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CN115028594A - Emotitabine medicinal precursor compound and preparation method and medical application thereof - Google Patents

Emotitabine medicinal precursor compound and preparation method and medical application thereof Download PDF

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CN115028594A
CN115028594A CN202010503226.9A CN202010503226A CN115028594A CN 115028594 A CN115028594 A CN 115028594A CN 202010503226 A CN202010503226 A CN 202010503226A CN 115028594 A CN115028594 A CN 115028594A
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entitabine
composition
precursor compound
treatment
dosage form
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吴卫东
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Abstract

The invention discloses an enticitabine medicinal precursor compound, a preparation method and medical application thereof, relates to the field of pharmaceutical and chemical research, constructs a novel nucleoside analogue and a precursor compound thereof, competitively occupies multi-phosphorylase, integrase and polymerase, specifically inhibits the replication of S-phase cell DNA and RNA, and is used for producing novel anticancer and antiviral medicaments. Novel nucleoside analogs 6-amino-4-amino-2-one-1- [ [ hydroxyl ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine, named enticitabine, are disclosed; a novel nucleoside analogue and its precursor are disclosed, its general structure, chemical structure, preparing process, purifying process, composition and medical application are disclosed.

Description

Emotitabine medicinal precursor compound and preparation method and medical application thereof
Technical Field
The invention relates to the field of pharmaceutical chemicals, and belongs to the category of original research and development of a new national medicine
Background
The novel nucleoside analogue and the precursor compound thereof related to the invention have similar design principle with the pharmacophore of the following anticancer and anti-virus drugs, and the specific analysis is as follows:
acyclovir is a nucleoside analogue [8] It can be used for treating herpes virus infection. The medicines of the same series are ganciclovir, valacyclovir, penciclovir and the like, which all belong to antiviral medicines. The ring-opening chain-shaped group is adopted to replace a ribofuranose group of guanosine, and a differential group modification is provided.
Cytarabine is a nucleoside analogue used in the treatment of leukemia. The arabinoside is adopted to replace the riboside group of cytosine nucleoside, and the method has a differentiation group transformation.
Azacitidine [2] Is a nucleoside analogue, and is used for MDS and leukemia treatment. The molecular chemical structure consists of an arabinoside group and an azacytosine group, and two differential group modifications are provided.
Lamivudine is a nucleoside analogue, adopts a sulfur-containing ring group to replace a ribose group of cytosine nucleoside, and has two differential group modifications.
Decitabine [3] Is a nucleoside analogue, and can be used for treating leukemia. The molecular chemical structure is composed of a deoxyglycoside group and an azacytosine group, and two differential group modifications are provided.
Gemcitabine [6] The nucleoside analogue is prepared by substituting a dideoxy nucleoside group for a nucleoside group, introducing two fluorine atoms and modifying three differential groups; has a broad spectrumAnd (4) anticancer activity. It can be used for treating lung cancer, pancreatic cancer, breast cancer, bladder cancer, ovarian cancer, and non-small cell advanced cases.
Disclosure of Invention
By constructing a novel nucleoside analogue and a precursor compound thereof which are combined by diversification, differentiation and structure optimization, polyphosphoric acid enzyme, polymerase, transcription enzyme and reverse transcription enzyme in S-phase cells are competitively occupied [11] Inhibiting cancer cells [10] And viral DNA and RNA replication process, and is expected to realize anticancer and antiviral effects [12] The medicine has the advantages of broad spectrum, high efficiency, radical cure and low side effect.
A novel nucleoside analog named 6-amino-4-amino-2-one-1- [ [ hydroxy ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine is disclosed.
Discloses the monophosphorylated nucleotide produced by the in vivo metabolism of the novel nucleoside analog [8] The chemical name of the analogue is 6-amino-4-amino-2-ketone-1- [ [ [ di- [ hydroxyl ] oxy]Oxygen phosphorus radical]Oxymethyl radical][ [ trifluoromethyl group ]]Ethyl radical]]-1, 3, 5-triazine, named empitabine monophosphorylated.
Discloses a diphosphorylation nucleotide analogue generated by the novel nucleoside analogue through in vivo metabolism, the chemical name is 6-amino-4-amino-2-ketone-1- [ [ [ [ [ [ di- [ hydroxyl ] oxyphosphoryl ] oxy ] [ [ hydroxyl ] oxyphosphoryl ] oxymethyl ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine, and the name is diphosphorylation entitabine.
Discloses triphosphorylated nucleotide analogs produced by in vivo metabolism of the novel nucleoside analogs, having the chemical name of 6-amino-4-amino-2-one-1- [ [ [ [ [ [ [ [ [ [ [ di- [ hydroxyl ] oxyphosphoryl ] oxy ] [ [ hydroxyl ] oxyphosphoryl ] oxymethyl ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine, named as triphosphorylated entitabine.
Novel prodrug compounds of nucleoside analogs are disclosed having the chemical name 6-amino-4-amino-2-one-1- [ [ [ [ [ [ [ [ [ [ [ [ oxyethyl ] carbonyl ] methyl ] amino ] [ [ [ [ [ [ cyclohexyl ] oxy ] oxyphosphatyl ] ] oxymethyl ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine, named entitabine hydroxyphenol ester.
Novel carboxylated pharmaceutical precursor compounds of nucleoside analogs are disclosed, having the chemical name 6-amino-4-amino-2-one-1- [ [ [ [ [ [ [ [ [ [ oxyethyl ] carbonyl ] methyl ] amino ] [ [ [ [ cyclohexyl ] oxy ] phospho ] oxy ] oxymethyl ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine- [3- [3, 4-bis- [ hydroxy ] -phenyl ] -2-acrylate ], designated entitabine hydroxyphenol ester caffeate.
Discloses a general structure, a chemical structure, a preparation method, a purification method, a composition dosage form and medical application of the novel nucleoside analogue and a medicinal precursor compound thereof in the field of anticancer and antivirus.
Brief description of the contents
The invention relates to a novel nucleoside analogue which accords with the following general structure and a medicinal precursor compound thereof, a preparation method, a purification method, a composition dosage form and medical application thereof in the field of anticancer and antivirus for the compound; the groups in the chemical structure are selected from the following group definitions.
General structure
Figure RE-RE-GSB0000198834190000031
Radical definition
<01>E is selected from: -O, -S, -CH 2 ；
<02>D is selected from: -C, -C 2 H 2 ，-C 3 H 4 ，-C 4 H 6 ；
-C 5 H 8 ，-C 6 H 10 ，-C 7 H 12 ，-C 8 H 14 ；
<03>S is selected from: -PO, -PO 2 ，-PO 3 ，-P 2 O 4 H，-P 3 O 7 H 2 ；
<04>A is selected from: -H, -F, -CFH 2 ，-CF 2 H，-CF 3 ，-O，-CN，-NH 2 ；
<05>G is selected from: -H, -F, -CFH 2 ，-CF 2 H，-CF 3 ，-O，-CN，-NH 2 ；
<06>M is selected from: -H, -F, -CFH 2 ，-CF 2 H，-CF 3 ，-CN，-CH 3 ，-C 2 H 5 ，-C 3 H 7 ；
-C 4 H 9 ，-C 5 H 11 ，-C 6 H 13 ，-C 7 H 15 ，-C 8 H 17 ，-C 9 H 19 ，-C 10 H 21 ；
<07>N is selected from: -H, -F, -CFH 2 ，-CF 2 H，-CF 3 ，-CN，-CH 3 ，-C 2 H 5 ，-C 3 H 7 ；
-C 4 H 9 ，-C 5 H 11 ，-C 6 H 13 ，-C 7 H 15 ，-C 8 H 17 ，-C 9 H 19 ，-C 10 H 21 ；
<08>B is selected from: -H, -F, -CFH 2 ，-CF 2 H，-CF 3 ，-O，-CN，-NH 2 ；
<09>K is selected from: -CH 2 ，-C 2 H 4 ，-C 3 H 6 ，-C 4 H 8 ，-C 5 H 10 ，-C 6 H 12 ；
-C 7 H 14 ，-C 8 H 16 ，-C 9 H 18 ，-C 10 H 20 ；
<10> Q is selected from: -1, 2, 3-Tri-azine; -1, 2, 4-Tri-azine; -1, 3, 5-Tri-azine;
<11>r is selected from: -H, -OH, -CH 3 ，-C 2 H 5 ，-C 3 H 7 ，-C 4 H 9 ，-C 5 H 11 ，-C 6 H 13 ，-C 7 H 15 ；
-C 8 H 17 ，-C 9 H 19 ，-C 6 H 5 ，-C 7 H 7 ，-OCH 3 ，-OC 2 H 5 ，-OCH 3 H7，-OC 4 H 19 ；
-O-C 5 H 11 ，-O-C 6 H 13 ，-O-C 7 H 15 ，-O-C 8 H 17 ，-OC 9 H 19 ，-O-C 6 H 5 ；
-O-C 3 H 5 ，-O-C 4 H 7 ，-O-C 5 H 9 ，-O-C 6 H 11 ，-O-C 7 H 13 ，-O-C 8 H 17 ；
-OC 7 H 7 ，-OCH 2 -OCOOCH 3 ，-OCH 2 -OCOO-C 2 H 5 ，-OCH 2 OCOOC 3 H 7 ；
-O-C 8 H 9 ，-CH 2 -OCOO-CH 3 ，-CH 2 -OCOO-C 2 H 5 ，-CH 2 -OCOOC 3 H 7 ；
-NH-CH 2 -CO-O-CH 3 ，-NH-CH 2 -COO-C 2 H 5 ，-NH-CH 2 COO-C 3 H 7 ；
-NH-CH 2 -COO-C 4 H 9 ，-NH-CH 2 -COOC 5 H 11 ，-NH-CH 2 -COO-C 6 H 13 ；
-NH-CH 2 -COO-C 7 H 15 ，-NH-C 2 H 4 COO-CH 3 ，-NHC 2 H 4 -COO-C 2 H 5 ；
-NH-C 2 H 4 -COOC 3 H 7 ，-NH-C 2 H 4 -COOC 4 H 9 ，-NH-C 2 H 4 COO-C 5 H 11 ；
-NH-C 2 H 4 -COOC 6 H 13 ，-NH-C 2 H 4 -COOC 7 H 15 ，-NH-C 3 H 6 COO-CH 3 ；
-NH-C 3 H 6 COOC 2 H 5 ，-NH-C 3 H 6 -COO-C 3 H 7 ，-NH-C 3 H 6 COO-C 4 H 9 ；
-NH-C 3 H 6 COO-C 5 H 11 ，-NH-C 3 H 6 COOC 6 H 13 ，-NH-C 3 H 6 -COOC 7 H 15 ；
-NH-C 4 H 8 COO-CH 3 ，-NH-C 4 H 8 -COOC 2 H 5 ，-NH-C 4 H 8 -COO-C 3 H 7 ；
-NH-C 4 H 8 COOC 4 H 9 ，-NH-C 4 H 8 COO-C 5 H 11 ，-NH-C 4 H 8 COO-C 6 H 13 ；
-NH-C 4 H 8 COO-C 7 H 15 ，-NH-C 5 H 10 COO-CH 3 ，-NH-C 5 H 10 COOC 2 H 5 ；
-NH-C 5 H 10 COOC 3 H 7 ，-NH-C 5 H 10 COOC 4 H 9 ，-NH-C 5 H 10 -COOC 5 H 11 ；
-NH-C 5 H 10 COOC 6 H 13 ，-NH-C 5 H 10 COOC 7 H 15 ，-NH-C 6 H 12 COOCH 3 ；
-NH-C 6 H 12 -COOC 2 H 5 ，-NH-C 6 H 12 -COOC 3 H 7 ，-NHC 6 H 12 COOC 4 H 9 ；
-NH-C 6 H 12 COOC 5 H 11 ，-NH-C 6 H 12 COOC 6 H 13 ，-NH-C 7 H 14 -COO-CH 3 ；
-NH-C 6 H 12 COOC 7 H 15 ，-NH-C 7 H 14 COO-C 2 H 5 ，-NHC 7 H 14 COOC 3 H 7 ；
-NH-C 7 H 14 COOC 4 H 9 ，-NH-C 7 H 14 COOC 5 H 11 ，-NH-C 7 H 14 COOC 6 H 13 ；
-NH-C 7 H 14 COOC 7 H 15 ，-NHC 8 H 16 -COOCH 3 ，-NH-C 8 H 16 -COOC 2 H 5 ；
-NH-C 8 H 16 COOC 3 H 7 ，-NH-C 8 H 16 COOC 4 H 9 ，-NH-C 8 H 16 -COOC 5 H 11 ；
-NH-C 8 H 16 COOC 6 H 13 ，-NH-C 8 H 16 COOC 7 H 15 ，-NHC 8 H 16 COOC 8 H 17 ；
-NH-C 9 H 18 COOC 2 H 5 ，-NH-C 9 H 18 COOC 3 H 7 ，-NHC 10 H 20 COOC 4 H 9 ；
<12>T is selected from: -H, -OH, -CH 3 ，-C 2 H 5 ，-C 3 H 7 ，-C 4 H 9 ，-C 5 H 11 ，-C 6 H 13 ，-C 7 H 15 ；
-C 8 H 17 ，-C 9 H 19 ，-C 6 H 5 ，-C 7 H 7 ，-OCH 3 ，-OC 2 H 5 ，-OCH 3 H 7 ，-OC 4 H 9 ；
-O-C 5 H 11 ，-O-C 6 H 13 ，-O-C 7 H 15 ，-O-C 8 H 17 ，-OC 9 H 19 ，-O-C 6 H 5 ；
-O-C 3 H 5 ，-O-C 4 H 7 ，-O-C 5 H 9 ，-O-C 6 H 11 ，-O-C 7 H 13 ，-O-C 8 H 17 ；
-OC 7 H 7 ，-OCH 2 -OCOOCH 3 ，-OCH 2 -OCOO-C 2 H 5 ，-OCH 2 OCOOC 3 H 7 ；
-O-C 8 H 9 ，-CH 2 -OCOO-CH 3 ，-CH 2 -OCOO-C 2 H 5 ，-CH 2 OCOO-C 3 H 7 ；
-NH-CH 2 -CO-O-CH 3 ，-NH-CH 2 -CO-O-C 2 H 5 ，-NH-CH 2 COO-C 3 H 7 ；
-NH-CH 2 -COO-C 4 H 9 ，-NH-CH 2 -COOC 5 H 11 ，-NH-CH 2 -COO-C 6 H 13 ；
-NH-CH 2 -COO-C 7 H 15 ，-NH-C 2 H 4 COO-CH 3 ，-NH-C 2 H 4 -COO-C 2 H 5 ；
-NH-C 2 H 4 -COOC 3 H 7 ，-NH-C 2 H 4 -COOC 4 H 9 ，-NH-C 2 H 4 COO-C 5 H 11 ；
-NH-C 2 H 4 -COOC 6 H 13 ，-NH-C 2 H 4 -COOC 7 H 15 ，-NH-C 3 H 6 COO-CH 3 ；
-NH-C 3 H 6 COO-C 2 H 5 ，-NH-C 3 H 6 -COO-C 3 H 7 ，-NH-C 3 H 6 COO-C 4 H 9 ；
-NH-C 3 H 6 COO-C 5 H 11 ，-NH-C 3 H 6 COOC 6 H 13 ，-NH-C 3 H 6 -COOC 7 H 15 ；
-NH-C 4 H 8 COO-CH 3 ，-NH-C 4 H 8 -COOC 2 H 5 ，-NH-C 4 H 8 -COO-C 3 H 7 ；
-NH-C 7 H 14 COOC 4 H 9 ，-NH-C 7 H 14 COOC 5 H 11 ，-NH-C 7 H 14 COOC 6 H 13 ；
-NH-C 4 H 8 COO-C 7 H 15 ，-NH-C 5 H 10 COO-CH 3 ，-NH-C 5 H 10 COOC 2 H 5 ；
-NH-C 5 H 10 COOC 3 H 7 ，-NH-C 5 H 10 COOC 4 H 9 ，-NH-C 5 H 10 -COOC 5 H 11 ；
-NH-C 5 H 10 COOC 6 H 13 ，-NH-C 5 H 10 COOC 7 H 15 ，-NH-C 6 H 12 COOCH 3 ；
-NH-C 6 H 12 -COOC 2 H 5 ，-NH-C 6 H 12 COOC 3 H 7 ，-NH-C 6 H 12 COOC 4 H 9 ；
-NH-C 6 H 12 COOC 5 H 11 ，-NH-C 6 H 12 COO-C 6 H 13 ，-NH-C 7 H 12 COOCH 3 ；
-NH-C 6 H 12 -COOC 7 H 15 ，-NH-C 7 H 14 COO-C 2 H 5 ，-NH-C 7 H 14 COOC 3 H 7 ；
-NH-C 7 H 14 COOC 4 H 9 ，-NH-C 7 H 14 COOC 5 H 11 ，-NH-C 7 H 14 COOC 6 H 13 ；
-NH-C 7 H 14 COOC 7 H 15 ，-NH-C 8 H 16 -COOCH 3 ，-NH-C 8 H 16 -COOC 2 H 5 ；
-NH-C 8 H 16 COOC 3 H 7 ，-NH-C 8 H 16 COOC 4 H 9 ，-NH-C 8 H 16 -COOC 5 H 11 ；
-NH-C 8 H 16 COOC 6 H 13 ，-NH-C 8 H 16 COOC 7 H 15 ，-NHC 9 H 18 -COOCH 3 ；
-NH-C 9 H 18 COO-C 2 H 5 ，-NH-C 9 H 18 COOC 3 H 7 ，-NH-C 9 H 18 COOC 4 H 9 ；
-NH-C 9 H 18 COOC 5 H 11 ，-NH-C 9 H 16 COOC 6 H 13 ，-NHC 9 H 16 COOC 7 H 15 。
Drawings
FIG. 1 is a general structural diagram; english letters in the general structure represent compound groups, and each thin line represents a chemical bond;
FIG. 2 is a chemical structure of enticitabine; containing a hydrogen group, a ketone group, a hydroxyl group, a parent-ring aza group, an ethyl group, a methyl group, a fluorine group, an amino group, a triazine group;
FIG. 3 is a chemical structure diagram of monophosphorylated entitabine; containing a hydrogen group, a ketone group, an oxy group, a parent-ring aza group, an ethyl group, a methyl group, a hydroxyl group, a fluoro group, an amino group, a triazine group, an oxyphosphoryl group, an oxymethyl group;
FIG. 4 is a chemical structure of empitabine diphosphonate; containing a hydrogen group, a ketone group, an oxy group, a parent-ring aza group, an ethyl group, a methyl group, a hydroxyl group, a fluoro group, an amino group, a triazine group, an oxyphosphoryl group, an oxymethyl group;
FIG. 5 is a chemical structure diagram of empitabine triphosphorylate; containing a hydrogen group, a ketone group, an oxy group, a parent-ring aza group, an ethyl group, a methyl group, a hydroxyl group, a fluoro group, an amino group, a triazine group, an oxyphosphoryl group, an oxymethyl group;
FIG. 6 is a chemical structure diagram of an emtabine diphenol ester; a hydrogen-containing group, a ketone group, an oxy group, a methyl group, a fluoro group, a triazine group, an oxyphosphoryl group, an oxymethyl group, an amino group, a carbonyl group, a parent-ring aza group, an oxyethyl group, an ethyl group, a cyclohexyl group;
FIG. 7 is a chemical structure of emtricitabine hydrogen phenol ester caffeate; containing a hydrogen group, a ketone group, an oxy group, a methyl group, a fluoro group, a triazine group, an oxyphosphoryl group, an oxymethyl group, an amino group, a carbonyl group, a parent-cyclic aza group, an oxyethyl group, an ethyl group, a cyclohexyl group, a phenyl group, an acrylic group;
Detailed Description
Four differential transformation measures are adopted, five groups with unique functions and differential and structure optimization are adopted to construct a novel entitabine nucleoside analogue and a medicinal precursor compound thereof, and the specific implementation mode is as follows:
1. the triazinone is adopted as a mother ring of the novel nucleoside, uric acid is not produced during metabolism, and side effects are obviously reduced:
some nucleoside antiviral drugs taking purine as a mother ring produce uric acid in the metabolic process, cause gout and skeleton deformation, and also have side effects on the urinary system. The triazine ketone is used as a mother ring of a novel nucleoside, uric acid is not produced in the metabolic process, and related side effects are obviously reduced.
2. The triazine ketone is adopted as a mother ring of the novel nucleoside, and the anticancer and antiviral activity of the medicament is obviously improved:
the novel nucleoside analogue is formed by adopting the triazinone and the chain-shaped group, and is converted into the triphosphorylated nucleotide analogue through the in vivo metabolic process, so that the cell efflux is reduced, the blood brain barrier transmission capacity is improved, the drug solubility and the absorption efficiency are improved, and the pharmacodynamic activity of the triazinone group is favorably exerted. By adopting the combination of the pharmacophores, the anticancer and antiviral activity of the entinostat precursor compound is obviously improved.
Because the entitabine medicinal precursor compound is converted into the triphosphorylated nucleotide analogue through in vivo metabolism, the entitabine medicinal precursor compound competitively occupies the polyphosphatase, the transcriptase and the reverse transcriptase required in the process of establishing the new DNA and RNA chains, plays a multiple inhibition role in the proliferation process of cancer cells and viruses and realizes the dual targets of broad spectrum and high efficiency.
3. The novel nucleoside is constructed by adopting trifluoromethyl and chain-shaped groups, so that the drug resistance is reduced, and the curative effect is obviously improved:
trifluoromethyl is an important medicinal chemical group and has the characteristics of high fat solubility, good metabolic stability, high electronegativity and high bioavailability. Because the trifluoromethyl group comprises three fluorine atom groups, the trifluoromethyl group is adopted to construct a novel nucleoside analogue chemical molecular structure, and the number of the groups for differential modification is multiplied; by adopting the ring-opening chain-like group, the characteristics of the differentiated modified group are obviously improved, and the drug resistance is obviously reduced; the combined structure of the two groups is used for constructing the core structure of the entitabine medicinal precursor compound related to the patent of the invention, so that the effect of overlapping drug effects can be obtained, the curative effect is improved, the selectivity is improved, the radical cure effect is improved, the drug resistance is reduced, and the side effect is reduced.
4. The novel nucleoside is constructed by adopting five differential groups, and the goals of broad-spectrum high-efficiency anticancer and antivirus are realized:
by comparative analysis of chemical structures of anticancer and antiviral drugs on the market, the drugs mainly take a nucleoside analogue form as a core structure, 1 to 3 differential modification groups exist in a molecular structure, and the differential modification rate is only 20 to 30 percent.
The chemical structure of the novel entitabine nucleoside analogue related to the patent of the invention is completely composed of five differentiation groups, the number of the differentiation modified groups is increased by 2-4 times, and the differentiation modified rate is as high as 100%; because all the differential modification groups are optimized, the entitabine medicinal precursor compound has a substance basis with broad-spectrum efficient anticancer and antiviral effects.
The numbers of carbon, nitrogen and fluorine on the periodic table are adjacent, and the chemical properties are greatly different. The nitrogen atom and the fluorine atom are adopted to construct the molecular structure of the nucleoside analogue, which is beneficial to improving the curative effect of the medicament.
In the design stage of the molecular structure of the drug, a series of problems such as drug resistance, efflux mechanism, blood brain barrier, blood concentration, intracellular concentration, half-life period, drug side effect, acute and chronic oral toxicity, reproductive toxicity, minimum effective dose, drug solubility, drug absorption efficiency, broad spectrum, high efficiency, radical treatment effect and the like need to be comprehensively solved, and the specific analysis is as follows;
1. the drug resistance mechanism of anticancer drugs is a major factor causing death of cancer patients:
when the wild Tp53 gene is mutated in the body of a patient, the gene can not transmit the instructions about cancer cell apoptosis sent by the anti-cancer drug, and the cancer patient can fall into the predicament of no drug and can die in a short time. After the monophosphorylated entitabine nucleotide analog enters cancer cells, the monophosphorylated entitabine nucleotide analog and the triphosphorylated entitabine nucleotide analog are converted under the catalytic occupation of polyphosphatase, and the polyphosphatase and the polymerase required by the replication of the cancer cells are competitively occupied, so that the proliferation process of the cancer cells is directly inhibited. Although cancer cell replication takes DNA as a template, protooncogene expression is closely related to RNA type virus infection, and the effect of indirectly inhibiting protooncogene expression is achieved by competitively consuming the polyphosphatase and the reverse transcriptase required for RNA type virus replication; this multiple inhibition of cancer cell proliferation is independent of the transduction of the P53 signaling pathway. Therefore, the entitabine prodrug compound can bypass the drug resistance mechanism of the anticancer drug.
2. The efflux mechanism obviously reduces the intracellular concentration of the drug and the stability of the curative effect:
the efflux mechanism is an important measure for the self-protection of cell tissues; the anticancer antiviral drug is also excreted out of the cell as a foreign substance by an efflux mechanism, resulting in a rapid decrease in the intracellular concentration of the drug. The entitabine medicinal precursor compound is converted into nucleotide analogs in vivo, has the same cell affinity as nucleotides, can bypass an efflux mechanism, and keeps higher intracellular concentration and curative effect stability.
3. The barrier effect of the blood brain barrier on the medicine seriously influences the curative effect of the medicine
Many anticancer and antiviral drugs are difficult to enter the cerebral nervous tissue due to the blood-brain barrier function; after the rabies viruses enter the brain tissues, the killing effect of antiviral medicaments is avoided, and the illness state is rapidly out of control; after the cancer cells are transferred to the brain, the killing function of the anti-cancer drugs is eliminated, and the disease condition is out of control. It is concluded that the virus and cancer cells use the cranial nerve tissue as a breeding ground and evade the killing effect of anticancer and antiviral drugs under the sheltering effect of the blood brain barrier. The monophosphorylentitabine nucleotide analog has nucleotides [8] The same blood brain barrier penetrating capacity, has the effect of killing viruses and cancer cells hidden in the blood brain barrier, and realizes the broad-spectrum efficient anticancer and antiviral target.
4. The quantity and quality of the groups optimized and modified in a differentiation way are closely related to the curative effect of the medicine:
the number of differentiated groups in the chemical structure of the entitabine nucleoside analogue is increased by 2-4 times respectively, and each group is optimized and modified, so that the entitabine nucleoside analogue has good pharmaceutical activity. Therefore, the anticancer and antiviral activity of the entitabine medicinal precursor compound is also improved by times.
5. The preparation of the precursor compound is an effective method for improving the curative effect of the medicament:
because the entecavir nucleoside analogue is modified by adopting a high-efficiency active group to prepare the medicinal precursor compound, the intracellular concentration and the half-life period of the medicament are obviously improved, the minimum effective dose is obviously reduced, and the double aims of high curative effect and low side effect are realized.
6. The influence of the target selectivity generated by the change of the content of the multi-phosphorylase on the curative effect of the medicament:
the HIV belongs to a reverse transcription type double-strand positive-strand RNA virus, replication is completed within 48 hours, wherein 33 hours are used for the reverse transcription process, and 100 hundred million new HIV viruses are generated every day; the influenza virus belongs to a positive myxovirus and a single-strand negative strand RNA virus, and has a replication cycle of only 8 hours because a reverse transcription process is not required; the Ebola virus belongs to a biohazard 4-grade virus, belongs to a single-strand negative strand RNA type filamentous virus, has a remarkable replication speed, and can generate ten thousand new Ebola viruses after one Ebola virus is replicated for several hours. The average life span of platelets is 7-10 days; the average life span of the white blood cells is 7-14 days; the average life span of the red blood cells is 100-120 days; the average life span of lymphocytes is 300 days; the lifespan of hepatocytes is 5 months; human population cells were split once in 2.4 years; the life span of the brain nerve cells is 110 years.
From the above two groups of data, it is found that the virus is in a fast replication state, and the human cells are in a relatively stable state. Because the concentration of the polyphosphoric acid enzyme in the cells shows the periodic change rule and the concentration values are very different, by utilizing the characteristic, the polyphosphoric acid enzyme is taken as a target, a period-specific cell inhibitor can be developed, and the aim of inhibiting the replication of cancer cells and viruses in a targeted manner is fulfilled.
After the entitabine medicinal precursor compound enters a human body, the entitabine medicinal precursor compound is converted into a monophosphorylation entitabine nucleotide analogue through a physiological metabolic process; since cancer cells and virus-infected cells contain abundant polyphosphatase, the monophosphorylentitabine nucleotide analog will be successfully converted into diphosphorylated and triphosphorylated nucleotide analog forms and participate in the construction of new strands of DNA and RNA.
Because the novel triphosphorylation entitabine nucleotide analogue has a large number of differential modification groups, after a large amount of doping occurs, a huge number of error point positions are generated in the structure of the newly-built DNA and RNA supermolecule, so that the virus replication process enters a disordered state, and finally, the replication failure of virus-infected cells is caused and the cells enter an apoptosis program. The majority of viruses require polyphosphatase for replication, and the targeting selectivity generated based on the change of the content of the polyphosphatase has a broad-spectrum antiviral function. Due to the lack of sufficient quantities of the polyphosphatase in the non-proliferating cells, the monophosphorylentitabine nucleoside analog cannot be successfully converted into the diphosphorylated and triphosphorylated nucleotide forms, and is insensitive to such cells. The target selectivity based on the content change of the polyphosphoric acid enzyme can not only obviously improve the curative effect of the medicine, but also reduce the side effect of the medicine.
7. Competitive occupation of integrase, polymerase, transcriptase and reverse transcriptase inhibits replication of cancer cells and virus-infected cells
The replication process of the virus includes fusion, integration, transcription, translation, assembly and release links, and requires the coordination of polyphosphatase, integrase, polymerase, transcriptase and reverse transcriptase. Integrases are the viral own enzymes and are not present in the host cell; thus, competitive occupation of this enzyme can reduce the rate of viral replication. The DNA polymerase is an enzyme which synthesizes a new DNA strand by phosphodiester bond using triphosphorylated nucleotide as a substrate and DNA as a template. RNA polymerase, also called transcriptase, is an enzyme that synthesizes a new RNA strand by phosphodiester bonds using DNA and RNA as templates and triphosphorylated nucleotides as substrates. Reverse transcriptase is a polymerase specific to retroviruses, and synthesizes a complementary new DNA strand by phosphodiester bond using triphosphorylated nucleotides as a substrate and RNA as a template.
The entitabine nucleoside analogue firstly serves as a substrate of the polyphosphoric acid enzyme to synthesize monophosphorylated, diphosphorylated and triphosphorylated entitabine nucleotide analogues respectively, and occupies a large amount of resources of the polyphosphoric acid enzyme; and then serve as substrates for integrase, polymerase, transcriptase and reverse transcriptase, competitively occupying a large amount of enzyme resources. Therefore, by competitively occupying the enzymes, catalytic enzymes required by the replication of the cancer cells and the viruses can be in short supply, and each link of the replication process is inhibited, so that the aim of inhibiting the replication of the cancer cells and the viruses is fulfilled.
8. Anticancer antiviral effects of nucleotide depletion induced by triphosphorylated entitabine nucleotide;
due to the doping effect of a large amount of triphosphorylation entitabine nucleotides, the synthesized DNA and RNA new chains enter a scrapped state, and a large amount of nucleotide resources are consumed while a large amount of catalytic enzyme resources are occupied, so that catalytic enzymes and nucleotide raw materials required by the replication of cancer cells and viruses are in short supply at the same time, and the aim of inhibiting the replication of the cancer cells and the viruses is fulfilled.
9. The blood concentration of the medicament is controlled to be in the nanomolar order of magnitude, so that the side effect of the medicament is effectively reduced;
the magnitude of the side effects of the medicine is mainly determined by the molecular chemical structure of the medicine and is closely related to the dosage and blood concentration, so that the contradiction between the curative effect and the side effects is difficult to reconcile. The method for reducing the minimum effective dose of a drug by greatly improving the therapeutic effect of the drug has an advantage in that the effect of reducing the side effects of the drug can be obtained while ensuring a sufficient therapeutic effect. Because the lowest effective dose of the precursor compound of the entitabine nucleoside analogue is obviously reduced, the blood concentration is controlled to be in nanomolar order of magnitude, and the side effect of the drug can be obviously reduced; by strictly controlling the dosage of the medicine for women in the childbearing period, the pregnant period and the lactation period, the side effect of the medicine on fetuses and infants can be reduced.
10. Effect of drug solubility and absorption efficiency on efficacy:
in the stage of drug molecule design, the problems of drug solubility and absorption efficiency need to be considered in advance, and the negative influence caused by adding an auxiliary solvent in the preparation production process is avoided. Many drugs have solubility limitation, and a method of adding a cosolvent is adopted in the preparation process; because of the limitation of absorption efficiency, the intravenous administration mode is adopted, and the side effect and the administration difficulty of the medicine are increased. Because the problems are solved in the design stage of the molecular structure, the pharmaceutical preparation of the entitabine medicinal precursor compound does not need to add an organic solvent, and the related side effects are obviously reduced; because of better absorption efficiency, the medicine can be taken by oral route, thereby reducing the administration difficulty and being suitable for simple administration of chronic diseases and mild cases. And meanwhile, an intravenous drip preparation is prepared, is used for rapid administration of severe cases and is beneficial to rapidly controlling the state of an illness.
11. The complementary and potentiating effect of the combined dosage forms of the pharmaceutical composition on the therapeutic effect:
the medicinal precursor compound of the novel entitabine nucleoside analogue is mainly used for inhibiting the replication of DNA and RNA viruses; cancer cells use DNA strands as replication templates, and the expression of protooncogenes is closely related to RNA type virus infection. Therefore, the combination drug type composition dosage form containing the medicinal precursor compound of the novel nucleoside analogue can generate double inhibition effect on the DNA and RNA replication process, and achieve the double aims of broad-spectrum anticancer and antivirus.
12. The curative effect of radical cure is closely related to the molecular chemical structure of the medicine and the formula of the composition:
the number of differentiated groups in the chemical structure of the entitabine nucleoside analogue is respectively increased by 2-4 times, each group is optimized and modified, the entitabine nucleoside analogue has good pharmaceutical activity, a medicinal precursor compound is formed by adopting high-efficiency modified groups, and a combination drug type composition is adopted. The entitabine nucleoside analogue and the medicinal precursor compound thereof intensively embody the latest results of antiviral drug research, and obtain radical treatment effect while ensuring broad-spectrum and efficient side effects.
Because five differentiated and structurally optimized groups with unique functions are adopted to construct a novel nucleoside analogue molecular structure, the entitabine medicinal precursor compound has broad-spectrum, high-efficiency and antiviral activity, and the performances in all aspects are comprehensively improved.
1. Triazine ketone is adopted as a nucleoside analogue mother ring, uric acid is not produced during metabolism, and side effects are remarkably reduced:
2. the triazine ketone is adopted as a nucleoside analogue mother ring, and the anticancer and antiviral activity of the medicament is obviously improved:
3. the novel nucleoside is constructed by adopting trifluoromethyl and chain-shaped groups, so that the drug resistance is reduced, and the curative effect is obviously improved:
4. the novel nucleoside is constructed by adopting five differential groups, and the goals of broad-spectrum high-efficiency anticancer and antivirus are realized:
5. the novel nucleoside analogue is adopted as a core, so that the efflux is obviously reduced, and the intracellular concentration stability is obviously improved;
6. the novel nucleoside analogue is adopted as a core, the blood brain barrier penetrating power is improved, and the broad-spectrum and high-efficiency target is realized;
7. the novel nucleoside analogue is adopted as a core, and the targeting selectivity based on the concentration of the multi-phosphorylase is realized;
8. the novel nucleoside analogue is adopted as a core, so that the side effect of phosphorus deficiency of bones of a human body can be avoided;
9. the medicine is taken in the form of precursor compound, so that the effective dose is obviously reduced, and the half-life of intracellular concentration is improved;
10. the carboxylate medical precursor is adopted for medicine application, so that the solubility and the absorption efficiency of the medicine are obviously improved;
11. the carboxylate precursor composition is adopted for medicine application, and the DNA and RNA replication process is effectively inhibited;
12. twelve dosage forms and forty-eight medical purposes are adopted, and the requirements of broad spectrum, high efficiency, cancer resistance and virus resistance are met.

Claims (69)

1. General structures which are met by the nucleoside analogue and the medicinal precursor compound thereof; the letters in the formula are each a radical selected from any one of the radical definitions, and each thin line represents a bond:
Figure RE-FSB0000198834180000011
2. the molecular chemical structure of the nucleoside analogue conforms to the general structure and consists of any selected group in the group definitions; ring-opening chain type nucleoside analogues containing a triazineone group, a trifluoromethyl group, an amino group and a nitrile group are named, wherein one nucleoside analogue is entitabine, and the chemical structural formula is as follows:
Figure RE-FSB0000198834180000012
name: entita banks
Name: EMTROTABINE
Name: 6-amino-4-amino-2-one-1- [ [ hydroxy ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine
Name: 6-hydroxy-4-azyl-2-one-1- [ [ hydroxy ] [ [ Tri-fluoro-methyl ] eth-yl ] ] -1, 3, 5- [ Tri-azine ]
The molecular formula is as follows: c 6 H 7 O 2 N 4 F 3 Molecular weight: 224.15 development code: EMTRO-128607 #.
3. The molecular chemical structure of the monophosphorylated nucleoside analogue produced by the metabolism of the nucleoside analogue in vivo conforms to the general structure and consists of any selected group in the group definitions; ring-opening chain type monophosphoryl nucleoside analogues containing a triazineone group, a trifluoromethyl group, an amino group and a nitrile group are named, one of the compounds is monophosphoryl entitabine, and the chemical structural formula is as follows:
Figure RE-FSB0000198834180000021
name: mono-phosphorylated entitabine
Name: EMTROTABINE PHOSPHATE
The name is as follows: 6-amino-4-amino-2-one-1- [ [ [ bis- [ hydroxy ] oxyphosphatyl ] oxymethyl ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine
Name: 6-hydroxy-4-azyl-2-one-1- [ [ [ [ di-hydroxy ] phosphoryl ] methyl ] [ [ Tri-fluoro-methyl ] eth-yl ] ] -1, 3, 5- [ Tri-azine ]
Molecular weight: 318.16 molecular formula: c 7 H 10 O 5 N 4 PF 3 Research and development numbering: EMTRO-128608 #.
4. The nucleoside analogue is metabolized in vivo to produce a diphosphorylated nucleoside analogue having a molecular chemical structure conforming to the general structure and consisting of any selected group of the group definitions; the ring-opening chain type diphosphorylated nucleotide analogue containing a triazineone group, a trifluoromethyl group, an amino group and a nitrile group is named as diphosphorylated entitabine, and the chemical structural formula is as follows:
Figure RE-FSB0000198834180000031
name: emotitabine diphosphate
Name: EMTROTABINE DIPHOSPHOHATE
Name: 6-amino-4-amino-2-one-1- [ [ [ [ [ [ di- [ hydroxy ] oxyphosphatyl ] oxy ] [ [ hydroxy ] - [ oxyphosphatyl ] oxymethyl ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine
Name: 6-hydroxy-4-azyl-2-one-1- [ [ [ [ [ [ [ [ [ dihydroxy ] phoryl ] oxy ] [ [ hydroxy ] phoryl ] methyl ] ] -1, 3, 5- [ Tri-azine ]
Molecular weight: 398.49 molecular formula: c 7 H 11 O 8 N 4 P 2 F 3 Research and development numbering: EMTRO-128609 #.
5. The nucleoside analogue is metabolized in vivo to generate a triphosphorylated nucleotide analogue with a molecular chemical structure conforming to the general structure and consisting of any selected group of the group definitions; the ring-opening chain type triphosphorylated nucleotide analogue containing a triazineone group, a trifluoromethyl group, an amino group and a nitrile group is named as one of the compounds triphosphorylated entitabine, and the chemical structural formula is as follows:
Figure RE-FSB0000198834180000041
name: emotitabine triphosphorylate
The name is as follows: the extract of the plant of the species EmtroABINE Tripolyphosphate
Name: 6-amino-4-amino-2-one-1- [ [ [ [ [ [ [ [ di- [ hydroxy ] oxyphosphatyl ] oxy ] [ [ hydroxy ] oxyphosphatyl ] oxymethyl ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine
Name: 6-hydroxy-4-azyl-2-Oxo-1- [ [ [ [ [ [ [ [ [ [ [ [ dihydroxyl ] phosphoryl ] oxy ] [ [ hydroxyyl ] phosphoryl ] ] -1, 3, 5- [ Triazine ] ] -1
Molecular weight: 478.47 molecular formula: c 7 H 12 O 11 N 4 P 3 F 3 Research and development numbering: EMTRO-128610 #.
6. The chemical structure of the nucleoside analogue medicinal precursor compound conforms to the general structure and consists of any selected group in group definitions; the medicinal precursor compound of the ring-opening chain type nucleoside analogue containing the triazinone group, the trifluoromethyl group, the amino group and the nitrile group is named as one of the medicinal precursor compounds, namely the entitabine hydrogen phenol ester, and has the following chemical structure:
Figure RE-FSB0000198834180000051
name: entitabine hydroxyphenol ester
The name is as follows: EMTROTABINE HYDROFENAMIDE
The name is as follows: 6-amino-4-amino-2-one-1- [ [ [ [ [ [ [ [ [ [ [ oxyethyl ] carbonyl ] methyl ] amino ] [ [ [ [ [ [ [ cyclohexyl ] oxy ] phosphinyl ] ] oxymethyl ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazin e
Name: 6-dydryyl-4-azyl-2-oxo-1- [ [ [ [ [ [ [ [ [ eth-oxy ] carbonyl ] methyl ] acryl ] [ [ [ cyclohexyloxy ] oxy ] phosphoryl ] methyl ] [ [ Tri-fluoromethoxy ] ethyl ] ] -1, 3, 5- [ Tri-azine ]
Molecular weight: 485-41 molecular formula: c 17 H 27 O 6 N 5 PF 3 Research and development numbering: EMTRO-128611 #.
7. The chemical structure of the molecule of the carboxylate medicinal precursor compound of the nucleoside analogue, the chemical structure of the core molecule of the chemical structure conforms to the general structure and is composed of any selected group in the group definition; the carboxylate medicinal precursor compound of the ring-opening chain nucleoside analogue containing a triazinone group, a trifluoromethyl group, an amino group and a nitrile group, wherein the organic acid comprises acetic acid, propionic acid, butyric acid, succinic acid, benzoic acid, phenylacetic acid, phenylpropionic acid, citric acid, cinnamic acid, ferulic acid and caffeic acid, the carboxylate medicinal precursor compound is enticitabine hydrochloride caffeate, and the molecular chemical structure is as follows:
Figure RE-FSB0000198834180000061
name: entitabine hydrochloride caffeate
The name is as follows: EMTROTABINE HYDROFENAMIDE CAFFEIATE
The name is as follows: 6-amino-4-amino-2-one-1- [ [ [ [ [ [ [ [ [ oxyethyl ] carbonyl ] methyl ] amino ] [ [ [ [ cyclohexyl ] oxy ] oxyphosphatyl ] ] oxymethyl ] [ [ trifluoromethyl ] ethyl ] ] -1, 3, 5-triazine- [3- [3, 4-bis- [ hydroxy ] -phenyl ] -2-acrylate ]
Name: 6-dynonyl-4-azyl-2-oxo-1- [ [ [ [ [ [ [ [ eth-oxy ] carbonyl ] methyl ] amyl ] [ [ [ cyclohexyloxy ] oxy ] phosphoryl ] ] methyl ] [ [ Tri-fluoromethyl ] ethyl ] ] -1, 3, 5- [ Tri-azine ] - [3- [3, 4- [ dihydroxy ] phenyl ] -2-acrylate ]
Molecular weight: 665.42 molecular formula: c 26 H 35 O 10 N 5 PF 3 Research and development numbering: EMTRO-128612 #.
8. The preparation method of the enticitabine and the medicinal precursor compound thereof comprises the following steps:
adopting commercially available triazone as a raw material, and carrying out nitration reaction with a composition of sulfuric acid and nitric acid to generate a first intermediate; after purification, reacting with an iron powder hydrochloric acid composition to generate a second intermediate product; after purification, the product reacts with trifluoromethyl linear alkyl alcohol acid ester to generate a third intermediate product which is the entitabine nucleoside analogue; after purification, the product is continuously reacted with methyl benzenesulfonyl alkyl alcohol phosphate, trimethylchlorosilane and trimethylbromosilane to generate a fourth intermediate product, namely the monophosphorylation entitabine nucleoside analogue; after purification, the intermediate product continuously reacts with cyclohexyl phosphate and glycine ethyl ester, and the fifth intermediate product is an entitabine hydrogen phenolic ester medicinal precursor compound; in the purification process, the caffeic acid is subjected to neutralization reaction, and the generated target product is the medicinal precursor compound of the emtricitabine hydrogen phenolic ester caffeic acid salt; the chemical reaction is carried out under normal pressure and at the reflux point and below, a glass or stainless steel reactor with a stirring and reflux device is selected, and a composition of ethanol, diethyl ether, ethyl acetate, acetone, cyclohexane, toluene, chlorobenzene, chloroform, dichloromethane, dioxane, propylene glycol methyl ether, tetrahydrofuran, dimethylformamide, dimethyl imidazolidinone and water is selected as a solvent.
9. The purification method of the enticitabine medicinal precursor compound and the intermediate thereof comprises the following steps:
washing the intermediate with 30 times of purified water, neutralizing with 1-2N aqueous solution of NAOH to obtain water soluble substance, removing water insoluble substance, neutralizing with 1-2N HCl to pH 5-7, extracting with ethyl acetate, removing water phase, and evaporating under reduced pressure; washing with clean water and ethanol, repeatedly washing, neutralizing, extracting, filtering, crystallizing and recrystallizing the intermediate product, the nucleoside analogue and the medicinal precursor compound thereof by using a composition of hydrochloric acid, nitric acid, sulfuric acid, acetic acid, propionic acid, butyric acid, succinic acid, benzoic acid, phenylacetic acid, phenylpropionic acid, citric acid, cinnamic acid, caffeic acid, ferulic acid, petroleum ether, diethyl ether, tetrahydrofuran, ethyl acetate, ethanol and water, and refining and sterilizing according to the application.
10. Sterile raw material dosage forms of a pharmaceutically acceptable precursor compound of entitabine:
sterile raw material medicine of 0.0001-1000 g/bottle of entitabine hydrogen phenol ester caffeic acid salt
Under the condition of GMP production of the medicine, the raw material medicine of the emtricitabine hydrogen phenol ester caffeate is purified and sterilized in a sterile workshop and is packaged to prepare the sterile raw material medicine.
11. A hard capsule dosage form comprising a combination of enticitabine pharmaceutical precursor compounds:
Figure RE-FSB0000198834180000081
under the GMP production condition of the medicine, the composition is uniformly mixed and then prepared into the oral medicine in the form of hard capsule by adopting a medicinal hard capsule filling machine and various packaging materials and packaging technologies.
12. A molded tablet dosage form comprising a composition of a pharmaceutical precursor compound of entitabine:
Figure RE-FSB0000198834180000082
under GMP production conditions, the composition is mixed uniformly and prepared into oral medicine in the form of molded tablet by adopting a medicinal molded pill making machine and various packaging materials and packaging technologies.
13. An intravenous drop dosage form of a composition comprising a pharmaceutically acceptable precursor compound of enticitabine:
0.0001-50g of injection-grade purified water per bottle,
0.0001-2 g/bottle of the entitabine hydrogen phenol ester caffeate,
0.0001-2 g/bottle of entofivir hydrogen phenolic ester caffeate,
under the GMP production condition of injection-grade medicine, the composition is uniformly mixed, and is prepared into the medicine for intravenous drip dosage form by adopting a medicinal filling machine and various packaging materials and packaging technologies.
14. Oral solution dosage forms of compositions comprising entinostat precursor compounds:
Figure RE-FSB0000198834180000091
under the condition of GMP production, the composition is uniformly mixed and then prepared into the oral liquid medicine by adopting a medicinal filling machine and various packaging materials and packaging technologies.
15. A composition comprising entinostat precursor compound in the form of a nebulized solution:
Figure RE-FSB0000198834180000092
under the condition of GMP production, the composition is mixed uniformly and then prepared into the medicine for atomizing solution by adopting a medicinal filling machine and various packaging materials and packaging technologies.
16. A powder inhalation dosage form comprising a composition of an entitabine pharmaceutical precursor compound:
Figure RE-FSB0000198834180000101
under GMP production conditions, the composition is mixed uniformly and then prepared into a powder inhalant type medicine by adopting a medicinal filling machine and various packaging materials and packaging technologies.
17. An eye drop dosage form comprising a combination of an enticitabine prodrug compound:
Figure RE-FSB0000198834180000102
under the condition of GMP production, the composition is mixed uniformly and then prepared into the eye drop medicament by adopting a medicinal filling machine and various packaging materials and packaging technologies.
18. A cream formulation comprising a composition of entinostat precursor compounds:
Figure RE-FSB0000198834180000103
under the condition of GMP production, the composition is mixed uniformly and then prepared into the external medicine with cream dosage form by adopting a medicinal filling machine and various packaging materials and packaging technologies.
19. An embolic pellet dosage form comprising a composition of an entitabine pharmaceutical precursor compound:
Figure RE-FSB0000198834180000111
under the condition of GMP production, the composition is mixed uniformly and then prepared into the external medicine for embolic pill dosage by adopting a medicinal filling machine and various packaging materials and packaging technologies.
20. A syrup dosage form comprising a composition of entinostat precursor compounds:
Figure RE-FSB0000198834180000112
under GMP production conditions, the composition is mixed uniformly and then prepared into bottled syrup type oral medicine by adopting a medicinal filling machine and various packaging materials and packaging technologies.
21. A soft capsule dosage form comprising a combination of an enticitabine pharmaceutical precursor compound:
Figure RE-FSB0000198834180000113
under the condition of GMP production, the composition is mixed uniformly and then prepared into the oral medicine in the form of soft capsules by adopting a medicinal filling machine and various packaging materials and packaging technologies.
22. Medical use of a soft capsule dosage form comprising a combination of entitabine pharmaceutical precursor compounds for the treatment of hepatitis b virus infection:
the soft capsule preparation of the oral composition containing the entitabine medicinal precursor compound is used for treating acute hepatitis B virus infection once a day, one to three pills are taken each time, and fifteen days are taken as a treatment course; after the treatment course is finished, the liver function and the hepatitis B virus loading level are checked; the soft capsule preparation of the oral composition containing the entitabine medicinal precursor compound is used for treating chronic hepatitis B virus infection once a day, one to three pills are taken each time, and one month is a treatment course; after the treatment course, the liver function and the hepatitis B virus load level are checked.
23. Medical use of a soft capsule dosage form comprising a composition of a pharmaceutically acceptable precursor compound of entitabine for the treatment of hepatitis c virus infection:
the soft capsule preparation containing the entitabine medicinal precursor compound composition is orally taken for treating hepatitis C virus infection, once a day, one to three pills each time, and one month is a treatment course; after the treatment period, liver function and hepatitis c virus load levels were examined.
24. The medical application of the soft capsule preparation of the composition containing the entitabine medicinal precursor compound in treating AIDS infection is as follows:
the soft capsule preparation containing the entitabine medicinal precursor compound composition is orally taken for treating the AIDS virus after high-risk exposure, once a day, one to three pills each time, and fifteen days are a treatment course; the soft capsule preparation containing the entitabine medicinal precursor compound composition is orally taken for treating the HIV infection, once a day, one to three pills each time, and one month is a treatment course; after the treatment course, liver function and HIV load level were examined.
25. Medical use of a syrup dosage form of a composition comprising an entitabine pharmaceutical precursor compound for the treatment of prostate cancer:
the syrup preparation of the composition containing the entitabine medicinal precursor is orally taken for treating the prostatic cancer, wherein the syrup preparation is taken once a day, one bottle is taken each time, and one month is a treatment course; after the treatment course, liver function and prostate cancer marker levels were examined.
26. Medical use of a syrup dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of gastric cancer:
the syrup preparation of the oral composition containing the entitabine medicinal precursor compound is used for treating the gastric cancer once a day, one bottle each time and one month as a treatment course; after the treatment course, the liver function and stomach cancer index levels were examined.
27. Medical use of a syrup dosage form of a composition comprising a pharmaceutical precursor compound of enticitabine for the treatment of renal cancer:
the syrup preparation of the composition containing the novel entitabine medicinal precursor compound is orally taken for treating the kidney cancer, wherein the syrup preparation is taken once a day, one bottle at a time and one month as a treatment course; after the treatment course, the liver function and kidney cancer index levels are checked.
28. Medical use of a syrup dosage form of a composition comprising an entitabine pharmaceutical precursor compound for the treatment of thyroid cancer:
the syrup preparation of the oral composition containing the entitabine medicinal precursor compound is used for treating thyroid cancer, and the syrup preparation is taken once a day, one bottle each time and one month as a treatment course; after the treatment course, the liver function and thyroid cancer index levels were examined.
29. Medical use of a syrup dosage form of a composition comprising an entitabine pharmaceutical precursor compound for the treatment of a neuroma:
the syrup preparation of the composition containing the entitabine medicinal precursor compound is orally taken for treating the neuroma, the syrup preparation is taken once a day, one bottle is taken every time, and one month is taken as a treatment course; after the treatment course, the liver function and neuroma index levels were examined.
30. Medical use of a syrup dosage form comprising a composition of an entitabine pharmaceutical precursor compound for the treatment of lymphoma:
the syrup preparation of the composition containing the entitabine medicinal precursor compound is taken orally once a day and one bottle each time, and one month is a treatment course; after the treatment course, liver function and lymph cancer index level were examined.
31. Medical use of a syrup dosage form comprising a composition of an entitabine pharmaceutical precursor compound for the treatment of esophageal cancer:
the syrup preparation of the composition containing the entitabine medicinal precursor compound is adopted for treating the esophageal cancer, and the syrup preparation of the composition containing the entitabine medicinal precursor compound is orally taken once a day and one bottle each time, wherein one month is a treatment course; after the treatment course, the liver function and esophageal cancer index levels are checked.
32. Medical use of a syrup dosage form comprising a composition of a pharmaceutically acceptable precursor compound of entitabine for the treatment of bladder cancer:
the syrup preparation of the composition containing the entitabine medicinal precursor compound is taken orally once a day and one bottle each time, and one month is a treatment course; after the treatment period, the liver function and bladder cancer index levels were examined.
33. Medical use of a syrup dosage form comprising a composition of entitabine prodrug compounds for the treatment of MDS:
a syrup dosage form orally comprising a composition of an entitabine prodrug compound is used to treat MDS once daily, one vial each time, for a period of one month; after the treatment course, the liver function and MDS index levels were examined.
34. Medical use of a syrup dosage form of a composition comprising a pharmaceutical precursor compound of enticitabine for the treatment of brain tumors:
the syrup preparation of the oral composition containing the entitabine medicinal precursor compound is used for treating the brain tumor once a day, one bottle each time and one month as a treatment course; after the treatment course, the liver function and brain tumor control level were examined.
35. Medical use of a syrup dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of melanoma:
the syrup preparation of the composition containing the entitabine medicinal precursor compound is adopted for treating the melanoma, and the syrup preparation of the composition containing the entitabine medicinal precursor compound is orally taken once a day and one bottle each time, wherein one month is a treatment course; after the treatment course, liver function and melanoma index level were examined.
36. Medical use of a syrup dosage form comprising a composition of an entitabine pharmaceutical precursor compound for the treatment of hemangiomas:
the syrup preparation of the composition containing the entitabine medicinal precursor compound is adopted for the treatment of hemangioma, and is orally taken once a day, one bottle of syrup preparation of the composition containing the entitabine medicinal precursor compound is taken each time, and one month is a treatment course; after the treatment course, liver function and hemangioma index level were examined.
37. Medical use of a hard capsule dosage form comprising a composition of an entitabine pharmaceutical precursor compound for the treatment of leukemia:
the composition containing the entitabine medicinal precursor compound is orally taken to be used for treating leukemia, wherein one to three pills are taken every day, and one month is a treatment course; after the treatment course, liver function and leukemia index level were examined.
38. Medical use of a hard capsule dosage form comprising a composition of an entitabine pharmaceutical precursor compound for the treatment of a papillomavirus infection;
the hard capsule dosage form of the oral composition containing the entitabine medicinal precursor compound is used for treating the papillomavirus infection once a day, one to three pills each time, and fifteen days are a treatment course; at the end of the treatment period, the level of papillomavirus load was checked.
39. Medical use of a cream dosage form comprising a composition of an entitabine pharmaceutical precursor compound for the treatment of skin cancer;
applying to the afflicted area of skin cancer in a cream formulation comprising a composition of an enticitabine prodrug; meanwhile, the oral drug containing the entitabine medicinal precursor compound hard capsule dosage form is used for treating skin cancer once a day, one to three pills are taken each time, and one month is a treatment course; after the treatment course, liver function and skin cancer index levels were examined.
40. Medical use of an embolic pellet formulation comprising a composition of a pharmaceutical precursor compound of entitabine for the treatment of rectal cancer;
an embolic pill dosage form comprising a composition of an entitabine prodrug compound is used for the treatment of rectal cancer, one pill every two days; simultaneously orally taking one to three pills of hard capsule dosage form containing the composition of the entitabine medicinal precursor compound once a day, wherein one month is a treatment course; after the treatment course, the liver function and rectal cancer index levels are checked.
41. Medical use of an embolic pellet formulation comprising a composition of a pharmaceutically acceptable precursor compound of enticitabine for the treatment of cervical cancer;
an embolic pill dosage form for the treatment of cervical cancer employing a composition comprising a pharmaceutically acceptable precursor compound of entitabine, one pill every ten days; simultaneously orally taking one to three pills of hard capsule dosage form containing the composition of the entitabine medicinal precursor compound once a day, wherein one month is a treatment course; after the treatment course, liver function and cervical cancer index levels were examined.
42. Medical use of a powder inhalation dosage form of a composition comprising a pharmaceutical precursor compound of entitabine for the treatment of nasopharyngeal laryngeal cancer;
use of a powder inhalation dosage form of a composition comprising a pharmaceutically acceptable precursor compound of enticitabine for the treatment of nasopharyngeal carcinoma once a day; simultaneously, the composition is orally taken once a day, one to three pills each time, and the hard capsule dosage form comprises the composition of the entitabine medicinal precursor compound, and one month is a treatment course; after the treatment course, the liver function and nasopharyngeal laryngeal cancer index levels are checked.
43. Medical use of a hard capsule dosage form comprising a composition of an entitabine pharmaceutical precursor compound for the treatment of lung cancer;
the oral hard capsule preparation containing the entitabine medicinal precursor compound is used for treating the lung cancer once a day, one to three pills are taken each time, and one month is a treatment course; after the treatment course, the liver function and lung cancer index levels are checked.
44. Medical use of a hard capsule dosage form comprising a composition of an entitabine pharmaceutical precursor compound for liver cancer treatment:
the hard capsule preparation containing the entitabine medicinal precursor compound is orally taken for treating liver cancer, once a day, one to three pills each time, and one month is a treatment course; after the treatment course, liver function and liver cancer index level were examined.
45. Medical use of a hard capsule dosage form comprising a composition of an entitabine pharmaceutical precursor compound for the treatment of breast cancer:
the hard capsule preparation containing the entitabine medicinal precursor compound is orally taken for treating the breast cancer, the hard capsule preparation is taken once a day, one to three pills are taken each time, and one month is a treatment course; after the treatment course, the liver function and breast cancer index levels were examined.
46. Medical use of a hard capsule dosage form comprising a composition of an entitabine prodrug compound for the treatment of pancreatic cancer:
the preparation method adopts a hard capsule preparation containing the entitabine medicinal precursor compound for treating the pancreatic cancer, and the hard capsule preparation is taken orally once a day, one to three pills each time, and one month is a treatment course; after the treatment course, the liver function and pancreatic cancer index levels were examined.
47. Medical use of an intravenous drip dosage form of a composition comprising an entitabine nucleoside analogue and its precursor compounds for the treatment of cancer:
an intravenous drip preparation containing the entitabine nucleoside analogue and the precursor compound thereof is adopted for treating the cancer, once a day and four days are taken as a treatment course; orally administering a vial of a syrup-type drug product comprising a composition of an entitabine prodrug compound daily for a one-month supplementation period; after the treatment course, liver function and corresponding cancer index level are checked.
48. Medical use of an intravenous drip dosage form of a composition comprising an entitabine pharmaceutical precursor compound for the treatment of marburg virus infection:
an intravenous drip formulation comprising an entitabine prodrug compound is used for the treatment of marburg virus infection once a day for a period of four days; orally administering a vial of a syrup-type drug product comprising a composition of an entitabine prodrug compound daily for a five-day supplementation period; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; controlling skin infections using aerosolized solution and cream formulations of compositions comprising enticitabine pharmaceutical precursor compounds; controlling ocular infections with eye drops of a composition comprising an entitabine prodrug compound; after the treatment period, the marburg viral load level was checked.
49. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of hantavirus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of hantavirus infection once daily for a period of four days; orally administering a vial of a syrup-type drug product comprising a composition of an entitabine prodrug compound daily for a five-day supplementation period; use of a nebulized solution dosage form for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; use of nebulized solution and cream formulations of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the control of skin infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment period, the hantavirus load was checked.
50. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of dengue virus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for treatment of dengue virus infectious disease, once daily for a period of four days; taking a five-day supplementation course of treatment, orally administering a bottle of a syrup-type drug comprising a composition of entitabine prodrug compound daily; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; controlling skin infections using nebulized solution and cream formulations containing a composition of an entitabine prodrug compound; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the course of treatment, dengue virus load levels were checked.
51. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically precursor compound of enticitabine for the treatment of ebola virus infections:
an intravenous drip formulation containing the novel entitabine medicinal precursor compound is adopted for treating the Ebola virus infection, once a day and four days are a treatment course; a syrup-based dose of a composition comprising the pharmaceutically acceptable precursor compound of entitabine may be administered orally one vial per day for a supplemental period of ten days; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; use of nebulized solution and cream formulations of compositions comprising novel entitabine pharmaceutical precursor compounds for the control of skin infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment period, the ebola virus load was checked.
52. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of enticitabine for the treatment of avian influenza virus infection:
an intravenous drip dosage form of a composition comprising the entecatabine medicinal precursor compound is used for treating avian influenza virus infection once a day, and four days is a treatment course; one to three pills of a molded tablet dosage form of the composition comprising the entitabine prodrug compound may be administered orally daily for a supplemental period of five days; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of enticitabine for the control of pulmonary infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment course is finished, the avian influenza virus load is checked.
53. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of a lassa virus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of a lassa virus infection once daily for a period of four days; one to three pills of a molded tablet dosage form of the composition comprising the entitabine prodrug compound may be administered orally daily for a supplemental period of five days; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; controlling skin infections using aerosolized solution and cream formulations of compositions comprising novel entitabine pharmaceutical precursor compounds; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment period, the lassa virus load was checked.
54. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of a nipavirus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of nipavirus infection once daily for a period of four days; one to three pills of a molded tablet dosage form of the composition comprising the entitabine prodrug compound may be administered orally daily for a supplemental period of five days; use of a pharmaceutical product in the form of a nebulized solution for the control of pulmonary infections by inhalation of a composition comprising a pharmaceutically acceptable precursor compound of entitabine; controlling skin infections using aerosolized solution and cream formulations of compositions comprising enticitabine pharmaceutical precursor compound; controlling ocular infections with eye drops of a composition comprising an entitabine prodrug compound; after the treatment period, the nipah viral load was checked.
55. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of MERS virus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for treating MERS virus infection once a day for a period of four days; one to three pills of a drug product in a molded tablet dosage form comprising the composition of the entitabine prodrug compound may be administered orally daily for a supplemental treatment period of five days; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of enticitabine for the control of pulmonary infections; controlling skin infections using aerosolized solution and cream formulations of compositions comprising enticitabine pharmaceutical precursor compounds; controlling ocular infections with eye drops comprising a composition of an entitabine pharmaceutical precursor compound; after the treatment period, the MERS viral load was checked.
56. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of SARS virus infection:
an intravenous drip dosage form of a composition comprising the pharmaceutical precursor compound of entitabine is used for the treatment of SARS virus infection, one bottle per day, four days as a course of treatment; one to three pills of a molded tablet dosage form of the composition comprising the entitabine prodrug compound may be administered orally daily for a supplemental period of five days; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; use of aerosolized solution and cream formulations of a composition comprising an entitabine prodrug compound for controlling skin infections; controlling ocular infections with eye drops comprising a composition of an entitabine pharmaceutical precursor compound; after the treatment period, the SAR5 viral load was checked.
57. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutical precursor compound of entitabine for the treatment of hendra virus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of hendra virus infection, one vial per day for a period of four days; can be used for a supplementary treatment course of five days, and one to three pills of the drug containing the entitabine medical precursor compound in a molded tablet dosage form are taken orally every day; controlling pulmonary infections using an ultrasonically nebulized solution of a composition comprising an entitabine pharmaceutical precursor compound; controlling skin infections using nebulized solution and cream formulations containing a composition of an entitabine prodrug compound; controlling ocular infections with eye drops comprising a composition of an entitabine pharmaceutical precursor compound; after the treatment period, the Hendra virus load was checked
58. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of encephalitis virus infection:
an intravenous drip dosage form of a composition comprising an entitabine prodrug compound is used for treating encephalitis virus infection, one bottle per day, and four days are a treatment course; taking one to three pills of a drug containing a compression molded tablet formulation of the entitabine medicinal precursor compound orally every day for a supplementary treatment period of five days; after the treatment period, the encephalitis viral load was checked.
59. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of measles virus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of measles virus infection, one bottle per day for a treatment period of four days; can be used for a supplementary treatment course of five days, and one to three pills of the drug containing the entitabine medical precursor compound in a molded tablet dosage form are taken orally every day; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of enticitabine for the control of pulmonary infections; controlling skin infections using aerosolized solution and cream formulations of compositions comprising enticitabine pharmaceutical precursor compounds; controlling ocular infections with eye drops comprising a composition of an entitabine pharmaceutical precursor compound; after the treatment period, measles virus load was checked.
60. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutical precursor compound of entitabine for the treatment of rabies virus infection:
an intravenous drip dosage form of a composition comprising a prodrug compound of entitabine is used for the treatment of rabies virus infection, one bottle per day, four days as a course of treatment; after the treatment course is finished, taking one to three pills of the drug in the hard capsule dosage form containing the composition of the entitabine medicinal precursor compound orally every day by adopting a supplementary treatment course with fifteen days; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of enticitabine for the control of pulmonary infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment course, the rabies virus load was checked.
61. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of a coronavirus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of coronavirus infection, one vial per day for a period of four days; taking a five-day supplementation course of one to three pills of a hard capsule dosage form of the composition containing the entitabine prodrug compound orally daily; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; controlling ocular infections with eye drops comprising a composition of an entitabine pharmaceutical precursor compound; after the treatment period, the coronavirus load was checked.
62. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of west nile viral infection:
an intravenous drip formulation of a composition comprising a pharmaceutical precursor compound of enticitabine is used for the treatment of west nile virus infection, one vial per day for a period of four days; taking a five-day supplementation course of one to three pills of a hard capsule dosage form of the composition containing the entitabine prodrug compound orally daily; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the course of treatment, the west nile viral load was checked.
63. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of an infection by ursavirus:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of wushu virus infection, one bottle per day for a period of four days; a drug in hard capsule dosage form comprising a combination of the entitabine prodrug compound may be administered orally one to three pills daily for a five day complementary period; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment course, the viral load of the Wusu chart is checked.
64. Medical use of an intravenous drip dosage form of a composition comprising an entitabine pharmaceutical precursor compound for the treatment of a crimia-congo hemorrhagic fever virus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutical precursor compound of entitabine is used for the treatment of congo hemorrhagic fever virus infection, one bottle per day with four days as a course of treatment; a drug in hard capsule dosage form comprising a combination of the entitabine prodrug compound may be administered orally one to three pills daily for a five day complementary period; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of enticitabine for the control of pulmonary infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment period, the viral load of the Congo hemorrhagic fever was checked.
65. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of rift valley fever virus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of rift valley fever virus infection, one bottle per day for a period of four days; a drug in hard capsule dosage form comprising a combination of the entitabine prodrug compound may be administered orally one to three pills daily for a five day complementary period; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment course, the rift valley fever virus load was examined.
66. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of smallpox viral infection:
an intravenous drip dosage form of a composition comprising a pharmaceutical precursor compound of entitabine is used for the treatment of smallpox viral infection, one vial per day for a period of four days; taking one to three pills of a hard capsule dosage form of the composition containing the entitabine prodrug compound orally every day for a complementary period of five days; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; controlling skin infections using nebulized solution and cream formulations containing a composition of an entitabine prodrug compound; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment period, the smallpox viral load was checked.
67. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutical precursor compound of entitabine for the treatment of equine infectious virus:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of equine Ro virus infection, one vial per day for a period of four days; a drug in hard capsule dosage form comprising a combination of the entitabine prodrug compound may be administered orally one to three pills daily for a five day complementary period; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment period, the equine viral load was checked.
68. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of chikungunya virus infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of chikungunya virus infection, one vial per day for a period of four days; a drug in hard capsule dosage form comprising a combination of the entitabine prodrug compound may be administered orally one to three pills daily for a five day complementary period; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of entitabine for the control of pulmonary infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment period, the chikungunya viral load was checked.
69. Medical use of an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine for the treatment of a viral infection:
an intravenous drip dosage form of a composition comprising a pharmaceutically acceptable precursor compound of entitabine is used for the treatment of viral infections, one vial per day for a period of four days; can be taken orally by one to three pills of a soft capsule dosage form of the composition containing the entitabine medicinal precursor compound every day for a supplementing course of five days; use of a medicament in the form of a nebulized solution for inhalation of a composition comprising a pharmaceutical precursor compound of enticitabine for the control of pulmonary infections; a pharmaceutical product in the form of a cream containing a prodrug compound of enticitabine for use in the control of skin infections; controlling ocular infections with eye drops comprising a composition of an entitabine prodrug compound; after the treatment period, the viral load was checked.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016055769A1 (en) * 2014-10-06 2016-04-14 Nucana Biomed Limited Methods of separating gemcitabine-phosphate diastereoisomers
CN106191172A (en) * 2015-05-06 2016-12-07 普拉斯米亚生物技术有限公司 Prepared by the enzyme process of cytosine nucleoside analogs
WO2017067447A1 (en) * 2015-10-19 2017-04-27 Sunshine Lake Pharma Co., Ltd. A salt of egfr inhibitor, crystalline form and uses thereof
CN108148098A (en) * 2018-02-08 2018-06-12 南通大学 The gemcitabine of target cancer cell high level ROS-aryl nitrogen mustard conjugate and preparation method thereof and medical usage

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016055769A1 (en) * 2014-10-06 2016-04-14 Nucana Biomed Limited Methods of separating gemcitabine-phosphate diastereoisomers
CN106191172A (en) * 2015-05-06 2016-12-07 普拉斯米亚生物技术有限公司 Prepared by the enzyme process of cytosine nucleoside analogs
WO2017067447A1 (en) * 2015-10-19 2017-04-27 Sunshine Lake Pharma Co., Ltd. A salt of egfr inhibitor, crystalline form and uses thereof
CN108148098A (en) * 2018-02-08 2018-06-12 南通大学 The gemcitabine of target cancer cell high level ROS-aryl nitrogen mustard conjugate and preparation method thereof and medical usage

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KAREL POMEISL ET AL: "Synthesis of fluorinated acyclic nucleoside phosphonates with 5-azacytosine base moiety", 《TETRAHEDRON》, vol. 75, 16 August 2019 (2019-08-16), pages 130529, XP085804191, DOI: 10.1016/j.tet.2019.130529 *

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