for a fixed dose, there will be more pharmaceutically active agents available at the target tissue location. The compounds in the combination of the invention may be "active components" or "pharmaceutical active agents" The term "prodrug" as used herein means a substance that is produced as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, and/or metabolic chemical reactions when applied to a biological system (ie, Any compound of the active ingredient. "Prodrug group" B represents an unstable functional group which undergoes hydrolysis, enzyme cleavage, or some in a systemic, intracellular metabolic process. Other methods, separate from active inhibitory compounds (Bundgaard, Hans, "Design and Application of Prodrug" in Textbook of Drug Design and Development (1991), P. Krogsgaard

Larsen and H. Bundgaard. Eds. Harwood Academic -12- (9)1355270

Publishers, ρρ. 1 1 , absorbency and lipophilic use and efficacy. Therefore, the analog of the price modification. Ϊ91) »Prodrug groups can be used to increase solubility errors for optimal drug delivery, bioavailable "prodrugs" is a single therapeutically active compound that is not derived from the parent alkane, alkene or alkyne. A carbon atom removes a saturated or unsaturated, branched 'linear' branch, or a cyclic hydrocarbon group derived from a hydrogen atom. A typical alkyl group consists of 8 saturated and/or unsaturated carbon atoms (e.g., a carbon chain of a normal chain, a secondary, a tertiary or a ring). Examples include the following groups 'but are not limited thereto: methyl 'Me (-CH3), ethyl, Et (-CH2CH3) 'ethynyl (.CeCH), ethyl, vinyl (-CH = CH2), 1 -propyl, n_Pr, η-propyl (-CH2CH2CH3), 2-propyl, i-Pr, i-propyl (-Ch2(CH3) 2), allyl (-CH2CH = CH2), propargyl (-CH2C = CH) 'Cyclopropyl (-C3H5), 1-butyl, n-Bu, η-butyl (-CH2CH2CH2CH3), 2-methyl-1-propyl, i-Bu, i-butyl Base (-CH2CH(CH3) 2), 2-butyl, s-

Bu, s-butyl (-CH (CH3) CH2CH3), 2-methyl-2-propyl, t-Bu, t-butyl (-C(CH3) 3), 1-pentyl, η· (CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)2CH2CH3), cyclopentyl (-C5H9), 3-methyl-2-butyl (-CHCCHs) CH(CH3) 2 ), 3-methyl Benzyl butyl (-CH2CH2CH(CH3)2), 2•methyl·dibutyl (-CH2CH(CH3)CH2CH3), 1-hexyl (•CH2CH2CH2CH2CH2CH3), 5-hexyl (-CH2CH2CH2CH2CH=CH2), 1•hexyl (- CH ( ch3 ) CH2CH2CH2CH3 ) ' 3-hexyl (-CH ( CH2CH3 )( -13- (10) 1355270 CH2CH2CH3 )) ' cyclohexyl (-C6Hn ) , 2-methyl-2-pentyl ( -C ( CH3 ) 2CH2CH2CH3) '3-Methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2) '3-A Benzyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2- Butyl (-C(CH3) 2CH(CH3) 2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3). The square base does not remove a monovalent aromatic hydrocarbon group having 6 to 20 carbon atoms derived from an argon atom from a single carbon atom of the parent tricyclic ring system. Typical aryl groups include, but are not limited to, those derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like. "Aryl group" means an acyclic alkyl group in which a hydrogen atom bonded to a carbon atom (usually a terminal or sp3 carbon atom) is replaced by an aryl group. Typical arylalkyl groups include the following groups, However, it is not limited thereto: benzyl group, 2-phenylethyl-1-yl group, 2-styryl group, naphthylmethyl group, 2 •naphthyl group, 2 naphthyl-1-yl group, naphthoquinone- 2 -naphthalene Phenylethyl, etc. For example, in a square having 6 to 2 carbon atoms, the alkyl group of the aralkyl group (including an alkyl 'alkenyl or alkynyl group) has 1 to 6 carbon atoms' The aryl group has 5 to 14 carbon atoms. "Substituted alkyl '',,, substituted aryl", and "substituted arylalkyl" One or more hydrogen atoms in each of them are independently substituted by a substituent. Typical substituents include the following groups, but

Not limited to this: -X

-OR, -SR -S ' -NR2 ' -NR3 ' -14- (11) (11)1355270 = NR, -CX3 ' -CN ' -OCN ' -SCN ' -N = C = 0 ' -NCS > -NO ' -NO2' =N2' -N3' NC(=0) R' -C(=0) K ' -C ( =0) NRR ' -S ( =〇) 2〇·, s ( =0) 2〇H ' -S ( =0) 2R ' -OS (=〇) 2〇R' -S (=0) 2NR' -S (=0) R ' -OP ( =〇) 02RR' -P(= 0) 02RR' -P(=0) (0.) 2, -P ( =0 ) (OH) 2, -c ( =0 ) R, -C(=0) X, -C(s) R , -C ( 0 ) OR, -C (0) 〇-, -C(S) OR, -C(〇) SR, -C (S) SR ' - C ( 0 ) NRR ' -C ( S ) NRR, -C(NR)NR, wherein each X is independently halo: F, Cl, Br or I; and R is each independently -H, alkyl 'aryl; heterocyclyl or prodrug group. "Heteroaryl" and "heterocyclyl" denote a ring system wherein one or more ring atoms are heteroatoms such as nitrogen, oxygen and sulfur. Heterocycles are described in the following literature: Katritzky, Alan R Rees, CW5 and Scriven, E. Comprehensive Heterocyclic Chemistry ( 19 9 6 ) Perg am on P ress ; Paquette, Leo A., Principles of Modern Heterocyclic Chemistry W . A . Benjamin, New York. ( 1968), Special It is chapters 1, 3, 4 '6, 7 and 9; ' 'The Chemistry of Heterocyclic Co mpounds, A series of

Monographs" (John Wiley & Sons, New York 5 1950 to present), especially Chapters 13, 3, 6, 6, and 28. Examples of the heterocyclic ring include the following groups, but are not limited thereto: a substituent derived from pyrrole, D fluorene, furan 'benzofuran, thiophene benzothiophene, 2-pyridine '3-pyridyl, 4-pyridine , 2 · 卩 卩 啉, 3 - 卩 卩 啉 、, 4 · 卩 卩 啉 、, 2 - imidazole ' 4 - 卩 卩 啉 、, 3 - pyrazole, 4 • pyrazole, pyridazine, pyrimidine, pyrazine, hydrazine, hydrazine Porphyrin 'pyridazine, g-oxazol-15 - (12) (12)1355270 porphyrin, D-quinoxaline, 3-( 1,2,4-N )-triazolyl, 5-( 1 ,2,4- N )-triazolyl, 5-tetrazolyl, 4·( 1-0,3-N)-oxazole ' 5- ( ]-〇,3-N) ·oxazole, 4· ( 1-S, 3_N)-thiazole, 5-(1-S,3-N)-thiazole, 2-benzoxazole, 2-benzothiazole, 4-(1;2,3-N)-benzotriazole, and Benzimidazole. In general, the stereochemical definitions and conventions used herein follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1 984) McGraw-Hill Book Company, New York; and E1 ie 1, E · and WΠ en, S . ereo ch emi st ry of Or gani c Compounds ( 1 994 ) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active form, i.e., the organic compound has the ability to rotate the plane of plane polarized light. When describing an optically active compound, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule with respect to its center of the hand. The prefixes d and 1 ' or (+) and (-) are used to indicate the signing of the compound for the rotation of the polarized light, and the compound (-) or 1 indicates that the compound is left-handed. Compounds with a prefix of (+) or d are dextrorotatory. For a known chemical structure, these compounds, referred to as stereoisomers, are identical 'except for mirror images of each other. A mixture of specific stereoisomers, also referred to as enantiomers, is often referred to as a mixture of ones. The 50:50 mixture of enantiomers is referred to as the racemic mixture or racemate. The word "racemic mixture" and, racemate" denotes a molar mixture of two enantiomeric structures, which is optically inactive. The word "hand" refers to a molecule having a property that does not overlap with a mirror image counterpart, and the "non-hand" word indicates a molecule that can overlap with its mirror image counterpart. -16- (13) 1355270 "Stereoisomers" B indicates compounds having the same chemical composition or different spatial arrangement of the groups. "Diastereomers" B indicates that there are two or two centromeric stereoisomers, and the molecules of the isomers have different physical properties, not the enantiomers. For example, melting point, spectral properties' and reactivity. A mixture of diastereomers can be separated by analytical methods such as electrophoresis and chromatography. "Diaster" means that the two stereoisomers of a compound are non-superimposable mirror images. Combination of Active Components The present invention provides the use of two or more active combinations in combination. In some implementation systems, a chemically stable combination is obtained in an implementation system in which the antiviral work is achieved. The active component of the combination is selected from the group consisting of: (i) fenoflavin diisopropoxy fumarate) and physiologically functional derivatives; and at least one active from: (2) amphibious and physiological functions derivative. The term "antiviral efficacy" as used herein refers to the effect of the combination of individual components (a) and (b) in the combination of the antiviral effect. Tiannovi Diisopropoxycarbonyl Oxygen Ester fumarate (known as (Vi read®), tiannufuwei DF, fenoflavin diisopropyl isopropyl ester, TDF, Bis-POC-PMPS] (see case number 5935946, 5922695 '5977089, 6043230, ), is a prodrug of tiannufuvi, which has the following structural formula: However, the atomic upper hand is a mirror image. The boiling point and light are highly decomposed by the new effects of their components. Others include at least carbonyl oxygen. The methyl ester component is selected for S" added to the simple pre-validation with the valeroxycarbonyloxy group. See US 6069249 -17- (14) (14) 1355270

And includes fumarate (H02CCH2CH2C02.). ^ ^ ^ ^ The chemical name of diisopropoxycarbonyloxymethyl ester includes the following: [2·(6-Amino-fluoren-9-yl)-bumethyl-ethoxymethyl]-phosphonic acid. Diisopropyloxy Methyl oxymethyl ester; 9-[(R) -2·[[bis[[isopropoxycarbonyl]oxy]methoxy]phosphino]methoxy]propyl] adenine; and 2,4,6 ,8-tetraoxa-5-lindioic acid (卩]105卩11&110113116<^0丨0 3£^(1),5·[[()R)-h(6-amino- 9H-嘌-9-yl)-]·methylethoxy]methyl]-, bis(1-methylethyl) ester, 5-oxide. CAS accession number includes: 201341-05-1; 202138- 50-9; 206184-49-8. It should be noted that 'the ethoxymethyl unit of the genofovir is a hand-centered center. It is confirmed to be the R (right-right-handed) enantiomer. However, The invention also includes S isomers. The present invention encompasses all enantiomers, diastereomers, racemates, and stereoisomers of the tenofovir (PMPA) and its physiologically functional derivatives. Mixtures of PMPA or Tenofovi (see U.S. Patent Nos. 4 8 0 8 7 1 6 , 5733788, 6057705) have the following structural formula: *18- (15) (15)1355270

The chemical name of PMPA's Novovir includes: (r)-9-(2-phosphonomethoxypropyl)adenine; and phosphonic acid, [[(ir)-2-(6-amino-1H) - Hiphop-9-yl)-1-methylethoxy]methyl]. The CAS registration number is 147127-20-6. Fumarate (DF) is a nucleoside reverse transcriptase inhibitor. The US and the other antiretroviral agents were licensed in the United States in 2001. Combination for treating infections. Fumarate or Viread® (Gilead Science) is a fumarate of dinoproxil oxycarbonyloxymethyl methoxide . Vi read® can be named as: 9·[(R)-2-[[bis[[isopropoxycarbonyl]oxy]methoxy]phosphino]methoxy]propyl] adenine Fumarate (1: 1); or 2,4,658-phosphonananedioic acid, 5-[[(11〇-2-(6-amino-91嘌呤-9-yl) )-]-Methylethoxy]methyl]-, bis(1-methylethyl) ester, 5-oxide, (2E)-2-butenedioate (1: 1). CAS No. 202138-50-9. Physiologically functional derivatives of fumarate of fenoflavin diisopropoxycarbonyloxymethyl ester include PMEA (adefovir, 9-((R)-2-(phosphorus carboxy) -19- (16) (16) 1355270 oxy)ethyl) adenine) and PMPA compounds. Combination examples include PMEA or PMPA compounds' in combination with ampazin or 3TC. pMEA and Ρ Μ PA compounds have the following Structure:

Wherein PMEA (R3 is H) and PMPA (R3 is alkyl, C]-C6 substituted alkyl, or CH2OR8, wherein 118 is CVC6 alkyl, (^•Ce hydroxyalkyl' or Crb haloalkyl. R6 and R7 is each independently Η or CrCe alkyl. R4 and R5 are each independently Η, NH2 'NHR or NR2', of which only CrQ alkyl. R] and R2 are each independently H, C, -C6 alkyl, (^-( :6 substituted alkyl, C6-C2G aryl, C6-C2Q substituted aryl 'C6-C2Q aralkyl' C6-C2() substituted arylalkyl 'methoxymethyl ester - CH2OC (=0) R9 (eg, pom), or methoxymethyl carbonate-CH2OC (=0) 〇r9 (eg, p〇c), wherein R9 is (^-(^ alkyl, C)-C6 substituted alkyl, C6-c2 〇 aryl, or c6-c2 〇 substituted aryl. For example, R1 and R2 may be a pentyl methoxy methoxy group, PO Μ ' -CH 2 〇 C ( =0 ) C ( CHs ) 3; -ch2oc ( =0) oc ( ch3) 3; or POC ' -CH2〇c ( =〇) OCH ( CH3 ) 2. For another example, in the structural formula of Tiannuowei, R3 is CH3, and RJ, R2 , R4, R5'R6 -20- (17) (17) 1355270 and R·7 are Η. According to Quast et al. (1974) Synthesis 409; Stowell et al. (1 990) Tetrahedron Lett. 3 26 1; A dihydrocarbyl phosphonate is prepared by the method described in U.S. Patent No. 5,663, 159. The Ρ Μ PA compound may be enantiomerically enriched; or purified (single stereoisomer) 'where the carbon atom carrying R3 may Is the r or S enantiomer. The PMPA compound can be a racemate, ie a mixture of R and s stereoisomers. 八 06(〇1^1:(9-(2-(phosphorus carboxymethoxy) Alkyl) adenine, wherein R^-RfH) is an exemplary PMEA compound (U.S. Pat. No. 4,087,716, 4,724,233). Adefovir dipivoxil, a bis-pivalate prodrug, is also known as bi- POM PMEA ( R3-R7 = H, Rj and R2 = -CH2〇C (=0) C(CH3) 3. Pivoxil, POM, Pentyloxymethoxy), effective against HIV and hepatitis B infection (US Patent No. 5663 1 59, 645 1 340). Adef0Vir dipivoxil has been shown to combine with other compounds having anti-HIV activity to have a mild to moderate additive effect on ΗIV replication, including PMPA 'd4T, ddC, nelfinal (ne) finavir) 'ritonavir and saquinavir MuUto et al. (1997) Antiviral Research 36: 91-97) » The present invention includes all enantiomers, diastereomers, racemates, and enrichments of PMEA and PMPA and their physiologically functional derivatives. A mixture containing stereoisomers. Take Tupper ((-)-cis-FTC, EmprivaTM) 'An enantiomer of FTC' is a potent nucleotide reverse transcriptase-21 - (18) 1355270 inhibition Agent, approved for the treatment of HIV (US Patent No. 5 04 7407 '5179104, 5204466, 5210085, 5486520, 5538975, 5587480 ' 5618820 ' 5763606 ' 5814639 ' 5914331 ' 611 4 343, 6 1 8 063 9 ' 6215004; WO 02/070518). This single enantiomer is taken from the formula: NH2 HO-

The chemical names of Tabin are: (·)-cis-FTC; β-L-hydroxymethyl.5-(5-fluorocytosin-1-yl)-1,3-oxothiane; (2R '5S)-5-fluoro·1·[ 2·(hydroxymethyl)·1,3·oxathiane-5-yl]cytosine; and 4-amino-5·fluoro-1-( 2-hydroxyl Methyl-[1,3]-(2R,5S)-oxothane-5-yl)·1Η-pyrimidine. 2-one. CAS registration number includes: 143491-57-0;

1 4349 1 -54-7. It should be noted that the FTC contains two hand-shaped centers at positions 2 and 5 of the oxetane ring, so that two pairs of optical isomers (ie, enantiomers) and mixtures thereof (including racemization) may be present. The form of the mixture). Thus, the FTC can be a cis or trans isomer, or a mixture thereof. Mixtures of cis and trans isomers are diastereomers having different physical properties. Each of the cis and trans isomers may be present in one of two enantiomers, or a mixture thereof (including a racemic mixture). The present invention encompasses the collection of all enantiomers, diastereomers, racemates, and mixtures of stereoisomers of the saponin and its physiologically functional derivatives. The present invention includes a -22-(19)(19)1355270 functional derivative, such as an enantiomer, (2 R, 5 S, cis) 4-amino-5-fluoro-1 - (2- Hydroxymethyl·1,3-oxathiazin-5-yl)·( 1 Η )-pyrimidin-2-one (Attattata) and its mirror image (2S,5R,cis)-4-amino-5- Fluoroquinone-(2-hydroxymethyl· 5 5 3 -oxathiane 5-yl)-(1 Η )-pyrimidin-2-one, a 1:1 racemic mixture; or both The construct is a mixture of any relative amounts. The invention also includes mixtures of cis and trans F T C . The physiologically functional derivatives of the tabin are included in the following formula: 1. 3 · oxothane nucleosides:

As shown above, in the structural formula of I,3-methothine nucleoside, hydrazine is a nucleobase "which includes a nucleoside or nucleobase analog capable of complementing (eg, '嘌呤, 7-de Nitrothene, or pyrimidine, is paired to form any nitrogen-containing heterocyclic group of the Watson-Crick hydrogen bond. Examples of B include naturally occurring nucleoside thiol groups: adenine, guanine, cytosine, uracil 'thymine' and minor components and analogs of such naturally occurring nucleobases, for example, 7-off Adenine, 7·deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azadenine' inosine, nebuUrine, nitropyrrole, nitrate Base, 2·aminopurine, 2·amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine, 5-chloro Cytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine, pseudoisopramin (-23-(20) (20)1355270

Pseudoisocytosine), 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymidine, 4-thio Uracil, indole 6-methylguanine, N 6-methyl adenine, 0, methyl thymine, 5,6-dihydrothymidine, 5,6-dihydrouracil 'methyl吲哚' pyridyl Azolo[3.,4-D]pyrimidine (U.S. Patent Nos. 6,1, 877 and 6,127.121; WO 0W3 8 5 84); and Fabman (1 989 ) in Practical Handbook of Biochemistry and Molecular Biology , pp. 3 8 5 -3 94, CRC

Press, Boca Raton, FI). In the configuration of a naturally occurring nucleic acid, via N- 9 (eg, glandularin-9-yl' and guanine-9-yl) or chewing steep N-1 (eg, thymine 1) · A covalent bond between a cytosine and a cytosine-1 yl group and a 1,3 - oxathioalkyl group, the nucleoside thiol group B can be bonded to a 1,3- oxathioalkyl group (Blackburn, G And Gait, M. Eds. "DNA and RNA structure" in Nucleic Acids in Chemistry and Biology, 2nd Edition, (1 996) 〇xfor (j University Press, pp. 15-81). In the structural formula of 3-oxoacetyl nucleoside, 11 is 11' (:, · C18 alkyl, c丨-C18 substituted alkyl, C2-C丨8 alkenyl, C2-C 8 substituted alkyl, C2-cls alkynyl, c2-c]8 substituted alkynyl, c6-c2Q aryl, Ce-C: 2. substituted aryl, c2-C2G heteroaryl, C2-C2G substituted heteroaryl, phosphine Acid vinegar, phosphophosphonate, phosphonate diphosphate, phosphate, bismuth sulphate, tristearate, polyvinyloxy, or a prodrug group. Physiologically functional derivatives of Tabin include 3 TC [1 am ivud ne], Epi vi rT vl ), which is a kind Reverse Transcription-24 - (21) (21) 1355270 Enzyme Inhibitor, approved by the United States as a Combivir® in combination with AZT and used to treat HIV-1 infection (GlaxoSmithKline). See U.S. Patent No. 5,585,021; 5,905,082; 6177435; 5627186; 6417191 S. Lamivudine (US Patent No. 5587480, 5696254, 5618820, 5756706 « 5744596 > 568164 > 5466806 > 5 1 5 1 42 6 ) has the following structural formula:

For example, in certain therapeutic uses, 3TC can be a physiologically functional derivative of tabin that is combined with a physiologically functional derivative of fenoflavin DF or fenoflavin DF. It will be understood that 'danovir DF and ampazin, and their physiologically functional derivatives may exist in keto or phenol tautomeric forms, and any tautomeric form thereof is used in the present invention. Within the scope. The fenoflavin DF normally used in the combination of the invention does not substantially correspond to the enantiomer of the octopine. That is, the corresponding enantiomer will not exceed about 5 〇/〇W / W 〇 Prodrugs The present invention includes all prodrugs of fenoflavin and ampam. The demonstration prodrug of Tiannuo Diwei is rich in fenoflavin diisopropoxycarbonyloxymethyl ester -25- (22) (22)1355270 methic acid [TDF ‘Virid® 】). A number of structurally different phosphonates have been described (FTeeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997)). A commonly used class of prodrugs are oxoxane esters, which were originally used as carboxylic acid prodrug strategies, followed by Farquhar et al. (] 983) J. Pharm. Sci. 72: 324; and U.S. Patent No. 4,816, 570' 4968788, 5663159 And 5792756, applied to phosphates and phosphonates. The oxoxane ester is then used to deliver phosphonic acid through the cell membrane and increase oral bioavailability. Alkoxycarbonyl oxyalkyl esters, which are intimate variants of the oxo oxyalkyl ester strategy, which are prodrug groups of the compounds of the combinations of the invention, may also increase oral bioavailability. Aryl esters having a phosphorus group, especially phenyl esters, have been described for their use in promoting oral bioavailability (DeLambert et al. (1994) J_ Med. Chem. 37:49 8 ). Also shown is a phenyl vinegar containing a carboxylic acid ester (adjacent to the phosphate ester) (Khamnei and Torrence, (1 9 9 6 ) J. Med. Chem. 39: 4109-41 15 ) » Benzyl ester has been described for production The parent phosphonic acid. In some cases, substituents in the ortho or para position accelerate hydrolysis. The benzyl analog and the deuterated phenol or the alkylated phenol can produce a phenolic compound which is sequentially cleaved at the benzyl C-0 bond via an enzyme such as an esterase, an oxidase or the like. An intermediate product of phosphoric acid and hydrazine methide is produced. Examples of such prodrugs are described in Mitchell et al. (1 992) J. Chem. Soc. Perkin Trans. 123 45; Brook et al. at W0 91Π 972 ]. It is known that other benzyl prodrugs contain a group attached to dibenzylmethane, which group contains a carboxylic acid ester (Glazier et al., WO 91/19721). Sulfur-containing prodrugs are described as being useful for intracellular delivery of serotonate drugs. These proesters (-26 (23) (23) 1355270 proesters) contain an ethylthio group in which the thiol group is not esterified with a thiol group or with another thiol group to form a disulfide. Deesterification or reduction of disulfide produces free thio intermediates which are subsequently decomposed into phosphoric acid and surface sulfides (Puech et al. (1 993) Antiviral Res., 22: 1 5 5 - 1 74; B enzaria et al. (1 996) plant

Med. Chem. 39: 4958). Cyclic phosphonates have also been described as prodrugs of phosphorus-containing compounds. The prodrugs according to the invention are independently selected from the group consisting of: (1) fenoflavin or a monophosphate, diphosphate, or triphosphate of the tabin, or can be supplied to the human body (directly or Indirect) any other compound of the monophosphate, diphosphate, or triphosphate; (2) a carboxylic acid ester; (3) a sulfonate such as an alkylsulfonyl group, or an aralkyl sulfonyl group (eg, 'methanesulfonyl); (4) an amino acid ester (for example, alanine, L-guanidinium, or L-iso-araminyl); (5) a phosphonate; and (6) a phosphine Amidoxime ester. The ester groups (1) to (6) may be substituted by a linear or branched alkyl group (for example, methyl 'n-propyl, tert-butyl, or n-butyl); cycloalkyl, An alkoxyalkyl group (e.g., methoxymethyl); an aralkyl group (e.g., benzyl); an aryloxyalkyl group (e.g., phenoxymethyl); a C5_C2 fluorenyl aryl group (e.g., 'phenyl' which can be Halo group, alkyl group, (^-(: 4 兀 兀 、, or amine group, etc.); 醯 methoxy ketone _CH 2 〇 c (= 〇) R9 (such as ' POM) or 醯 醯Ester-CH2〇c (=〇) OR9 (eg 'POC) 'where R9 is a C1-C6 alkyl group, a C1-C6 substituted alkyl 'C 6 - C 2 aryl group, or a c 6 - C 2 hydrazine group For example, the ester group (24) (24) 1355270 can be: -ch2oc(=o) c(ch3) 3' -CH2〇C ( =0) OC ( CH3 ) 3, or -CH2OC ( =0 OCH (CH3) 2. Exemplary aryl groups present in these esters include phenyl or substituted phenyl. A variety of phosphate prodrug groups are described in U.S. Patent No. 63 1 2662; Johes et al. (1 995) Antiviral Research 27 : 1·17; Kucera et al. (1 9 9 ) AIDS Res. Hum. Retro Viruses 6 : 491-501; Pianta Dosi et al. (19 9 1) J. Med. Chem. 34 : 1 40 8 - 1 4 ;

Hosteller et al. (1 992) Antimicrob. Agents Chemother. 36:2025-29; Hostetler et al. (1990) J. Biol. Chem. 265: 611127; and Siddiqui et al. (1 99 9 ) J. Med. Chem. 42 : 4122-28. A pharmaceutically acceptable prodrug means a compound which is metabolized in a host by enzyme action, or by general acid or base solvolysis, such as hydrolysis or oxidation, to form an active ingredient. A typical example of a prodrug of an active component of the combination of the present invention is a biologically labile protecting group on the functional group of the active compound. Prodrugs include compounds which can be oxidized, reduced, aminated, deaminated, esterified, de-esterified, alkylated, deuterated, deuterated, deuterated, pyrolyzed, or degassed, or Compounds on this prodrug that are involved in the alteration or conversion of other functional groups that form or cleave chemical bonds. Chemical Stability of Pharmaceutical Formulations The chemical stability of active ingredients in pharmaceutical formulations is to minimize the formation of impurities -28 - (25) (25) 1355270 and to ensure proper shelf life. In the pharmaceutical formulation of the present invention, the active ingredient (the diprocarbodioxycarbonyl methyl ester of fumarate and the saponin) has a relatively low pKa 値, indicating that the active components are present. Acid hydrolysis potential. Take Tabin with a 2.65 pKa値 (Emtriva® product, Gilead Sciences, 2003, available from gilead.com), prone to hydrolysis of 5-fluorocytosine nucleobases Amination reaction to form a 5-fluorouracil nucleobase. The fumarate of dinofosyloxyisopropoxycarbonyloxymethyl ester has a pKa of 3.75 (Yuan L. et al., "Degradation Kinetics of 0 xyca rb ο ny 1 oxymethy 1 Prodrugs of Phosphonates in Solution", Pharmaceutical Research ( 2 00 1 ) Vol. 8, No. 2, 23 4-23 7 ), also susceptible to hydrolysis of the exocyclic amine group of adenosine nucleosides, and one or two POCs Hydrolysis of ester groups (US Patent No. 5,922,695). It is expected that a therapeutic combination consisting of a fumarate of dinofenoxycarbonyloxymethyl ester and a physiologically functional derivative of the saponin and its physiological functions can be formulated, which has the fewest Impurities and proper stability. The combination of the invention provides a combined pharmaceutical dosage form which is chemically stable for the acid degradation reaction of: (1) the first component (eg, fenoflavin diisopropoxycarbonyloxymethyl ester) a horse salt, and a physiologically functional derivative thereof; (2) a second component (for example, a saponin and a physiologically functional derivative thereof); and optionally a third component having an antiviral activity . The third component includes an anti-Η IV agent and includes a protease inhibitor (ΡΙ), a nucleoside reverse transcriptase inhibitor (NRTI) 'non-nucleoside reverse -29- (26) (26) 1355270 enzyme inhibitor (NNRTI) And integrase inhibitors. Exemplary third active ingredients for administration in combination with the first and second components are listed in Table A. The first and second components are defined in the section entitled: Combined Active Components. Salts Any of the compounds in the compositions of the present invention, including any of their physiologically acceptable salts. Examples of physiologically acceptable salts of Cyclosporin, DF, and their physiologically functional derivatives, including salts derived from a suitable base such as a metal (eg, sodium), test Earth metal (e.g., magnesium), ammonium and cesium 4+ (wherein X is a Cl_C4 alkyl group); or a salt derived from an organic acid such as fumaric acid, acetic acid, and acesulfonic acid. A physiologically acceptable salt having one hydrogen atom or one amine group, including an organic carboxylate such as acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid , isothio acid, lacturonic acid and succinic acid; organic sulfonate, including methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acid salts, such as inorganic minerals, for example Hydrochloric acid, sulfuric acid, phosphoric acid and aminosulfonic acid. A physiologically acceptable salt of a compound having a hydroxyl group, including an anion of the compound, is combined with a suitable cation such as Na + and NX 4 + (wherein X is each independently selected from hydrazine or C]-C 4 alkyl). For use in therapy, the salts of the active ingredients of the combination of the invention will be physiologically acceptable, i.e., these salts are salts derived from a physiologically acceptable acid or base. Nonetheless, salts of physiologically acceptable acids or bases - 30 (27) (27) 1355270 can also be used, for example, to prepare or purify physiologically acceptable compounds, whether or not derived from a physiologically acceptable The acid or base, all salts are included in the scope of the present invention. Formulation Method of Formulation While the active ingredients of the combination may be administered separately and separately, such as monotherapies, it is preferred to administer the components as a pharmaceutically co-formulation. Combinations of the two components or a combination of the three components may be administered simultaneously or sequentially. When administered sequentially, the combination can be administered once, twice, or three times. Preferably, the two or three component combinations are administered in a single pharmaceutical dosage form. More preferably, the combination of the two components is administered in a single oral dosage form, and the combination of the three components is administered in two identical oral dosage forms. Examples include a single lozenge in which fumarate from dinofosyloxyisopropoxycarbonyloxymethyl ester is combined with an anti-Tabin, or a rich horse from dinofosime diisopropoxycarbonyloxymethyl ester. The acid salt, the two kinds of tablets of the combination of Tabin and Efavirenz. It will be appreciated that the compounds of the combination may be administered by (1) simultaneous administration by combining the compounds in a common formulation; or (2) alternating application, ie, continuously, sequentially These compounds are delivered in parallel or simultaneously in separate pharmaceutical formulations. In alternation therapy, the benefit of the multiplicative therapeutic efficacy of the combination of active ingredients should not be lost due to the administration of the second active ingredient and the delay of the optional third component. Preferably, the combination should be applied to achieve the highest plasma concentration of each active ingredient, whether or not () or (2). Apply a combination of -31 - (28) (28) 1355270 with the formula once a day 'each time a drug nine feeding method, for some HIV-positive patients is feasible. The effective peak plasma concentration of the combined active ingredient ranges from about 〇.〇〇] to 〇〇μΜ. The optimal peak plasma concentration can be achieved by formulating the formulation and medication regimen for a specific patient. It is also to be understood that the derivative of the physiological function of either of the neufovid DF and the octopine, or both, can be independently, repeatedly, or in any combination, whether simultaneously or sequentially. The form of medication. Usually, in the alternation therapy (2), the effective dose of each compound is administered continuously, whereas in the common formulation therapy (1), an effective dose of two or more compounds is administered together. Formulation of Combinations When individual components of a combination are administered separately, typically the components are each presented as a pharmaceutical formulation. Unless otherwise stated, when a formulation is referred to below, it is meant that it is not a formulation containing the combination, or a formulation containing the component compounds of the combination. It can be understood that the invention is applied by a single patient kit, or a patient kit for each formula, and the package is instructed to guide the patient to correctly use the replica of the present invention. Another technical feature that is satisfactory. The present invention also encompasses a duplicate kit comprising separately applied but associated formulations consisting of novavir DF and amphibious or any of the above compounds or both physiologically functional derivatives. The combination therapies of the present invention comprise: (1) a combination of novavir DF and ampamine, or (2) a formulation comprising a physiologically functional derivative of either or both of the above compounds. -32- (29) (29)1355270 This combination can be formulated as a unit dose formulation containing a fixed amount of an active pharmaceutical ingredient to provide a periodic (eg, 'daily') dose or dose of the active ingredient. dose. A pharmaceutical formulation according to the invention comprises a combination according to the invention, and one or more pharmaceutically acceptable carriers or excipients, and, optionally, other therapeutic agents. The pharmaceutical formulation containing the active ingredient may be in any form suitable for the desired method of administration. For oral administration, for example, lozenges, tablets, diamonds, aqueous or oily suspensions, dispersible powders or granules, latex, hard or hard shell capsules, syrups, or elixirs (Remington s) Pharmacheutical Science, Mack Publishing C ο ·, E ast ο η, PA ). The composition intended for oral administration can be prepared according to any of the known methods in the art for preparing pharmaceutical compositions, and in order to provide a savory preparation, such compositions may contain one or more of the following agents, including · Antioxidants, sweeteners, flavoring agents, coloring agents and preservatives. Tablets containing the active ingredient are acceptable in combination with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of sharp agents. For example, the animal excipient can be an inert diluent such as sodium carbonate or sodium carbonate, lactose, lactose-hydrate, croscame Uose, hydrazolone, calcium or sodium silicate; a granulating or disintegrating agent, such as corn starch or alginic acid; a binder such as cellulose, microcrystalline cellulose, vermiculite, gelatin or gum arabic; and a lubricant such as magnesium stearate, stearin Acid or talc. The lozenge may be uncoated; or it may be coated by conventional techniques (for example, microencapsulation method, microencaPsulati〇n), thus delaying disintegration and absorption in the gastrointestinal tract 'to provide a continuous operation for a longer period of time -33- (30) (30) 1355270. For example, a time delaying substance such as only glyceryl monostearate or glyceryl distearate may be used or may be mixed with the wax. The formulation for oral administration can also be presented as a hard gelatin capsule in which the active ingredient is admixed with an inert solid diluent, for example, pregelatinized starch, calcium phosphate or kaolin; or gelatin soft capsules, wherein the active group The mixture is blended with a water or oily medium (for example, peanut oil, liquid paraffin, or olive oil). The aqueous suspensions of the present invention comprise the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose 'hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; and dispersing agents or Wetting agents, such as naturally occurring phospholipids (eg, lecithin), condensation products of alkylene oxides with fatty acids (eg, polyoxyethylene stearate), condensation products of alkylene oxides with long chain aliphatic alcohols (eg, a mixture of alkylene oxide and cetyl alcohol, and a condensation product of an alkylene oxide and a partial ester derived from a fatty acid and a hexitol anhydride (for example, polyethylene sorbitan) Oleate). The aqueous suspensions may also contain one or more preservatives (for example, ethyl P-hydroxybenzoate or n-propyl P-hydroxybenzoate), one or more coloring agents, one or more flavoring agents. And one or more sweeteners, for example, sucrose 'sucralose' or saccharin. An oily suspension is prepared by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil; or in mineral oil > for example, liquid paraffin. Oral suspensions may contain a thickening agent, for example, beeswax, hard-34-(31)1355270 paraffin or cetyl alcohol. Sweeteners such as those listed above may be added and oral preparations which provide a delicious taste. These compositions can be preserved by the addition of an antioxidant (blood acid 'BHT, etc.). The dispersible powders and granules of the present invention are suitable for use in the preparation of a suspension which is admixed with a dispersing agent, a suspending agent, and one or more preservatives by the addition of water. Dosing or wetting agents, and suspending agents are listed above. Excipients such as sweeteners, flavoring agents, and color formers are also acceptable. The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion or a square. The oil phase may be a vegetable oil (for example, olive oil or mineral oil (for example, liquid paraffin), or a mixture thereof. Emulsifiers include naturally occurring gums, for example, gum arabic and naturally occurring phosphoesters, for example, Soy lecithin; an ester or partial ester derived from a lipitol anhydride, for example, a sorbitan-oil and a condensation product of these partial esters with an alkylene oxide, for example, polyoxysorbitol monooleate Ester. This latex may also contain a sweetener and a sweetener such as glycerin, sorbitol or sucrose, which can also be used as a demulcent. An agent, a flavoring agent or a coloring agent. The pharmaceutical composition of the present invention may be in the form of a sterile injectable solution, an aqueous or oleaginous suspension for injectables. The suspension may be formulated according to the art, and the above is suitable for use. Dispersing or wetting agent, the sterilized injectable preparation may also be a sterile injectable solution, a non-toxic and parenterally acceptable diluent or solvent odorant, such as a septic-based aqueous humectant. Scattered amount Microparticles formulated with oils; suitable silicones; acids and hexyl esters; with ethylene yam "also syrup, antiseptic, such as conventional and dispersed or suspended, -35- (32) (32) 1355270, for example, ], a solution of 3-butane-diol, or may be prepared as a freeze-dried powder. Among these acceptable carriers and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. Further, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil such as a synthetic monoglyceride or diglyceride may be used. Fatty acids such as oleic acid find use in the preparation of injectable preparations. The pharmaceutical composition of the present invention may be administered parenterally, for example, intravenously, intraperitoneally, intraperitoneally, intraluminally, intrastemally, intracranically, intramuscularly or subcutaneously, or The pharmaceutical compositions can be administered by perfusion techniques. Preferably, the pharmaceutical composition is in the form of a sterile aqueous solution which may contain other materials, for example, sufficient salts or glucose to render the solution isotonic with the blood. If necessary, the aqueous solution should be suitably buffered (preferably buffered to a pH of 3 to 9). Suitable parenteral formulations can be readily prepared under sterile conditions using standard pharmaceutical techniques well known to those skilled in the art. The pharmaceutical compositions of the present invention may also be administered intranasally or by inhalation, conventionally in the form of a dry powder inhaler or a gel spray dispenser, delivered from a pressurized container or a nebulizer equipped with a propellant, the propellant For example, dichlorodimethane 'trichlorofluoromethane' dichlorotetrafluoroethane, hydrofluoroalkane (eg '1,1,1,2-tetrafluoroethane (}^(:1343), carbon dioxide, or other suitable Gas. As for the pressurized gas gel, the dosage unit can be delivered by providing a valve to deliver the calculated dose. The pressurized container or nebulizer can contain a solution or suspension of the composition, for example, using ethanol and a propellant as a solvent. , -36 - (33) (33) 1355270 It may further contain a lubricant (for example, sorbitan trioleate). Capsules and packs for use in an inhaler or insufflator (for example, by gelatin) The formulator can be formulated to contain a powder mixture of a compound of formula (I) and a suitable powder base (for example, lactose or starch). For the purpose of delivering the drug, it is preferred to use a gas gel or a dry powder. Formulated to make each pass Calculate the dose, or every "spray" once, containing 20 micrograms to 20 milligrams of composition. The total daily dose of the gas gel will range from 20 micrograms to 20 milligrams, which can be single dose in one day. Ingestion, or more commonly, sub-dosing. The dosage of the active ingredient in combination with the carrier materials to form a single dosage form will vary depending upon the host to be treated and the particular mode of administration. For example, oral administration The human release formulation over time may contain from about 1 to 1000 milligrams of active substance, mixed with a suitable and convenient level of carrier material, the carrier material being present in an amount from about 5 to about 95% of the total composition. : Weight) A pharmaceutical composition can be prepared to provide an easily measurable application amount. For example, 'in order to allow a suitable volume to perfuse at a rate of about 30 ml/hour, the aqueous solution to be used for intravenous perfusion may contain About 3 to 500 micrograms of active ingredient per milliliter of solution. As indicated above, the formulations of the invention suitable for oral administration may be in separate units, such as capsules, cachets or lozenges, each having a preset Dose a component or a granule; a solution or suspension in an aqueous or non-aqueous liquid; or an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient can also be applied as a large nine-dose, elixirs or ointment. The combination of the present invention facilitates the presentation of a pharmaceutical formulation in unit dosage form. A convenient unit dosage formulation containing an active ingredient in an amount between 1 mg and 1 g to 37-(34) (34) 1355270, respectively. For example, (not limited to this), 10 mg to 300 mg. The multiplying effect of the combination of neufowe DF and ampazin can be achieved over a wide range of ratios, for example 1: 5 〇 to 5 〇. : 1 (Dinuoweiwei DF: Take Tabin). In an implementation system, the ratio can be in the range of about I: 10 to 10:]. In the other embodiment, in the combined formulation of the co-formulation, the weight/weight ratio of the tenofovir to the ampere is about 1 'that is close to the equivalent of the nunofo DF and the tabin . Among other exemplary co-formulations, Tiannovi DF is more or less than FTC. For example, '3 mM of vorofol df can be combined with 200 mg of ampam to form a ratio of 1.5:1 (Dinuoweiwei DF: Take Tabin). In the embodiment, the content of each compound to be used in the combination is an amount which exhibits antiviral activity when the compound is used alone. Exemplary formulations A'B, C, D, E, and F (Examples) have a ratio of 12:1 to 1:1 (Dinoflav DF: Tambin). Demonstration formula A ' B ' C, D '£ and F used in the amount of fenoflavin DF and ampazes, ranging from 25 mg to 300 mg. Other ratios and amounts of the compounds of this combination are also contemplated within the scope of the invention. The unit dosage form may further comprise novavir DF and ampazin, or a physiologically functional derivative of any of them, and a pharmaceutically acceptable carrier. It will be understood by those skilled in the art that the therapeutically required amount of the active ingredient in the combination of the invention will vary depending on a variety of factors, including the nature of the condition being treated, and the age and condition of the patient, Ultimately, it will depend on the discretion of the attending physician or health practitioner. The factors to be considered include the nature of the route and formula, the animal's weight, age and general condition -38- (35) (35) 1355270, and the nature and severity of the disease to be treated. For example, in Phase I/1I unilateral therapy with Tabin, patients take a dose between 25 mg and 200 mg twice a day for two weeks. A viral inhibition of 98% (1.75 log 10) or higher was observed when the dose per dose was greater than or equal to 200 mg. Take 200 mg of Tabin and take it once a day to reduce the amount of virus by 99% ( 1.92 log 1 0). Viread® (DF) has been approved by the US Food and Drug Administration (FDA) for the treatment and prevention of HI V infection, which is an oral tablet of 300 mg. Empriva TM (Tabbin) has been approved by the FDA for the treatment of HIV, a 200 mg oral tablet. It is also possible to combine any two active ingredients with a third active ingredient in a unit dosage form for simultaneous or sequential administration. Such triad combinations can be administered simultaneously or sequentially. When administered sequentially, the combination can be administered twice or three times. The third active component has anti-HIV activity, including protease inhibitor (PI), nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and integrase inhibitor . Exemplary third active ingredients for administration in combination with Cyclosporine DF, amphibidin, and their physiological functional derivatives are shown in Table A.

Table A 5,6-dihydro-5-azacytidine; 5-nitro 2'-deoxycytidine; 5-azacytidine; 5-yl-carbocycle 2'-deoxy bird (BMS200, 475); -39- (36) (36)1355270 9-(arabinofuranosyl)guanine; 9-(2,deoxyribosefuranosyl)guanine; 9-(2'-deoxy21fluororibosefuranosyl -2,6-diaminopurine» 9-( 2'·deoxy 2'fluororibosefuranosyl)guanine; 9-(arabinofuranosyl)·2,6·diaminopurine; Abacavir, Ziagen®; Acyclovir, ACV; 9-(2·ethoxymethyl) guanine; Adefovir diisopropoxy Dipivoxil, Hepsera®; amdoxivir, DAPD; Amprenavir, Agenerase® f araA, arabinose Vitalabine; Atazanivir Sulfate [Reyataz®]·. AZT; 3' -azido·2·,3'-dideoxythymidine, Nitto Fu (Zidovudine), Retrovir®; BHCG; ( . + -·) - ( la, 2b, 3a) · 9-[ 2,3 · bis (hydroxymethyl) Butyl]guanine; BMS200: 475: 5-based carbocyclic 2匕 deoxyguanosine; Buciclovir; (R) 9. (3,4-dibutyl) guanine; 40- (37) 1355270

BvaraU; Ι-β-D-arabinofuranosyl-E-5-(2-bromovinyl) urinary sputum Sorivudine; Calanolide A; Capravirine; CDG; carbocyclic 2'-deoxyguanosine; Cidofovir >HPMPC;(S)-9-(3-hydroxy-2-phosphinomethoxypropyl)cytosine;

Clevudine, L-FMAU; 2 '-Fluoro-5-methyl-β-L-arabinose-furanosyluracil; Combivir (Zambivudine) )]; Cytallene; [1-(4'-hydroxy-l',2'-butadienyl)cytosine]; d4C; 3'-deoxy-2,3'-didehydrogenate Glycoside

DAPD; (-)-β-ϋ2,6-diaminostilbene dioxane; ddA; 2':3'-dideoxyadenosine; ddAPR; 2,6-diaminopurine·2',3 '·DDE ribonucleoside; (1(^; 2',3'-dideoxycytidine (231 £:431^116); ddl; dideoxyinosine, didanosine, (Videx® > Videx® EC); Delavirdine, Rescriptor®; Didanosine, ddl, Videx®; 2',3'-dideoxyinosine; DXG; Alkylguanosine; -41 - (38) 1355270 E-5- (2-bromoethenyl)-2·-deoxyuridine; Efavirenz, Sustiva®; (Enfuvirtide), Fuzeon®; F-ara-A; Fludarabine; FDOC; (-)-0-〇-5-fluoro-1-[2_(hydroxymethyl) )-1,3-dioxane cytosine;

FEAU; 2'-deoxy-2'-fluoro-Ι-β-D-arabinofuranosyl-5-ethyluracil; FIAC; Bu (2-deoxy-2-fluoro-β-D-arabinofuran) Glycosyl)-5-iodocytosine; FIAU; 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-iodouridine; FLG; 2',3'-dideoxy -3'-Fluoroguanosine; FLT; 3'-deoxy-3'-fluorothymidine; Fludarabine; F-ara-A; fluoroarabinos

Glycosides; FMAU; 2'-fluoro-5-methyl-β-L·arabinose-furanosyluracil; FMdC; Foscarnet; benzoic acid, PFA; FPMPA; 9- ( 3-fluoro-2-phosphonium methoxypropyl) adenine; Gancyclovir, GCV; 9·(1,3-di-2-propyloxymethyl)guana; GS-7340 9-[R-2-[ [S)-[(S)-1((isopropyloxycarbonyl)ethyl)amino]phenoxyphosphinyl]methoxy]propyl] adenine; 42 - (39) 1355270 HPMPA; (S) -9·(3-Butyl-2-phosphonium methoxypropyl) adenine: HPMPC; (S) -9-(3-hydroxy-2-phosphonium methoxy Propyl) cytosine (Cidofovir); hydroxyurea, Droxia®; Indinavir 'Crixivan®; Kaletra® Lopina (1〇pinavir) / ritonavir (ritonavir):

Lamivudine, 3TC, EpivirTM, (2R, 5S, cis)-4. Amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiane- 5-based)-(1 Η)-pyrimidine-2-one; L-d4C; L-31-deoxy-2,3'-didehydrocytidine; L-ddC; L-2', 31·2 Dehydrocytidine; L-Fd4C; L-3'-deoxy-2',3'-didehydro-5-fluorocytidine; L-FddC; ]^·2_,3'-dideoxy-5- Fluorocytidine; Lopinavir;

Nelfinavir, Viracept; Nevirapine, Viramune;

Oxetanocin A; 9-(2-deoxy-2-hydroxymethyl-β-D-erythro-oxetanosyl) adenine;

Oxetanocin G; 9-(2.deoxy-2-hydroxymethyl-β-D-erythro-oxetanosyl) guanine; Penciclovir; PMEDAP; 9-(2-phosphonium methoxyethyl) -2,6-diaminopurine-43 - (40) (40) 1355270 PMPA, tenofovir; (R) -9-(2-phosphine methoxypropyl) adenine PPA; Phosphate carboxyacetic acid; Ribavirin; β-D-arabinofuranosyltriazol-3-carboxycarboxamide; Ritonavir, Norvir®; (Saquinavir), Invirase®, Fortovase®; Sorivudine, BvaraU; Ι-β-D·arabinose glycosyl·Ε·5- ( 2-bromovinyl)uracil; Stavudine, d4T, Zerit®; 2',3'-didehydro-3'-deoxythymidine; trifluorothymidine, TFT, trifluoro Thymidine; Trizivir® [abacavir sulfate / zidovudine]; Vidarabine, araA; 9-β-ϋ-A Glucofuranosyl gland exposure; Zalcitabine, Hivid®, ddC; 2', 3'-dideoxy ; Zidovudine, AZT, Retrovir®; 3'_azido-2',3'-dideoxythymidine; Zonavir; 5-propynyl-buarose Basal uracil. Another aspect of the invention is a three-part combination comprising Tenofovir-44-(41)(41)1355270 DF'FTC, and 9-[(R)-2-[[(S)-[ [ (S)-l-(Isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]propyl]adenine; the final compound is also referred to as GS-7340 in this specification, and has the following Structure:

GS-734〇 is a former drug of Tiannuowei, and is the subject of the following patent applications: the pending application filed by the applicant in this case, US serial number: Ν〇·09/909,560, application on July 20, 2001 ; and WO 02/08241, filed by Becker et al. For example, a ternary unit dosage form may contain from 1 mg to 1000 mg of diprofenium diisopropoxycarbonyloxymethyl fumarate, from 1 mg to 1000 mg of ampam, and 1 The third active ingredient is from milligrams to 1000 milligrams. The unit dosage form, which is another technical feature of the present invention, may further comprise tianfufuwei DF, ampazin, a third active ingredient, or a physiologically functional derivative of the three active ingredients, and is pharmaceutically acceptable Carrier. The combination of the present invention allows patients to achieve greater freedom than multi-dose regimens' and reduces the diligence required to memorize and follow complex daily dosing times and times -45 - (42) (42) 1355270. Combining the fenoflavin diisopropoxycarbonyloxymethyl fumarate with the saponin in a single dosage form, the desired daily regimen can be expressed as a single dose per day, or two or two doses. The above doses. The combination of the co-formulated fenoflavin DF and the amphibious tabin can be administered as a single medicinal drug once a day. Another aspect of the invention is a kit for a patient comprising at least one active ingredient selected from the group consisting of: fumarate of dinofosime diisopropoxycarbonyloxymethyl ester, amphibious or any of them a physiologically functional derivative; and a data description set or product copy containing instructions for using the combination of the invention. Segregation and granulation of the active ingredient in a pharmaceutical powder is a generally recognized problem that can result in uneven dispersion of the active ingredient within the final dosage form. Some of the main factors affecting dispersion are particle size, shape and density. Separation is particularly troublesome when attempting to formulate a single homogeneous tablet containing multiple active ingredients of different densities and different particle sizes. Glidants are materials that have traditionally been used to enhance the flow characteristics of particles and powders by reducing friction between particles. See the literature L i e b e r m a n 5 L a c h m a η & S c h w a r t z, Pharmaceuticaal Dosage Forms: Tablets, Volume 1, p 1 77-1 7 8 (1 9 8 9 ), which is incorporated herein by reference. The slip agent is typically added to the pharmaceutical composition immediately prior to compression of the tablet, thus facilitating the flow of the particulate material into the dead pocket of the tablet compact. The slip agent includes the following materials: cerium oxide, talc without asbestos, sodium aluminosilicate, calcium citrate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid metal Salts, calcium stearate, magnesium stearate, zinc stearate-46- (43) 1355270, stelovett C, starch-based magnesium sulfate, and magnesium oxide. An exemplary ingot bismuth oxide (Example). Anti-HIV medicinal agents can be used to increase and assist the mixed composition No. 6 1 1 3 920 ). The novel composition of the present invention achieves and maintains the present invention in a sufficiently homogeneous form during the treatment prior to tableting. The following active ingredients are available: dinavir DF and anenergy derivatives; and the use of this pharmaceutical formulation lies in In the course of pre-compressed material processing, a slip agent is used to reduce the active component phenomenon. Another object of the present invention is to provide a mixed formulation characterized by an acceptable degree of homogeneity of the active ingredient (Dinovir DF and Anta Biosystems) and a pharmaceutically acceptable slip agent group, including a suitable oral solution. Unit dosage form is prepared by transrectal, transdermal, buccal and sublingual, transvaginal or intramuscular, intravenous and intradermal, and these methods can be utilized in the pharmaceutical art to represent the present invention. Another technical feature is to mix the active ingredient with the carrier and to maintain one or more accessory ingredients. In general, the active component and the liquid carrier, or subdivided solids are uniform and sufficient, if necessary, the product is fixed, splashed powder] 500, dodecane! 1 Formulation A contains a formulation consisting of colloidal two Medium, slip homogeneity (U.S. patents may contain a slip agent, whereby the homogeneity of the active component. The formula, the combination of the combination of Tabin, or its physiological work. One of the objects of the present invention is pre-compressed material treated with pharmacy An isolated pharmaceutical formulation in the composition, the formula, or a physiological function thereof, produces a pharmaceutical product. Nasal, topical (including parenteral (including subcutaneous. The formula may conveniently be any conventional) The method comprises the following steps: the method comprises a step-by-step stability, the carrier structure, the preparation of the formula can be carried out by using a body carrier, or a mixed type of 0-47 - (44) (44) 1355270, which is suitable for oral administration. The formulation may be a separate unit, such as a capsule 'sugar lozenge, sachet, or lozenge, each containing a predetermined amount of the active ingredient; a powder or granule; a solution or suspension in an aqueous or non-aqueous liquid; or water package Liquid latex, or water-in-oil liquid latex. The active component can also be a large nine-agent, elixirs or ointment. By compression or casting, a tablet can be prepared, which optionally contains one or more auxiliary components. To prepare a compressed tablet, the active component in a free-flowing form (for example, powder or granule) can be compressed in a compressor, and the binder can be optionally mixed (for example, pyrrolidone, gelatin, hydroxypropylmethylcellulose) , lubricant 'inert diluent, preservative, disintegrating agent (for example, sodium glycolate, cross-linked pyrrolidone, cross-linked sodium carboxymethyl cellulose), surfactant, or separating agent. In a suitable machine The cast tablet can be prepared by wetting the mixture of the powdered compound with an inert liquid diluent. The tablet can be optionally coated or scored and can be formulated to provide a sustained release or controlled release active group. For example, a plurality of ratios of a cellulose ether derivative (for example, hydroxypropylmethylcellulose) or a methacrylate derivative are used to provide a desired drug release data chart. The casing can be optionally given 'so that in addition to the stomach, it is also locally released in the intestine. Formulations suitable for topical use in the oral cavity include diamond shaped ingots containing the active ingredient in a flavored base which is usually sucrose and arabic a gum or tragacanth; a tablet containing an active ingredient in an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic; and a mouthwash containing the active ingredient in a suitable liquid carrier The formulation for rectal administration can be presented as a suppository containing a suitable base (including coconut oil or salicylate). The -48 - (45) (45) 1355270 part can also be treated by means of skin-type iontophoresis ( Iontophoretic device 〇 a formulation suitable for transvaginal administration may be presented as a vaginal suppository, a tampon, a cream 'gel, an ointment, a foaming agent, or in addition to the active ingredient, which is also known to be suitable for the art. Spray formulation of the agent. A prophylactic or therapeutic formulation suitable for administration via the penis, which may be presented as a condom, cream, gel 'ointment' foaming agent, or in addition to the active ingredient, a spray formulation of the art known as a suitable carrier. . In a pharmaceutical formulation suitable for rectal administration, the carrier is a solid which preferably exhibits a single dosage form of a suppository. Suitable carriers include coconut oil and other materials commonly used in the art. The suppository can be conveniently prepared by blending the active combination with a softened or dissolved carrier which is then cooled and shaped in a mold. Suitable for parenteral formulations, including aqueous and non-aqueous isotonic sterilized injections, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that cause the formulation to be in tension with the intended recipient's blood; Non-aqueous sterile suspensions, which may contain suspending and thickening agents; and lipid microparticles or other particulate systems designed to direct the target of the compound to a blood component or to one or more organs. The formulation can be provided in a single or multiple dose sealed container, for example, ampoules and vials, and can be stored under lyophilization (lyophilization). Prior to use, only sterile liquid carriers need to be added, for example, injections. Use water. The instant injections and suspensions can be prepared from sterile powder 'granules and lozenges of the above type. Exemplary unit dosage forms are those containing -49-(46)(46)1355270 prior to the daily dose or daily dose, or a suitable fraction thereof. It will be understood that in addition to the components specifically mentioned above, the formulations of the present invention may include other agents known in the art for the type of formulation desired, for example, formulations suitable for oral administration may include, for example, sweeteners, Other agents such as thickeners and flavoring agents. The compounds of the combinations of the invention can be obtained by conventional methods known to those skilled in the art. For example, the preparation of the fumarate salt of fenoflavin diisopropoxycarbonyloxymethyl ester can be as described in U.S. Patent No. 5,977,089. A method of preparing an FTC is described in WO 92/1 4 743, the disclosure of which is hereby incorporated by reference. Use of the Composition The compositions of the present invention are administered to a human or other mammal at a safe and effective level as described herein. The safe and effective amount will vary depending on the type and size of the mammal to be treated, and the desired therapeutic result. Any of a variety of methods known to those skilled in the art for packaging tablets, tablets, or other suitable solid dosage forms for oral administration, and which do not detract from the compositions of the present invention, Suitable for packaging. The package can be packaged in glass and plastic bottles. Tablets, tablets, or other solid dosage forms suitable for oral administration can be packaged and stored in a wide variety of packaging materials, optionally including a dehumidifying agent such as silicone. The package may be in the form of a unit dose blister pack. For example, the package may contain a blister pack of Cyclosporin DF, and another blister pack of the urethane lotion, tablet, tablet, or capsule. The patient will take one dose from one tank (for example, one drug nine) = and take one dose from the other tank. Alternatively, the package may contain a -50-(47) 1355270. blister pack having a combination of ten-five, tablet, tablet or capsule co-formulated with fenoflavin DF and ampazin. In other combinations and assemblies, the combination of the invention includes physiological derivatives of fenoflavin DF and FTC. The label of the pharmaceutical composition can also be printed on the packaging material and the description of the product can include a product brochure, report, note, brochure, or a copy containing the product information. In the pharmaceutical industry, the form of pharmaceutical information refers to the "package copy". The package can be attached to or contained in the pharmaceutical factory. The package and any tagged items provide information about the pharmaceutical composition. Information. This information package provides a wide range of information on the use of health professionals and patients, their components, their dosages and the various other parameters required by the competent authority (eg, US food and drug tubes). The assay can test the activity sensitivity of the combination of the present invention against ΗIV in vitro, and the cytotoxicity of blood mononuclear cells (PBMC) in laboratory-acclimated cell lines (for example, Μ2). Standard analytical methods developed by HIV compounds, for example, 02/068058 and U.S. Patent No. 6,475,491. The combination of compounds can be carried out at different concentrations using successive dilutions, ec50. [Embodiment] Package functional materials. Matters attached to the manufacturing and labeling instructions and Min and Zhou measured WO, the group to determine -51 - (48) (48) 1355270 demonstration formula The following examples further illustrate and demonstrate specific embodiments of the invention within the scope of the invention. Techniques and formulations are generally referred to Remington's Pharmaceutical Sciences (Mack Publisshing Co., Easton, PA). These examples are provided for illustrative purposes only and should not be construed It is to be understood that there are many variations of the present invention, and the following examples are merely illustrative and are not intended to limit the scope of the invention in any way. The fumarate of diisopropyloxycarbonyloxymethyl ester, the physiologically functional derivative of any of them, or any of them. Tablet Formulations The following exemplary formulations A, B, C, D, E were prepared. And F, the component is wet granulated with an aqueous solution, then magnesium stearate is added and compressed.

-52- (49)1355270 Formulation A: mg/ingots of fenoflavin diisopropoxycarbonyloxymethyl fumarate 300 amps of Tabin 200 retinoic cellulose 200 lactose monohydrate 175 carboxymethyl Cellulose Sodium 60 Pregelatinized Starch 50 Colloidal Ceria 5 Magnesium Stearate 10 Total: 1000

Formulation B: mg/ingot fenoflavin diisopropoxy oxyoxymethyl ester fumarate 300 ampere tabin 100 retinoic cellulose 200 lactose monohydrate 180 starch sodium glycolate 60 pregelatinized starch 50 magnesium stearate 10 Total: 900

-53- (50)1355270 Formulation c: mg/ingot fenoflavin diisopropoxycarbonyloxymethyl fumarate 200 ampere Tupper 200 retinoic cellulose 200 lactose monohydrate 180 starch glycolic acid Sodium 60 Pregelatinized Starch 50 Magnesium Stearate 10 Total: 900 Formulation D: mg/ingot novolvir diisopropoxycarbonyloxymethyl fumarate 300 Ampere Tupper 25-dimensional crystalline cellulose 200 Lactose monohydrate 180 Starch sodium glycolate 60 Pregelatinized starch 50 Magnesium stearate 10 Total: 825 -54 - (51)1355270 Formulation E: mg/ingots of fenoflavin diisopropoxycarbonyloxy Ester fumarate 200 Anthraquinone 25-dimensional crystalline cellulose 200 Lactose monohydrate 180 Beach powder sodium glycolate 60 Pre-gelled starch 50 Magnesium stearate 10 Total: 725 Formula F: mg/Ritano Fuwei diisopropoxycarbonyloxymethyl fumarate 100 Anthraquinone 100 Dimensional cellulose 200 Lactose monohydrate 180 Starch sodium glycolate 60 Pre-gel source powder 50 Magnesium stearate 10 Total : 700 -55 - (52) (52)13 55270 Formulation G (Controlled Release Formulation): This formulation was prepared by wet granulating the components with an aqueous solution, then adding magnesium stearate and compressing it. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ br> 28 Magnesium stearate 7 Total: 700 The release of the drug lasted approximately 6-8 hours and was completed after 12 hours. Capsule Formulation φ Formulation Η : Prepare a capsule formulation' by blending the components into a two-part hard gelatin capsule or hydroxypropyl methylcellulose capsule. -56- (53) (53)1355270 mg/capsule Active ingredient 500 Microcrystalline cellulose 143 Sprinkling powder sodium glycolate 25 Magnesium stearate 2 Total: 670

Formulation I (Controlled Release Capsule): The following controlled release capsule formulation was prepared by extruding components a, b and c using an extruder, and spheroidizing and drying the extruded product. The dried pellets are then coated with a controlled release film (d) and mounted into two pieces of hard gelatin capsules or hydroxypropyl methylcellulose capsules. Mg/capsule (a) active ingredient 500 (b) microcrystalline cellulose 125 (c) lactose BP 125 (d) ethyl cellulose 1 3 Total: 763 Formula J (oral suspension) Active ingredient with other groups Blend and mix in a dry powder form -57- (54) (54) 1355270. Add pure water and mix well before use. Active ingredient 500 mg cake sugar 2000 mg Ximethicone 300 mg methylparaben 30 mg propylparaben 10. mg flavor, peach flavor 500 mg pure water, the amount is added to 5.00 ML Formulation K (Suppository): . Dispense one-fifth of Waitepol H15 in a steam bath at the highest temperature of 45 °C. The active ingredient was filtered through a 200 micron perforation and added to the melted substrate while stirring using a high speed homogenizer (Silverson) fixed with a cutting head until a uniform suspension was obtained. The mixture was maintained at 45 ° C. The remaining Waitepso Η ] 5 was added to the suspension and stirred to ensure a homogeneous mixture. Allow all of the suspension to cool through a 250 micron stainless steel filter 'continuous agitation' to 401:. When the temperature is between 38 ° C and 40 ° C, 2.02 g of the mixture is poured into a suitable 2 ml plastic mold. The suppository is allowed to cool to room temperature. -58 - (55) (55)1355270 mg/suppository active ingredient 500 stearin, Β·P.white (Witepsol H)5)-Dynamit Nobel) 1770 Total 2270 fixed dose combination ingots using wet granulation/flow The bed drying method was prepared by combining a fixed dose of a combination of 300 mg of fenoflavin diisopropoxycarbonyloxymethyl fumarate with 200 mg of ampam. This is a known method and can be found in the following documents: US 5935946; L. Young (ed.) Tablet in g Specification Manual, fifth edition, American Pharmaceutical Association, Washington, DC (200); L. Lachman, H.

Li eberman (ed.) Pharmaceutical Dosage Forms: Tablets (Volume 2), Marcel Dekker, New York, 185-202 (1981); JT Fell and JM Newton, J. Pharm. Pharmacol. 20,6 5 7 - 65 9 ( 1 968 ) ; US Pharmacopeia 24-

National Formulary 19, “Tablet Friability”, Chapter 12, Chapter 6, page 2148 (2000). Study the granulated water content (between 40% and 50%) and the wettizing time for the physicochemical properties of the final powder blend and its associated mixing uniformity and compressibility (slurryness) The impact of performance. Furthermore, the content uniformity of the TDF/ampurable Tabin fixed-dose combination ingot was evaluated, (56) (56) 1355270 stability and decomposition performance. The instrumentation equipment includes a high-cut mixer equipped with a pressure tank and a nozzle head for adding granulated water, a fluid bed dryer, a mill, a rolling mixer, a rotary press, and a lozenge dust remover. . Method of Preparation The dried and milled powder is mixed with extra granulated microcrystalline cellulose and croscarmellose sodium and then mixed with magnesium stearate. After mixing with magnesium stearate, the powdery sample was removed. Assess the bulk density, sieving and compressibility of the mixed samples. On the press equipment, a powdery blend of magnesium stearate is extruded into an ingot. Raw Materials The quantitative composition of the TDF/ampurable tabin tablet formulation is listed in Table 1 below. -60- (57) (57)1355270 Table 1 Component% by weight/weight Unit scheme for ingot core (mg/ingot) Content per batch of 12 kg (kg) Tiannovi Diisopropoxy Fumarate a 30.0 300.0 3.60 Anthracene 20.0 200.0 2.40 Pre-gelatinized starch, NF/EP 5.0 50.0 0.60 Sodium carboxymethylcellulose, NF/EP 6.0 60.0 0.72 Lactose monohydrate , NF/EPa 8.0 80.0 0.96 Divinated cellulose, NF/EP ^ 30.0 300.0 3.60 Magnesium stearate, NF/EP 1.0 10.0 0.12 Pure water, USP/EP bbb Total 100.0 1000.0 12.00 Exact weight is based on Tiannuowei The fumarate of diisopropoxycarbonyloxymethyl ester was adjusted with the drug substance content factor (DCF) of the Tabin. φ b Drying process to remove moisture Qualitative instrument Measure the moisture content according to the amount of loss from drying with the heating bulb/balance system. Sampling from the powdered blend is sampled using a multi-chambered sample to determine the uniformity of the powder blend. Repeated samples were taken from each of the positions of the blend. A sample obtained at each location was subjected to blend homogeneity analysis. -61 - (58) (58) 1355270 Determine the particle size analysis of the final powder blend by using a sonic sieve filter to filter several gram samples through a sieve. The amount of final powdery blend remaining on each screen and fines collector was determined by calculating the difference in weight between the screen and the fines collector before and after testing. Calculating the geometric mean diameter The particle size' is the logarithmic weight of the sieved distribution. Determination of bulk density' is the final powdery blend into the graduated cylinder, and the difference in weight between the unfilled and unfilled graduated cylinders per unit volume is measured, and the friability is determined. Use the fragile machine, the hardness tester 'with the thickness of the printing gas micrometer' and the balance balance. To determine the compression characteristics, a roller compactor equipped with a flat bevel punch (target weight of 400 mg) was used. The powdery blend is compressed using an impact pressure higher than the target and between about 100 to 250 MPa. The extrusion force normalized to the surface was measured and the thickness and diameter of the tablet were normalized. The hardness of the ingot was measured using a hardness tester. The thickness of the ingot was measured using a micrometer, and the weight of the ingot was measured using a top placed balance. Wet granulation In the granulator, the powder is blended and then granulated using water. During the granulation and wet mass operation, the speed of the propeller and cutter is maintained at the low speed setting of the blender. After adding water, stop the propeller and cutter, open the bowl of the granulator, and observe the granulation and texture. Close the lid and perform the wet pack stage. Acceptable granules are 40% w/w and 60% w/w water, respectively. (59) (59) 1355270 Wet grinding method In order to facilitate a consistent drying operation, a mill equipped with a sieve and a propeller was used to remove the agglomerate from each wet granulation result. After wet grinding, the milled wet granules are immediately poured into a fluid bed dryer. Flow Bed Drying The milled wet granules were dried using an inlet air set temperature of about 70 ° C and a gas flow of about 100 cfm. The target LOD is approximately 1.0% and its range does not exceed (NMT) 1.5%. The total flow bed drying time is in the range of 53 to 75 minutes. The final L 0 D of all batches produced by drying is in the range of 〇 . 4 % to 0.7 %. The final exhaust temperature for all batch productions is between 47 ° C and 50 ° C. Dewatering and Milling Method All dried granules are crushed through a perforated sieve. This mill is equipped with a square thruster and is operational. The batch was milled and manually delivered to a V-blender. Blending Each batch was blended using a V-blender. The final powdery blend yield that can be used for compression after blending with '12 kg of raw material' in one of the three formulations ranges from 1 〇 5 kg (87.5%) to 11.1 kg (92.5%). The bulk density of the final powder blend is in the range of 〇·48 to 58·58 -63- (60) (60)1355270 g/ml, and the geometric mean diameter particle size ranges from 1-2 to 22 μm. Inside. The percentage of water and the wet agglomeration time affect the particle size and bulk density of the final powdery blend. The powder blending between Tiannufuwei DF and Antabin is obtained, and the average (n=10) strength 値 of the neufofur DF is in the range of 100.6% to 02.8% (relative to the batch). Target strength), and the relative standard deviation (RSD) is from 0. 5 % to 1 · 7 %. The average number of strengths (n = ] 0.) is between 101.3% and 04.1% (relative to the target strength of the batch), and the relative standard deviation (RSD) is from 0.6% to 1. 7%. The final powder blend has a humidity in the range of 0.8% to 1.% LOD. Ingot Compression The final blend was compressed using a rotary press and the tablet was coated with a film. Three 300 gram formulations (Table 2) were granulated in a granulator equipped with a 1 liter bowl. The amount of the components in the granules is based on the total batch size of 300 grams. The difference in the formulation of Batches 1 and 2 is the content of microcrystalline cellulose, which is 30% vs. 20% by weight/weight, respectively. Batches 2 and 3 were identical except for the binder. Batch 2 contained 5% w/w pre-geled source powder as binder&apos; and Batch 3 contained 5% w/v pyrrolidone as binder. -64 - (61) (61) 1355270 Table 2 Component Batch 1 Batch 2 Batch 3% Weight/wt% Weight/wt% Weight/Weight Tenofovir Diisopropoxycarbonyl Oxymethane 30.0 30.0 30.0 fumarate is taken from Tabin 20.0 20.0 20.0 pregelatinized starch, NE/EP 5.0 5.0 N/A pyrrolidone, USP/NF (C-30) N/AN/A 5.0 sodium carboxymethylcellulose, NF/EP 6.0 6.0 6.0 Lactose monohydrate, NF/EP 8.0 18.0 18.0 Microcrystalline cellulose, NF/EPa 30.0 20.0 20.0 Magnesium stearate, NF/EP 1.0 1.0 1.0 Pure water, USP/EP aaa Total 100.0 100.0 100.0 After the drying process removes the water and water, the propeller and cutter are terminated, and the granulator bowl is opened to observe the granulation consistency and texture. In order to achieve similar granulation consistency, batches I, 2, and 3 were granulated with 45% '40% and 30% water, respectively. Close the lid' to perform the wet agglomeration stage. All batches were wetted for 30 seconds to give acceptable granulation results. The wet granules of all batches are passed through a sieve screen by hand to remove the agglomerates. The resulting granules were panned and dried in a convection oven set at 6 ° C for about 20 hours to achieve LOD &lt; 1.0%. The dry granules of all batches were screened by hand through a sieve. -65 - (62) (62)1355270 In order to allow the pellets to fit into a small-scale (300 ml) V-splicer, the final blend batch size was adjusted to 00 grams. The resulting blend from one portion (8 grams) of the batch] was blended with 15 grams of microcrystalline cellulose, 3 grams of residual sodium cellulose acetate, and 1 gram of magnesium stearate. 86 g of the granules from Batches 2 and 3 were each blended with 1 g of microcrystalline cellulose, 3 g of residual methylcellulose sodium and 1 g of magnesium stearate. Purity analysis was performed by reverse phase HPLC (High Performance Liquid Chromatography). Before formulating the three batches of Table 2, identify and measure the relevant impurities of the flavonoid DF and the sorbin in the main API (active pharmaceutical component), and prepare and re-identify and measure the impurity after the obtained tablet. . Impurities include by-products derived from the cyclic anthranyl group derived from fenoflavin diisopropoxy oxycarbonyloxymethyl fumarate and hydrolyzed by sorbin, and oxaprovir diisopropoxy oxyoxymethane a by-product of the hydrolysis of diisopropoxycarbonyloxymethyl (POC) fumarate. After preparation and ingot making, the total amount of fumarate and sulfonium-related impurities in the batch of each of the batches was less than 1%. The physicochemical properties of fenoflavin diisopropoxycarbonyloxymethyl fumarate and amphibious tablet are based on visual appearance, water content, label strength, impurities and degradation products, and dissolution of tablets. To evaluate. The stability analysis is performed on the drug packaged in the container sealing system, which is the same as the desired clinical and commercial container sealing system. During the stability analysis, there were no signs of discoloration or cracking of the tablet. When packaged and stored with a silicone dehumidifying agent, at 40 ° C / 75% RH (relative humidity), the coated film of fenoflavin diisopropoxy oxyoxymethyl ester fumarate and the tower The tablet tablets showed satisfactory stability for up to six months. When packaged and stored with the knee-bit desiccant 1-66-(63) 1355270, after six months at 40 r /75% RH, no percent strength of the label of neufofur DF or tabin was found. Significantly reduced (defined as &gt; 5% degradation). When packaged with 3 grams of dehumidifying agent and stored at '4 ° ° C / 75% RH after six months, the total degradation product increased the neufovir DF was 1.5%, and the Tabin was 0.6-0.7. %. All documents and patent applications cited in this specification are incorporated herein by reference in its entirety as if each individual document or patent application is specifically and individually indicated that it is incorporated herein by reference. Although some of the implementation systems are as described above, those skilled in the art can understand the present invention and can make various modifications without departing from the teachings of the scope of the patent application. These modifications are all included in the scope of the patent application of the present invention. Embodiment of the Invention A1. A pharmaceutical composition comprising an effective amount of a compound of the formula: 7YR6

(1) -67- (64) (64)1355270 wherein R1 and R1 are each independently selected from H'CrCe alkyl, C, -C6 substituted alkyl 'C6-C2Q aryl, C6-C2G substituted aryl, C6- C20 aralkyl, C6-C2 fluorene substituted aralkyl, decyl methyl ester-CH20C(=0)R9, and methoxymethyl carbonate-ch2oc(=o)or9, where 119 is C,-C 6 alkyl C]-C 6 substituted alkyl, c 6 - C 2 0 aryl, or C 6 - C 2 . Substituted aryl; R2 is selected from the group consisting of hydrazine, alkyl, C^-Ce substituted alkyl, or CH2OR3, wherein R3 is C]-C6 alkyl\CrC6 hydroxyalkyl, or C,-C6 haloalkyl; R4 and R5 are each independently selected from the group consisting of h, nh2, nhr and nr2, wherein R is a C]-C6 group; and R6 and R7 are each independently selected from an alkyl group; or a physiologically functional derivative thereof; Compound,

-68 - 1 2 wherein B is selected from the group consisting of adenine, guanine, cytosine, uracil, thoracic 3 5 · fluorocytosine, 5-chlorocytosine, 5-bromocytosine, 5-iodo 4 adenine, 7-deaza adenine, 7-deazaguanine, 7-deaza-8-azapine 5 嘌呤, 7-deaza-8 azadenine, inosine 'asarum ( 6 nebularine ), nitropyrrole, nitroguanidine, 2-aminoindole ' 2 ·amine 7 - 6 -chloropurine ' 2,6-diaminopurine, hypoxanthine, pseudouridine, 65) (65)1355270 pyrimidine, pseudocytosine, pseudoisopramin (pseud〇is〇cyt〇sine), 5_propynylcytosine, isocytosine, guanine, 7-deazaguanine 2_sulfur唆Π 唆Π 6 6 - thiophene exposure, 4 - thiothymidine, 4 · thiouridine, 06-methyl guanine, methyl adenine, 〇 4 - methyl thymine, 5, 6-dihydrothymidine '5,6-dihydrouracil, cardiomethylpurine, and oxime 〔[3 5 4 - D] chelate B; and R is selected from H, Cl-C18 alkyl , c, _Cl8 substituted alkyl 'C2_cI8 alkenyl, c2-c〗 8 substituted alkenyl, c2_C|8 alkynyl, c2 C] 8 substituted alkynyl c 6-c2{) aryl, C6-C2Q substituted aryl 'c2_c2Q heteroaryl, Cy Cu substituted heteroaryl, phosphonate, phosphophosphonate, diphosphoric acid vinegar, pity ester 'two O. vinegar, three-disc vinegar, polyvinyloxy, or a physiologically functional derivative thereof; and a pharmaceutically acceptable carrier. Β2. A composition consisting of the implementation system a1, wherein, in the compound of the formula 1, R1 and R2 are each independently selected from H, CpC6 alkyl, C^C6 substituted alkyl, c6-c2G aryl, C6_C2Q Substituted aryl 'aralkyl, c6-c2C substituted aralkyl, decyl methyl ester _Ch2〇c(= 0)r9, and methoxymethyl carbonate-CH20C(=0)0R9, where 9 It is a C6 alkyl group, c]-c6 substituted alkyl group, c6-c2. The aryl group, or C6_C2Q, is substituted by a radical ' and R' R4' r5, R6 and R / are each independently Η or c). C6 alkyl. C 3 - a composition consisting of the implementation system A1 in which 'B is a cytosine or a 5-halocytosine. D4· A composition consisting of the implementation system A 1 wherein, in the formula -69-(66) (66)1355270, r1 and R2 are each independently selected from H, CrCe alkyl 'C, -C6 substituted , C6-C2D aryl, C6-C20 substituted aryl 'C6-C2O aralkyl, C6-C2 (l substituted arylalkyl, decyl methyl ester-CH20C(=0)R9, and cesium carbonate Oxymethyl ester - CH20C(=0)0R9' wherein c is -C6 alkyl' (^-(:6 substituted alkyl, c6-c2G aryl, or c6-c2G substituted aryl; and 113 , 114, 115, 116 and 117 are each independently 1^ or (:, · c6 alkyl; and, in the compound of formula 2, B is cytosine or 5-halogenated cytosine D &lt;= E5 · A composition consisting of system D4, wherein, in the compound of formula 1, W and R2 are each independently selected from the group consisting of hydrazine, decyloxymethyl ester-ch2oc (=0) R9' and decyloxymethyl carbonate-CH2OC (=〇) R9, wherein R9 is C丨-C6 alkyl; and R3, R4'H5, R6 and R7 are each independently Η or (^-(:6 alkyl; and, in the compound of formula 2, B is cytosine or 5 a halogenated cytosine, and R is a fluorene. F6. A composition consisting of the implementation system Ε5, wherein, in the compound of formula i, R1 And R2 are each independently selected from the group consisting of hydrazine and -CH2OC (=0) OCH(CH3)2; R3 is -CH3; and R4, R5, r6 and R7 are H; and in the compound of formula 2, B is a 5-fluorocell Pyrimidine D, and R is Η G. A pharmaceutical composition comprising a pharmaceutically effective amount of [2 (6-amino-indol-9-yl)-methyl-ethoxymethyl]-phosphine Acidic diisopropoxycarbonyloxy acetonate fumarate (dinovir diisopropoxycarbonyloxymethyl fumarate) or a physiologically functional derivative thereof; and a pharmaceutically effective amount ( 2R,5S) -4 -amino-5.fluoro-; 1-(2-hydroxymethyl-]:3-oxathiane·5-70-(67) 1355270)-(1H)-pyrimidine-2- a ketone (retaining tabin) or a physiologically functional derivative thereof; and a pharmaceutically acceptable carrier. H8. A pharmaceutical formulation consisting of the implementation system A to G7, further comprising a protease inhibitor nucleoside or a third active ingredient of a nucleotide reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, and an integrase inhibitor. 19. A pharmaceutical formulation consisting of the implementation systems A1 to H8 in unit dosage form J10. - used to treat or prevent infection The method of HIV infection was the symptoms or effects, comprising administering to the animal a pharmaceutical composition of the embodiments A1 to systems consisting of I 9. -71 -

Claims (1)

Μ 9. 1355270 Annex 3Α: Dijon frl〇 (I813 patent application scope amendments. The Republic of China, September 15, 100, revised, applied for a patent garden 1. A pharmaceutical composition for treating or preventing the symptoms or effects of HI V infection in infected animals a compound containing [2-(6-amino-indol-9-yl)-1·methyl-ethoxymethyl]phosphonic acid•diisopropoxycarbonyloxymethyl fumarate (Day a fumarate of tenofovir disoProxil or a physiologically functional derivative thereof; and (2R,5S,cis)-4-amino-5-gas-1-( 2-Methyl-1,3-Dilden-5-yl)-(114)-furan-2-one (Anthony's emtricitabine) or a physiologically functional derivative thereof; The ratio of the fumaric acid salt of diisopropoxycarbonyloxymethyloxyl or a physiologically functional derivative thereof to the salt or the physiologically functional derivative thereof is from about 1:50 to about 50:1 by weight. A pharmaceutical composition according to claim 1, which comprises a fumarate of dinofosime diisopropoxycarbonyloxymethyl ester and a saponin. 3. The pharmaceutical composition as claimed in claim 2 Object, which contains about 300 millimeters The sulphonic acid of sulphonic diisopropoxy oxycarbonyl oxymethyl ester and about 2 mM of benzoate. 4. The pharmaceutical composition of claim 1 of the patent scope, wherein the genus The ratio of fumarate or a physiologically functional derivative thereof to diazepam or its physiologically functional derivative is from about 1:1 to about 10:1 by weight. 5. The pharmaceutical composition according to claim 1, wherein the difufosyl diisopropoxycarbonyloxymethyl fumarate or a physiologically functional derivative thereof 1355270 and the saponin or its physiology The functional derivative is present in an amount of from about 1 mg to about 1000 mg per unit dosage form. 6. The pharmaceutical composition of claim 5, wherein the novovir diisopropoxycarbonyloxymethyl ester is rich. The content of the horse salt or its physiologically functional derivative and the saponin or its physiologically functional derivative is about 1 mg to about 300 mg per unit dosage form respectively. 7. The pharmacy composition as claimed in claim 1 And containing [2-(6-amino-indol-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid·diisopropyl Yl carbonyloxy methyl ester fumarate (days Nuofu Wei diisopropoxy methyl ester carbonyl oxygen of the fumarate) or a physiologically functional derivative thereof; and a compound of the formula: Wherein B is selected from the group consisting of adenine, guanine, cytosine, uracil, thymine, 7-deaza adenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza -8-azadenine, inosine, nebularine, nitropyrrol, nitroguanidine, 2-aminopurpur, 2-amino-6-chloropurine, 2,6- Diaminoguanidine, hypoxanthine, pseudouridine, 5-fluorocytosine, 5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine, pseudoisopram (pseudoisocytosine), 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2_thiopyrimidine, 6-thioguanine, 4-thiothymidine, 4-thio Uropirin, indole 6-methylguanine, N6-methyladenine, indole 4-methylthymidine, 5,6-dihydrothymidine, 5,6-dihydrouracil, 4-methylindole哚, and mouth ratio -2 - 1355270 oxazolyl, c2-c ester, 1,3-ΐ in the group, 5S)-( (2' mixed product [3,4-D啼 定 π 定; and the system from H CVCl8 alkyl, Ci-Cu substituted alkyl, h e &quot; C 2 c18fe substituted dilute group, C2_Ci8 fluorenyl group, c2_c" substituted fast C6_C2g aryl group, C6_C2 fluorene substituted aryl group, h en heteroaryl group, 2. substituted heteroaryl group, phosphonate, phosphophosphonate, phosphine diphosphate Acid phosphate, diphosphate, triphosphate, polyvinyloxy, or prodrug. 8. A pharmaceutical composition according to the scope of the application of the invention, wherein one component of the composition is (2R, 5S, cis) 4-amino-1-(2-hydroxymethyl-oxothothan-5-yl)-(iH)-pyrimidin-2-one (3TC). 9. Pharmaceutical composition according to claim 1 , wherein the composition is a physiologically functional derivative of the octopine, which is an enantiomer (2R 'cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3- Othothane-5-yl 1H)-pyrimidin-2-one with (2S,5R,cis)-4-amino-5-fluoro-1-methyl-1,3-oxothane-5- A pharmaceutically acceptable composition of the formula (1H)-pyrimidin-2-one. The pharmaceutical composition according to claim 1, wherein the group comprises fenoflavin diisopropoxy having the following structural formula: Physiological functional derivatives of methyl oxomethionate: 1355270 R7YR6 Wherein R1 and R2 are each independently selected from the group consisting of H, Ci-Cs alkyl, C^-Ce substituted alkyl, C6-C2Q aryl, C6-C2Q substituted aryl, C6-C2Q aralkyl, C6-C2 〇 Substituted aralkyl 'meroxymethyl ester-CH2OC (=0) R9, and cesium carbonate-oxy-methyl ester-CH2〇C-(=0) OR9, wherein R9 is C+-C6 alkyl, Ci- Ce substituted alkyl, C6-C2G aryl, or C6-C2G substituted aryl; R3 is selected from fluorene, fluorenyl 6 alkyl, Ci-C^ substituted alkyl, or CH2OR8, wherein. -. An alkyl 'Ci-Ce hydroxyalkyl group, or a haloalkyl group; R4 and R5 are each independently selected from the group consisting of H, NH2, NHR and NR2, wherein R is a Q-Cfi alkyl group; and R6 and R7 are each independently selected from H&amp;C1 a -C6 alkyl group; or a pharmaceutically acceptable salt or solvate thereof. A pharmaceutical composition according to claim 10, wherein at least one of R1 and R2 is -CH20C(=0)C(CH3)3. 12. The pharmaceutical composition of claim 10, wherein at least one of R1 and R2 is -CH20C(=0)0C(CH3)3. A pharmaceutical composition according to claim 10, wherein at least one of R1 and -4-1355270 R2 is -CH2OC(=0)OCH(CH3)2. 14. The pharmaceutical composition of claim 1, wherein the animal is a human. The pharmaceutical composition of claim 1, wherein the composition further comprises a third antiviral agent. The pharmaceutical composition of claim 15, wherein the third antiviral agent is selected from the group consisting of a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), and a non-nucleoside reverse transcriptase. Inhibitors (NNRTI), and integrase inhibitors. 1 7. The pharmaceutical composition of claim 16 wherein the third antiviral agent is 9-[R-2-[[S)-[[(S)-l-(isopropoxy) Carbonyl)ethyl]amino]-phenoxyphosphino]methoxy]propyl]adenine (GS-7340). 18. The pharmaceutical composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable slip agent. 19. The pharmaceutical composition of claim 18, wherein the slip agent is selected from the group consisting of cerium oxide, powdered cellulose, microcrystalline cellulose, metal stearate, sodium aluminosilicate, sodium benzoate, carbonic acid Calcium, calcium citrate, corn starch, magnesium carbonate, talc without asbestos, stearowet C, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof. The pharmaceutical composition of claim 19, wherein the metal stearate is selected from the group consisting of calcium stearate, magnesium stearate, zinc stearate, and combinations thereof. A pharmaceutical composition according to claim 1, wherein the further -5 to 1355270 contains one or more pharmaceutically acceptable carriers or excipients. 22. The pharmaceutical composition of claim 21, wherein the pharmaceutically acceptable carrier or excipient is selected from the group consisting of pregelatinized starch, crosarmellose sodium, and bismuth. Povidone, lactose monohydrate, microcrystalline cellulose, magnesium stearate, and combinations thereof. 23. The pharmaceutical composition of claim 1 of the patent application, which is suitable for oral administration. 24. A pharmaceutical composition according to item 1 of the patent application, which is in the form of a troche or a capsule. 2 5. The pharmaceutical composition according to claim 1 of the patent application, which comprises a physiological functional derivative of tabin, ie (2R, 5S, cis)-4-amino-1-(2-hydroxyl) a 1,3- oxathiazol-5-yl)-(111)-pyrimidin-2-one (31'(:) 〇26. The pharmaceutical composition of claim 16, wherein the third The antiviral agent is NNRTI or PI. 27. The pharmaceutical composition according to claim 26, wherein the third antiviral agent is PI. 28. The pharmaceutical composition according to claim 26, wherein the first The three antiviral agents are NNRTIs. 29. The pharmaceutical composition according to claim 16, wherein the second antiviral agent is selected from the group consisting of Reyataz, Kaletra and Chetiva. (Sustiva) 30. The pharmaceutical composition of claim [01], which is a pharmaceutical preparation for oral administration, which contains -6- 1355270 fumarate containing fenoflavin diisopropoxycarbonyloxymethyl ester. Retaining Tabin and Reyataz. 3 1. A pharmaceutical composition according to claim 29, which is a pharmaceutical preparation for oral administration, which contains a genus a fumarate of isopropoxycarbonyloxymethyl ester, which is obtained by the use of a pharmaceutical composition according to claim 29, which is an oral pharmaceutical preparation containing The fumarate of dinofenoxycarbonyloxymethyl ester, the saponin and the Sustiva. 33. For the treatment or prevention of symptoms or effects of HIV infection in infected animals. a kit comprising [2-(6-amino-indol-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid/diisopropoxycarbonyloxymethyl ester in a chamber Fumarate (Dinoprovir diisopropoxycarbonyloxymethyl fumarate) or a physiologically functional derivative thereof; and (2 R, 5 S, cis)-4- in another chamber Amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiazin-5-yl)-(1H)-pyrimidin-2-one (Tabatin) or its physiologically functional derivative Wherein the components of the two compartments can be administered in combination or alternately; and wherein the fernyl diisopropoxycarbonyloxymethyl fumarate or a physiologically functional derivative thereof The ratio of physiological functional derivatives is from about 1:50 to about 50: The weight ratio of 1 is 34. The kit of claim 33, wherein the fumarate or its physiologically functional derivative of fenoflavin diisopropoxycarbonyloxymethyl can be used with the sampan Or a physiologically functional derivative thereof is applied alternately. 3 5. A kit according to claim 33, wherein the fumarate or its physiologically functional derivative of fenoflavin diisopropoxycarbonyloxymethyl ester Take Tupper or its physiologically functional derivative, which can be administered in a single combination of formulas and 1355270. 3 6. The kit of claim 35, wherein the single combination formulation is administered to the infected animal once daily. 37. A kit for treating or preventing a symptom or effect of HIV infection in an infected animal, comprising [2-(6-amino-indol-9-yl)· 1-methyl-ethoxy Methyl]-phosphonic acid•diisopropoxycarbonyloxymethyl ester of fumaric acid φ salt (Dinoprovir diisopropoxycarbonyloxymethyl fumarate), and (2R, 5S, cis )-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiazin-5-yl)-(1H)-pyrimidin-2-one (Tabatin); Description of the data, - the imitation list contains instructions for the combination of fumarate for dinofosine diisopropoxycarbonyloxy vinegar and ampazin; The ratio of the fumarate of the carbonyloxymethyl ester to the octabutene is from about 1:50 to about 50:1 by weight. 3 8. A kit for a patient according to the scope of claim 37, which comprises a fumarate of 100 to 1000 mg of fenoflavin diisopropoxycarbonyloxymethyl ester and 100 to 1000 The milligrams are taken from the nine doses, tablets or capsules prepared by Tabin. 39. A kit for a patient according to claim 38, which comprises the preparation of a fumarate via 300 mg of fenoflavin diisopropoxycarbonyloxymethyl ester and 200 mg of an acantatin. Nine doses, lozenges or capsules obtained. 40. A kit for a patient according to claim 37 of the patent application, which comprises 100 to 1000 mg of fenoflavin diisopropoxycarbonyloxymethyl ester. Nine doses, lozenges or 1355270 capsules separately packaged with 100 to 1 000 mg of Tamarin. 41. A kit for a patient according to claim 40, which comprises a package of 300 mg of dinuclear diisopropoxycarbonyloxymethyl fumarate and 200 mg of Tamper. Agent, lozenge or capsule. -9-