CN106977548A - Times Si Fuwei compounds and its production and use - Google Patents
Times Si Fuwei compounds and its production and use Download PDFInfo
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- CN106977548A CN106977548A CN201710033868.5A CN201710033868A CN106977548A CN 106977548 A CN106977548 A CN 106977548A CN 201710033868 A CN201710033868 A CN 201710033868A CN 106977548 A CN106977548 A CN 106977548A
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- acid
- fuwei
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
Abstract
The present invention relates to Si Fuwei compounds and its production and use again, the structural formula of described times of Si Fuwei compound is as shown in Formula II.The invention further relates to the preparation method of described times of Si Fuwei compound, pharmaceutical composition containing this times of Si Fuwei compound, and this times of Si Fuwei compound is preparing prevention and/or is treating virus infection, the application in the medicine of special hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
Description
Technical field
The present invention relates to organic chemistry filed and pharmaceutical field, and in particular to prevention or/and treatment virus infective medicament times
Si Fuwei compounds and preparation method thereof and these compounds are preparing prevention and/or treatment virus infection, special hepatitis B
Purposes in viral (HBV) and/or the medicine of human immunodeficiency virus (HIV) infection, and the medicine containing these compounds
Compositions and application thereof.
Background technology
Besifovir, chemistry is entitled：3- [({ 1- [(2- amino -9H- purine -9- bases) methyl] cyclopropyl } epoxide) first
Base] -3 λ of -8,8- dimethyl -3,7- dioxo -2,4,6- trioxas5- phospha nonyl- 1- bases-pivalate, due to the compound
At present without Universal Chinese character name, for convenience of description, the present invention is named as, and " times Si Fuwei ", its molecular structure is shown in formula I：
Times Si Fuwei is the acyclic class nucleoside phosphonate derivative antivirotic of a class, and its antiviral activity is strong, effect and grace
Quite and resistance is difficult for card Wei, and has significant effect to the patient of lamivudine resistance, therefore Si Fuwei is expected to turn into again
Antiviral (the particularly Anti-HBV activity and/or inhibition of HIV) medicine of a new generation.
Times Si Fuwei stability under heating and moist environment is disclosed in CN101616674A not good and higher
The low shortcoming of dissolubility under pH environment, while the case also discloses times Si Fuwei maleic acid monosalts in dissolubility, hygroscopicity and heat
Had greatly improved in terms of stability compared with a times Si Fuwei, the especially improvement in terms of hygroscopicity and heat endurance is particularly dashed forward
Go out.But, by the maleic acid monosalt dissolubility that obtains Si Fuwei again and maleic acid into salt (in the range of 2~6.5 pH,
Times Si Fuwei maleic acid monosalts show about 3~7mg/ml solubility) it is still relatively low.In addition, the case only have studied Malaysia
Acid, p-methyl benzenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acids and ethyl sulfonic acid and salt heat endurance, hygroscopicity and dissolubility formed by times Si Fuwei.
Therefore, it is necessary to further study the solid-state form of Si Fuwei again, times Si Fuweixin solid-state form is developed, to
Times Si Fuwei can further be improved or containing the physical behavior of Si Fuwei preparations, chemical stability and process controllability etc. again, and then
Strengthen the safety and effectiveness of product, more preferable medicine selection is provided for many patients.
The content of the invention
A purpose of the invention is to provide new times Si Fuwei compounds.The compound is in physical behavior, chemically stable
Property and process controllability in terms of be better than prior art.
Another object of the present invention is to provide the preparation method of above-mentioned times of Si Fuwei compound.
A further object of the present invention is to provide the composition for including above-mentioned times of Si Fuwei compound.
A further object of the present invention is that providing above-mentioned times of Si Fuwei compound or its composition is preparing prevention and/or controlling
Treat the application in the medicine of virus infection.
To realize the purpose of the present invention, on the one hand, the present invention provides times Si Fuwei compounds shown in a kind of Formula II,
Wherein, n=1/3,1/2,1,2 or 3, B are selected from：Hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphorus
Acid, nitric acid, carbonic acid, dodecyl sulphate, phosphoglycerol, 2- ethylenehydrinsulfonic acids, taurine, camphorsulfonic acid, cyclamic acid, ammonia
Base sulfonic acid, 1,2- ethionic acids, 1,4- fourths disulfonic acid, benzene sulfonic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2,5- dihydroxy
Benzene sulfonic acid, p-aminobenzene sulfonic acid, saccharin, naphthalene -1,5- disulfonic acid, formic acid, acetic acid, glycolic, 2,2- dichloroacetic acid, propionic acid, L-
Lactic acid, D-ALPHA-Hydroxypropionic acid, racemic lactic acid (also known as：DL-LACTIC ACID), pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, octanoic acid, n-nonanoic acid,
Capric acid, undecenoic acid, laurate, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D-malic acid,
Racemization malic acid (also known as：DL-malic acid), L-TARTARIC ACID, D- tartaric acid, racemic tartaric acid (also known as：DL- tartaric acid), it is interior
Recemic-tartaric acid, fumaric acid, 1,5- glutaric acids, 2- oxo -1,5,-glutaric acid, 1,6- adipic acids, 1,10- decanedioic acid, lemon
Acid, benzoic acid, P-methoxybenzoic acid, 4- acetaminobenzoic acids, salicylic acid, acetylsalicylic acid, gentianic acid, 4- aminosalicyclics
Acid, phenylacetic acid, L- mandelic acids, D- mandelic acids, racemic mandelic acid (also known as：DL- mandelic acids), 3- phenylpropionic acids, cinnamic acid, coffee
Acid, benzenebutanoic acid, picric acid, nicotinic acid, orotic acid, chinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic acid,
Glucoheptonic acid, lactobionic acid, camphoric acid, galactosaccharic acid (also known as：Glactaric acid), tannic acid (also known as：Tannic acid), alginic acid, 3- hydroxyls-
2- naphthoic acids (also known as：Hydroxyl naphthoic acid), 4,4'- methylene two (3- hydroxy-2-naphthoic acids) (also known as：Pamoic acid or Piao acid), ammonia
Base acid or acylated amino (such as acetylgiycine, hippuric acid, asparatate, glutamic acid, pyroglutamic acid, glutamine, Tianmen
Winter acid amides etc.).In above-mentioned Formula II, " compound " refers to times Si Fuwei with corresponding acid by non-covalent bonds such as hydrogen bond, ionic bonds
Effect combine and the compound that coexists, including salt, eutectic etc..The compound still further comprise it polycrystalline, solvate,
The forms such as solvate polycrystalline, hydrate, hydrate polycrystalline.
The definition of " salt " of the present invention is well known to those skilled in the art of the present technique, refers to be led to by cation and anion
Cross compound formed by the effect of ionic bond." times Si Fuwei salt " is to refer in solids of the Si Fuwei again with acid composition, in acid
Proton translocation on times Si Fuwei, times Si Fuwei cations and acid radical anion of protonation are acted on and phase by ionic bond
Mutually combine.
" eutectic " of the present invention refers to times Si Fuwei with acid with the solid of eutectic form formation." eutectic " (Co-
Crystals) refer to a kind of multicomponent crystal with fixed stoichiometric proportion, in the crystal each component be with molecular level,
Combined and coexisted by hydrogen bond or other non-covalent bonds, the effect of nonionic key.In pharmaceutical co-crystals, pharmaceutical activity is generally comprised
In composition and another or a variety of eutectic forming bodies (Co-crystal former), such as " times Si Fuwei eutectics ", a times Si Fuwei is
Active constituents of medicine, acid is eutectic forming body.When single pure eutectic forming body at room temperature with liquid in the presence of, the eutectic
It is referred to as " solvate ", is referred to as " hydrate " when wherein solvent is water, such as the eutectic of times Si Fuwei and acetic acid formation, can be with
Referred to as times Si Fuwei acetic acid solvate.
Above-mentioned " eutectic " also includes so some multicomponent crystal with fixed stoichiometric proportion, in these crystal Chinese medicines
Between thing active component and other components, a part is by hydrogen bond or other non-covalent bond effects, and another part passes through ionic bond
Or active force between hydrogen bond and ionic bond and combine.Such as, times Si Fuwei and the compound of dicarboxylic acids formation, wherein
A carboxyl in the carboxylic acid is combined with ionic bond with a times Si Fuwei, and another carboxyl is combined with hydrogen bond with a times Si Fuwei, this feelings
Also eutectic is formd under condition depending on times Si Fuwei and the dicarboxylic acids.
Above-mentioned " times Si Fuwei salt or eutectic " also includes the forms such as solvate, the hydrate of times Si Fuwei salt or eutectic.
Prepared in certain solvent when Si Fuwei salt or eutectic again, pulp or during crystallization, the solvent is likely to enter Si Fuwei salt again
Or in eutectic crystal, form solvate；When the solvent is water, that is, it is likely to form hydrate.
In above-mentioned Formula II, n refers to the molar composition ratio of acid B and times Si Fuwei in times Si Fuwei composite structures, Ke Yitong
Cross1The modes such as H-NMR, elementary analysis, HPLC, Advances in crystal X-ray diffraction are characterized.
In one embodiment, in Formula II, n=1/3, i.e., there is provided sour B and times Si Fuwei with 1:3 molar composition ratios are formed
Compound, be represented by " B times of Si Fuwei (1:3) ", wherein B is selected from：Phosphoric acid, citric acid, tannic acid (also known as：Tannic acid) or sea
Alginic acid.In the present embodiment, a times Si Fuwei compounds are preferably phosphoric acid times Si Fuwei (1:Or citric acid times Si Fuwei (1 3):
3)。
In one embodiment, in Formula II, n=1/2, i.e., there is provided sour B and times Si Fuwei with 1:2 molar composition ratios are formed
Compound, be represented by " B times of Si Fuwei (1:2) ", wherein B is selected from：Sulfuric acid, persulfuric acid, phosphoric acid, carbonic acid, phosphoglycerol, 1,
2- ethionic acids, 1,4- fourths disulfonic acid, naphthalene -1,5- disulfonic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D-malic acid, disappear
Rotation malic acid (also known as：DL-malic acid), L-TARTARIC ACID, D- tartaric acid, racemic tartaric acid (also known as：DL- tartaric acid), interior disappear
Revolve tartaric acid, fumaric acid, 1,5- glutaric acids, 2- oxo -1,5- glutaric acids, 1,6- adipic acids, 1,10- decanedioic acid, citric acid, camphor tree
Olic acid, galactosaccharic acid (also known as：Glactaric acid), tannic acid (also known as：Tannic acid), alginic acid, (3- hydroxyl -2- the naphthalenes of 4,4'- methylene two
Formic acid) (also known as：Pamoic acid or Piao's acid), asparatate or glutamic acid.In the present embodiment, times Si Fuwei compounds are excellent
Elect phosphoric acid times Si Fuwei (1 as:2), carbonic acid times Si Fuwei (1:2), oxalic acid times Si Fuwei (1:2), malonic acid times Si Fuwei (1:
2), butanedioic acid times Si Fuwei (1:2), L MALIC ACID times Si Fuwei (1:2), D-malic acid times Si Fuwei (1:2), racemization malic acid
Times Si Fuwei (1:2), L-TARTARIC ACID times Si Fuwei (1:2), D- tartaric acid times Si Fuwei (1:2), racemic tartaric acid takes charge of good fortune again
Wei (1:2), mesotartaric acid times Si Fuwei (1:2), fumaric acid times Si Fuwei (1:2), citric acid times Si Fuwei (1:2)、4,
4'- methylene two (3- hydroxy-2-naphthoic acids) (also known as：Pamoic acid or Piao's acid) times Si Fuwei (1:2), sulfuric acid times Si Fuwei
(1:2), 1,2- ethionic acids times Si Fuwei (1:2), 1,4- fourths disulfonic acid times Si Fuwei (1:Or naphthalene -1,5- disulfonic acid is taken charge of again 2)
Fu Wei (1:2).
In one embodiment, in Formula II, n=1, i.e., there is provided sour B and times Si Fuwei with 1:The formation of 1 molar composition ratio
Compound, is represented by " B times of Si Fuwei (1:1) ", wherein B is selected from：Hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydrogen iodine
Acid, phosphoric acid, nitric acid, carbonic acid, dodecyl sulphate, phosphoglycerol, 2- ethylenehydrinsulfonic acids, taurine, camphorsulfonic acid, hexamethylene ammonia sulphur
Acid, sulfamic acid, 1,2- ethionic acids, 1,4- fourths disulfonic acid, benzene sulfonic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2,5- bis-
Hydroxy benzene sulfonic acid, p-aminobenzene sulfonic acid, saccharin, naphthalene -1,5- disulfonic acid, formic acid, acetic acid, glycolic, 2,2- dichloroacetic acid, third
Acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemic lactic acid (also known as：DL-LACTIC ACID), pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, octanoic acid,
N-nonanoic acid, capric acid, undecenoic acid, laurate, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D- apples
Tartaric acid, racemization malic acid (also known as：DL-malic acid), L-TARTARIC ACID, D- tartaric acid, racemic tartaric acid (also known as：DL- winestones
Acid), mesotartaric acid, fumaric acid, 1,5- glutaric acids, 2- oxo -1,5- glutaric acids, 1,6- adipic acids, 1,10- decanedioic acid,
Citric acid, benzoic acid, P-methoxybenzoic acid, 4- acetaminobenzoic acids, salicylic acid, acetylsalicylic acid, gentianic acid, 4- amino
Salicylic acid, phenylacetic acid, L- mandelic acids, D- mandelic acids, racemic mandelic acid (also known as：DL- mandelic acids), 3- phenylpropionic acids, cinnamic acid,
Caffeic acid, benzenebutanoic acid, picric acid, nicotinic acid, orotic acid, chinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic
Acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactosaccharic acid (also known as：Glactaric acid), tannic acid (also known as：Tannic acid), alginic acid, 3- hydroxyls
Base -2- naphthoic acids (also known as：Hydroxyl naphthoic acid), 4,4'- methylene two (3- hydroxy-2-naphthoic acids) (also known as：Pamoic acid or Piao's acid),
Acetylgiycine, hippuric acid, asparatate, glutamic acid, pyroglutamic acid, glutamine or asparagine.In this embodiment party
In case, a times Si Fuwei compounds are preferably phosphoric acid times Si Fuwei (1:1), carbonic acid times Si Fuwei (1:1), acetic acid times Si Fuwei (1:
1), propionic acid times Si Fuwei (1:1), Pfansteihl times Si Fuwei (1:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (1:1), racemic lactic acid times Si Fuwei
(1:1), palmitic acid times Si Fuwei (1:1), stearic acid times Si Fuwei (1:1), oxalic acid times Si Fuwei (1:1), malonic acid takes charge of good fortune again
Wei (1:1), butanedioic acid times Si Fuwei (1:1), L MALIC ACID times Si Fuwei (1:1), D-malic acid times Si Fuwei (1:1), racemization
Malic acid times Si Fuwei (1:1), L-TARTARIC ACID times Si Fuwei (1:1), D- tartaric acid times Si Fuwei (1:1), racemic tartaric acid
Times Si Fuwei (1:1), mesotartaric acid times Si Fuwei (1:1), fumaric acid times Si Fuwei (1:1), citric acid times Si Fuwei (1:
1), benzoic acid times Si Fuwei (1:1), L- mandelic acids times Si Fuwei (1:1), D- mandelic acids times Si Fuwei (1:1), racemic mandelic acid
Times Si Fuwei (1:1), nicotinic acid times Si Fuwei (1:1), 3- hydroxy-2-naphthoic acids (also known as：Hydroxyl naphthoic acid) times Si Fuwei (1:1)、4,
4'- methylene two (3- hydroxy-2-naphthoic acids) (also known as：Pamoic acid or Piao's acid) times Si Fuwei (1:1), hippuric acid times Si Fuwei
(1:1), hydrochloric acid times Si Fuwei (1:1), sulfuric acid times Si Fuwei (1:1), thiocyanic acid times Si Fuwei (1:1), hydrobromic acid times Si Fuwei
(1:1), nitric acid times Si Fuwei (1:1), taurine times Si Fuwei (1:1), 1,2- ethionic acids times Si Fuwei (1:1), 1,4- fourths
Disulfonic acid times Si Fuwei (1:1), benzene sulfonic acid times Si Fuwei (1:Or 2,5- dihydroxy benzenes sulfonic acids times Si Fuwei (1 1):1).
In one embodiment, in Formula II, n=2, i.e., there is provided sour B and times Si Fuwei with 2:The formation of 1 molar composition ratio
Compound, is represented by " B times of Si Fuwei (2:1) ", wherein B is selected from：Hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydrogen iodine
Acid, phosphoric acid, nitric acid, carbonic acid, dodecyl sulphate, phosphoglycerol, 2- ethylenehydrinsulfonic acids, taurine, camphorsulfonic acid, hexamethylene ammonia sulphur
Acid, sulfamic acid, 1,2- ethionic acids, 1,4- fourths disulfonic acid, benzene sulfonic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2,5- bis-
Hydroxy benzene sulfonic acid, p-aminobenzene sulfonic acid, saccharin, naphthalene -1,5- disulfonic acid, formic acid, acetic acid, glycolic, 2,2- dichloroacetic acid, third
Acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemic lactic acid (also known as：DL-LACTIC ACID), pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, octanoic acid,
N-nonanoic acid, capric acid, undecenoic acid, laurate, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D- apples
Tartaric acid, racemization malic acid (also known as：DL-malic acid), L-TARTARIC ACID, D- tartaric acid, racemic tartaric acid (also known as：DL- winestones
Acid), mesotartaric acid, fumaric acid, 1,5- glutaric acids, 2- oxo -1,5- glutaric acids, 1,6- adipic acids, 1,10- decanedioic acid,
Citric acid, benzoic acid, P-methoxybenzoic acid, 4- acetaminobenzoic acids, salicylic acid, acetylsalicylic acid, gentianic acid, 4- amino
Salicylic acid, phenylacetic acid, L- mandelic acids, D- mandelic acids, racemic mandelic acid (also known as：DL- mandelic acids), 3- phenylpropionic acids, cinnamic acid,
Caffeic acid, benzenebutanoic acid, picric acid, nicotinic acid, orotic acid, chinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic
Acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactosaccharic acid (also known as：Glactaric acid), tannic acid (also known as：Tannic acid), alginic acid, 3- hydroxyls
Base -2- naphthoic acids (also known as：Hydroxyl naphthoic acid), 4,4'- methylene two (3- hydroxy-2-naphthoic acids) (also known as：Pamoic acid or Piao's acid),
Acetylgiycine, hippuric acid, asparatate, glutamic acid, pyroglutamic acid, glutamine or asparagine.In this embodiment party
In case, a times Si Fuwei compounds are preferably phosphoric acid times Si Fuwei (2:1), carbonic acid times Si Fuwei (2:1), acetic acid times Si Fuwei (2:
1), propionic acid times Si Fuwei (2:1), Pfansteihl times Si Fuwei (2:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (2:1), racemic lactic acid times Si Fuwei
(2:1), palmitic acid times Si Fuwei (2:1), stearic acid times Si Fuwei (2:1), oxalic acid times Si Fuwei (2:1), malonic acid takes charge of good fortune again
Wei (2:1), butanedioic acid times Si Fuwei (2:1), L MALIC ACID times Si Fuwei (2:1), D-malic acid times Si Fuwei (2:1), racemization
Malic acid times Si Fuwei (2:1), L-TARTARIC ACID times Si Fuwei (2:1), D- tartaric acid times Si Fuwei (2:1), racemic tartaric acid
Times Si Fuwei (2:1), mesotartaric acid times Si Fuwei (2:1), fumaric acid times Si Fuwei (2:1), citric acid times Si Fuwei (2:
1), benzoic acid times Si Fuwei (2:1), L- mandelic acids times Si Fuwei (2:1), D- mandelic acids times Si Fuwei (2:1), racemic mandelic acid
Times Si Fuwei (2:1), nicotinic acid times Si Fuwei (2:1), 3- hydroxy-2-naphthoic acids (also known as：Hydroxyl naphthoic acid) times Si Fuwei (2:1)、4,
4'- methylene two (3- hydroxy-2-naphthoic acids) (also known as：Pamoic acid or Piao's acid) times Si Fuwei (2:1), hippuric acid times Si Fuwei
(2:1), hydrochloric acid times Si Fuwei (2:1), sulfuric acid times Si Fuwei (2:1), thiocyanic acid times Si Fuwei (2:1), hydrobromic acid times Si Fuwei
(2:1), nitric acid times Si Fuwei (2:1), taurine times Si Fuwei (2:1), 1,2- ethionic acids times Si Fuwei (2:1), 1,4- fourths
Disulfonic acid times Si Fuwei (2:1), benzene sulfonic acid times Si Fuwei (2:Or 2,5- dihydroxy benzenes sulfonic acids times Si Fuwei (2 1):1).
In one embodiment, in Formula II, n=3, i.e., there is provided sour B and times Si Fuwei with 3:The formation of 1 molar composition ratio
Compound, is represented by " B times of Si Fuwei (3:1) ", wherein B is selected from：Hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydrogen iodine
Acid, phosphoric acid, nitric acid, carbonic acid, dodecyl sulphate, phosphoglycerol, 2- ethylenehydrinsulfonic acids, taurine, camphorsulfonic acid, hexamethylene ammonia sulphur
Acid, sulfamic acid, 1,2- ethionic acids, 1,4- fourths disulfonic acid, benzene sulfonic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2,5- bis-
Hydroxy benzene sulfonic acid, p-aminobenzene sulfonic acid, saccharin, naphthalene -1,5- disulfonic acid, formic acid, acetic acid, glycolic, 2,2- dichloroacetic acid, third
Acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemic lactic acid (also known as：DL-LACTIC ACID), pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, octanoic acid,
N-nonanoic acid, capric acid, undecenoic acid, laurate, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D- apples
Tartaric acid, racemization malic acid (also known as：DL-malic acid), L-TARTARIC ACID, D- tartaric acid, racemic tartaric acid (also known as：DL- winestones
Acid), mesotartaric acid, fumaric acid, 1,5- glutaric acids, 2- oxo -1,5- glutaric acids, 1,6- adipic acids, 1,10- decanedioic acid,
Citric acid, benzoic acid, P-methoxybenzoic acid, 4- acetaminobenzoic acids, salicylic acid, acetylsalicylic acid, gentianic acid, 4- amino
Salicylic acid, phenylacetic acid, L- mandelic acids, D- mandelic acids, racemic mandelic acid (also known as：DL- mandelic acids), 3- phenylpropionic acids, cinnamic acid,
Caffeic acid, benzenebutanoic acid, picric acid, nicotinic acid, orotic acid, chinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic
Acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactosaccharic acid (also known as：Glactaric acid), tannic acid (also known as：Tannic acid), alginic acid, 3- hydroxyls
Base -2- naphthoic acids (also known as：Hydroxyl naphthoic acid), 4,4'- methylene two (3- hydroxy-2-naphthoic acids) (also known as：Pamoic acid or Piao's acid),
Acetylgiycine, hippuric acid, asparatate, glutamic acid, pyroglutamic acid, glutamine or asparagine.In this embodiment party
In case, a times Si Fuwei compounds are preferably phosphoric acid times Si Fuwei (3:1), carbonic acid times Si Fuwei (3:1), acetic acid times Si Fuwei (3:
1), propionic acid times Si Fuwei (3:1), Pfansteihl times Si Fuwei (3:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (3:1), racemic lactic acid times Si Fuwei
(3:1), palmitic acid times Si Fuwei (3:1), stearic acid times Si Fuwei (3:1), oxalic acid times Si Fuwei (3:1), malonic acid takes charge of good fortune again
Wei (3:1), butanedioic acid times Si Fuwei (3:1), L MALIC ACID times Si Fuwei (3:1), D-malic acid times Si Fuwei (3:1), racemization
Malic acid times Si Fuwei (3:1), L-TARTARIC ACID times Si Fuwei (3:1), D- tartaric acid times Si Fuwei (3:1), racemic tartaric acid
Times Si Fuwei (3:1), mesotartaric acid times Si Fuwei (3:1), fumaric acid times Si Fuwei (3:1), citric acid times Si Fuwei (3:
1), benzoic acid times Si Fuwei (3:1), L- mandelic acids times Si Fuwei (3:1), D- mandelic acids times Si Fuwei (3:1), racemic mandelic acid
Times Si Fuwei (3:1), nicotinic acid times Si Fuwei (3:1), 3- hydroxy-2-naphthoic acids (also known as：Hydroxyl naphthoic acid) times Si Fuwei (3:1)、4,
4'- methylene two (3- hydroxy-2-naphthoic acids) (also known as：Pamoic acid or Piao's acid) times Si Fuwei (3:1), hippuric acid times Si Fuwei
(3:1), hydrochloric acid times Si Fuwei (3:1), sulfuric acid times Si Fuwei (3:1), thiocyanic acid times Si Fuwei (3:1), hydrobromic acid times Si Fuwei
(3:1), nitric acid times Si Fuwei (3:1), taurine times Si Fuwei (3:1), 1,2- ethionic acids times Si Fuwei (3:1), 1,4- fourths
Disulfonic acid times Si Fuwei (3:1), benzene sulfonic acid times Si Fuwei (3:Or 2,5- dihydroxy benzenes sulfonic acids times Si Fuwei (3 1):1).
To realize the purpose of the present invention, on the other hand, the invention provides times Si Fuwei compounds shown in a kind of Formula II
Preparation method, the preparation method includes：
(1) in suitable solvent, a kind of solution for including times Si Fuwei and acid B is formed；
(2) solid is separated out；
(3) separated out solid is separated；
(4) alternatively, the solid of separation is dried, or rear re-dry is further purified.
In the step of above-mentioned preparation method (1), times Si Fuwei can be made according to the method disclosed in CN100347185A.
The document is incorporated into the application by reference.Times Si Fuwei can exist with any form, such as include crystal formation, amorphous
Or their mixed form.
In the step of above-mentioned preparation method (1), " suitable solvent " refers to there is certain solubility to Si Fuwei again and acid,
The solvent of times Si Fuwei eutectics or salt can be formed wherein simultaneously.These suitable solvents are selected from water, ethanol, methanol, propyl alcohol, isopropyl
Alcohol, n-butanol, ethylene glycol, Ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ether, isopropyl ether,
N-butyl ether, glycol monoethyl ether, glycol dimethyl ether, t-butyl methyl ether, tetrahydrofuran, petroleum ether, acetonitrile, dichloromethane,
Chloroform, n-hexane, hexamethylene, acetone, butanone, pentanone, cyclohexanone, toluene, dimethylbenzene, dimethyl acetamide, dimethyl
Formamide etc. or their mixture.The suitable solvent and times Si Fuwei weight ratio generally 3:1~100:1.
In the step of above-mentioned preparation method (1), described " sour B " is selected from the acid representated by B in Formula II.Sour B and times Si Fuwei
Molar ratio be generally 0.2:1~4:1, when in formula II n for 1/3 times Si Fuwei compounds when, sour B and times department's good fortune
The molar ratio of Wei is generally 0.2:1~0.4:1；When in formula II n for 1/2 times Si Fuwei compounds when, sour B with times
Si Fuwei molar ratio is generally 0.5:1~0.7:1；When in formula II n for 1 times Si Fuwei compounds when, sour B with
Times Si Fuwei molar ratio is generally 0.8:1~1.5:1；When in formula II n for 2 times Si Fuwei compounds when, sour B
1.7 are generally with the molar ratio of Si Fuwei again:1~2.5:1；When in formula II n for 3 times Si Fuwei compounds when,
Sour B and times Si Fuwei molar ratio is generally 2.7:1~3.5:1.
In the step of above-mentioned preparation method (2), " precipitation solid " method includes cooling and separates out solid, adds anti-solvent
Solid is separated out, concentrates out and solid is separated out after partial solvent, crystal seed precipitation solid etc. is added, these methods, which can be used alone, also may be used
To be applied in combination.Described " anti-solvent " refers to bad to times Si Fuwei compound dissolubilities that are formed at normal temperatures and energy
Miscible solvent, such as n-hexane, hexamethylene, petroleum ether with dissolving times Si Fuwei and acid suitable solvent.The anti-solvent with
The volume ratio of the suitable solvent of dissolving times Si Fuwei and acid is generally 0.2:1~5:1.
In the step of above-mentioned preparation method (3), " separation " method includes filtering or centrifugation etc..It is alternatively possible to
Suitable solvent is washed to collected solid.
In the step of above-mentioned preparation method (4), " drying " mode includes constant pressure and dry, is dried under reduced pressure or their group
Close application.The method of " being further purified " includes the forms such as recrystallization, pulp, washing.
To realize the purpose of the present invention, on the other hand, the present invention provides a kind of pharmaceutical composition, and it includes therapeutically effective amount
Formula II shown in times Si Fuwei compounds, or times Si Fuwei compounds made from the preparation method shown in Formula II, and
Pharmaceutic adjuvant.Preferably, described pharmaceutical composition exists with dosage form.
Alternatively, aforementioned pharmaceutical compositions can further include another or various active composition, including but not limit
In levocarnitine or derivatives thereof etc..The structural formula of levocarnitine is as shown in formula III：
" the levocarnitine derivative " includes acetyl levocarnitine, chloracetyl levocarnitine, propionyl-L-carnitine, chlorine third
Acyl levocarnitine etc. or their pharmaceutically useful salt.Wherein, this can the medicinal salt of medicine include but is not limited to Acetyl-L-carnitine hydrochloride,
ST 261, hydrochloric acid chloracetyl levocarnitine or hydrochloric acid chlorine propionyl-L-carnitine etc..Wherein, acetyl levocarnitine,
Chloracetyl levocarnitine, propionyl-L-carnitine, chlorine propionyl-L-carnitine structural formula are as follows：
Aforementioned pharmaceutical compositions or preparation can orally or not oral administrations., can be using conventional preparation during oral administration
Tablet, capsule, pill, granule, solution, syrup, supensoid agent, powder, sustained release preparation or controlled release preparation is made in technology
Deng.During non-oral administration, preparation capable of permeating skin, parenteral solution, infusion solution or suppository etc. can be made into using conventional preparation technique.
Aforementioned pharmaceutical compositions or preparation can be prepared according to the conventional method of pharmaceutical field.For example by therapeutically effective amount
Times Si Fuwei compounds and optional another or various active composition shown in Formula II, are mixed with one or more pharmaceutic adjuvants
Or contact, then it is made into required formulation.
Aforementioned pharmaceutical compositions or the preferred peroral dosage form of preparation, including tablet, capsule, pill, granule, solution,
Syrup, dry suspensoid agent, supensoid agent, powder, sustained release preparation or controlled release preparation etc..Wherein preferred tablet, capsule, granule,
The solid orally ingestible such as dry suspensoid agent and sustained release preparation or controlled release preparation, wherein more preferably tablet and capsule.Can be according to
Any conventional method that solid orally ingestible used is prepared to prepare currently preferred pharmaceutical composition or preparation.Such as
Tablet can be prepared using modes such as wet granule compression tablets, and any form of coating can be carried out as needed；Capsule can use wet
It is prepared by the method mode such as encapsulated dose of pelletizing.
In one embodiment, the particle diameter distribution control for times Si Fuwei compounds shown in Formula II that the present invention is provided exists
95% less than 200 μm, preferably smaller than 180 μm, more preferably less than 150 μm, more preferably less than 100 μm.The ability in peroral dosage form
The conventional pharmaceutic adjuvant in domain, including filler, disintegrant, adhesive, dispersant, lubricant or retention agent and all types of bags
Clothing material etc..
The filler generally comprises pregelatinized starch, starch, lactose, dextrin, calcium monohydrogen phosphate, calcium carbonate, mannitol, micro-
Crystalline cellulose, sorbierite, glucose etc., they, which can be used alone, to be used in mixed way, wherein it is preferred that pregelatinized starch, breast
Sugar, microcrystalline cellulose, mannitol.
It is poly- that the disintegrant generally comprises cross-linked carboxymethyl cellulose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, crosslinking
Vinylpyrrolidone, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose etc., they, which can be used alone, to mix
Use, wherein preferably cross-linked carboxymethyl cellulose sodium, sodium carboxymethyl starch, PVPP, microcrystalline cellulose, low
Replace hydroxypropyl cellulose.
Described adhesive generally comprises microcrystalline cellulose, pre-paying starch, hydroxypropyl methyl cellulose, hydroxy propyl cellulose
Element, PVP, starch slurry, Arabic gum, Macrogol 4000, polyvinyl alcohol, alginates, water, the ethanol solution of various concentration,
They, which can be used alone, to be used in mixed way, wherein it is preferred that hydroxypropyl methyl cellulose, hydroxypropylcellulose, PVP, shallow lake
Slurry.
The lubricant generally comprises the rich horse of magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, stearic acid
Sour potassium, palmitic acid, differential silica gel, stearmide, talcum powder, solid polyethylene glycol, glyceryl triacetate etc..They can be independent
Using that can also be used in mixed way, wherein it is preferred that magnesium stearate, stearic acid, talcum powder, differential silica gel, glyceryl triacetate.
If desired, you can add other auxiliary materials into above-mentioned composition or preparation, such as sweetener (such as aspartame,
Steviosin etc.), colouring agent (such as lemon yellow, iron oxide various medicinal or food coloring), stabilizer (such as calcium carbonate, bicarbonate
Calcium, sodium acid carbonate, sodium carbonate, calcium phosphate, calcium monohydrogen phosphate, glycine etc.), surfactant (such as Tween 80, dodecyl sulphate
Sodium etc.) coating material (such as Opadry, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, acrylic resin copolymer) etc..
In one embodiment, it is compound the invention provides times Si Fuwei shown in a kind of Formula II comprising therapeutically effective amount
The folk prescription composition or preparation of thing and pharmaceutic adjuvant.Said composition or the preferred oral formulations of preparation, more preferably tablet and capsule；
In the unit composition or preparation, the weight content of times Si Fuwei compounds shown in Formula II is generally 1mg to 2g, preferably
100mg to 800mg, e.g., from about 150mg (in terms of Si Fuwei again), wherein " about " refers to ± 5% scope.
Preferably, present embodiment provides following composition or preparation：
A kind of pharmaceutical composition or preparation, it, which is included, is selected from phosphoric acid times Si Fuwei (1:3), citric acid times Si Fuwei (1:3)、
Phosphoric acid times Si Fuwei (1:2), carbonic acid times Si Fuwei (1:2), oxalic acid times Si Fuwei (1:2), malonic acid times Si Fuwei (1:2), amber
Amber acid times Si Fuwei (1:2), L MALIC ACID times Si Fuwei (1:2), D-malic acid times Si Fuwei (1:2), racemization malic acid is taken charge of again
Fu Wei (1:2), L-TARTARIC ACID times Si Fuwei (1:2), D- tartaric acid times Si Fuwei (1:2), racemic tartaric acid times Si Fuwei (1:
2), mesotartaric acid times Si Fuwei (1:2), fumaric acid times Si Fuwei (1:2), citric acid times Si Fuwei (1:2), pamoic acid
Times Si Fuwei (1:2), sulfuric acid times Si Fuwei (1:2), 1,2- ethionic acids times Si Fuwei (1:2), 1,4- fourths disulfonic acid takes charge of good fortune again
Wei (1:2), naphthalene -1,5- disulfonic acid times Si Fuwei (1:2), phosphoric acid times Si Fuwei (1:1), carbonic acid times Si Fuwei (1:1), acetic acid times
Si Fuwei (1:1), propionic acid times Si Fuwei (1:1), Pfansteihl times Si Fuwei (1:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (1:1), racemization breast
Acid times Si Fuwei (1:1), palmitic acid times Si Fuwei (1:1), stearic acid times Si Fuwei (1:1), oxalic acid times Si Fuwei (1:1), third
Diacid times Si Fuwei (1:1), butanedioic acid times Si Fuwei (1:1), L MALIC ACID times Si Fuwei (1:1), D-malic acid times Si Fuwei
(1:1), racemization malic acid times Si Fuwei (1:1), L-TARTARIC ACID times Si Fuwei (1:1), D- tartaric acid times Si Fuwei (1:1) it is, outer
Recemic-tartaric acid times Si Fuwei (1:1), mesotartaric acid times Si Fuwei (1:1), fumaric acid times Si Fuwei (1:1), citric acid
Times Si Fuwei (1:1), benzoic acid times Si Fuwei (1:1), L- mandelic acids times Si Fuwei (1:1), D- mandelic acids times Si Fuwei (1:
1), racemic mandelic acid times Si Fuwei (1:1), nicotinic acid times Si Fuwei (1:1), hydroxyl naphthoic acid times Si Fuwei (1:1), pamoic acid is taken charge of again
Fu Wei (1:1), hippuric acid times Si Fuwei (1:1), hydrochloric acid times Si Fuwei (1:1), sulfuric acid times Si Fuwei (1:1), thiocyanic acid is taken charge of again
Fu Wei (1:1), hydrobromic acid (1:1) times Si Fuwei, nitric acid times Si Fuwei (1:1), taurine times Si Fuwei (1:1), 1,2- second two
Sulfonic acid times Si Fuwei (1:1), 1,4- fourths disulfonic acid times Si Fuwei (1:1), benzene sulfonic acid times Si Fuwei (1:1), 2,5- dihydroxy benzenes
Sulfonic acid times Si Fuwei (1:1), phosphoric acid times Si Fuwei (2:1), carbonic acid times Si Fuwei (2:1), acetic acid times Si Fuwei (2:1), propionic acid
Times Si Fuwei (2:1), Pfansteihl times Si Fuwei (2:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (2:1), racemic lactic acid times Si Fuwei (2:1)、
Palmitic acid times Si Fuwei (2:1), stearic acid times Si Fuwei (2:1), oxalic acid times Si Fuwei (2:1), malonic acid times Si Fuwei (2:
1), butanedioic acid times Si Fuwei (2:1), L MALIC ACID times Si Fuwei (2:1), D-malic acid times Si Fuwei (2:1), racemization malic acid
Times Si Fuwei (2:1), L-TARTARIC ACID times Si Fuwei (2:1), D- tartaric acid times Si Fuwei (2:1), racemic tartaric acid takes charge of good fortune again
Wei (2:1), mesotartaric acid times Si Fuwei (2:1), fumaric acid times Si Fuwei (2:1), citric acid times Si Fuwei (2:1), benzene
Formic acid times Si Fuwei (2:1), L- mandelic acids times Si Fuwei (2:1), D- mandelic acids times Si Fuwei (2:1), racemic mandelic acid is taken charge of again
Fu Wei (2:1), nicotinic acid times Si Fuwei (2:1), hydroxyl naphthoic acid times Si Fuwei (2:1), pamoic acid times Si Fuwei (2:1), hippuric acid
Times Si Fuwei (2:1), hydrochloric acid times Si Fuwei (2:1), sulfuric acid times Si Fuwei (2:1), thiocyanic acid times Si Fuwei (2:1), hydrobromic acid
Times Si Fuwei (2:1), nitric acid times Si Fuwei (2:1), taurine times Si Fuwei (2:1), 1,2- ethionic acids times Si Fuwei (2:
1), 1,4- fourths disulfonic acid times Si Fuwei (2:1), benzene sulfonic acid times Si Fuwei (2:1), 2,5- dihydroxy benzenes sulfonic acids times Si Fuwei (2:
1), phosphoric acid times Si Fuwei (3:1), carbonic acid times Si Fuwei (3:1), acetic acid times Si Fuwei (3:1), propionic acid times Si Fuwei (3:1)、L-
Lactic acid times Si Fuwei (3:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (3:1), racemic lactic acid times Si Fuwei (3:1), palmitic acid times Si Fuwei (3:
1), stearic acid times Si Fuwei (3:1), oxalic acid times Si Fuwei (3:1), malonic acid times Si Fuwei (3:1), butanedioic acid times Si Fuwei
(3:1), L MALIC ACID times Si Fuwei (3:1), D-malic acid times Si Fuwei (3:1), racemization malic acid times Si Fuwei (3:1)、L-
Tartaric acid times Si Fuwei (3:1), D- tartaric acid times Si Fuwei (3:1), racemic tartaric acid times Si Fuwei (3:1), meso wine
Stone acid times Si Fuwei (3:1), fumaric acid times Si Fuwei (3:1), citric acid times Si Fuwei (3:1), benzoic acid times Si Fuwei (3:
1), L- mandelic acids times Si Fuwei (3:1), D- mandelic acids times Si Fuwei (3:1), racemic mandelic acid times Si Fuwei (3:1), nicotinic acid times
Si Fuwei (3:1), hydroxyl naphthoic acid times Si Fuwei (3:1), pamoic acid times Si Fuwei (3:1), hippuric acid times Si Fuwei (3:1), salt
Acid times Si Fuwei (3:1), sulfuric acid times Si Fuwei (3:1), thiocyanic acid times Si Fuwei (3:1), hydrobromic acid times Si Fuwei (3:1), nitre
Acid times Si Fuwei (3:1), taurine times Si Fuwei (3:1), 1,2- ethionic acids times Si Fuwei (3:1), 1,4- fourths disulfonic acid times
Si Fuwei (3:1), benzene sulfonic acid times Si Fuwei (3:1), 2,5- dihydroxy benzenes sulfonic acids times Si Fuwei (3:1) one kind times Si Fuwei in
Compound, and pharmaceutic adjuvant.It is preferred that oral formulations, more preferably tablet and capsule；In unit composition or preparation, they
Weight content is generally 1mg to 2g, preferably 100mg to 800mg, and such as above-mentioned times Si Fuwei compounds about 150mg (to take charge of good fortune again
Wei meter), wherein " about " refers to ± 5% scope.
In one embodiment, it is compound the invention provides times Si Fuwei shown in a kind of Formula II comprising therapeutically effective amount
The compound or preparation of levocarnitine shown in thing, formula III or derivatives thereof and pharmaceutic adjuvant.Said composition or preparation are excellent
Select oral formulations, more preferably tablet and capsule；In the unit composition or preparation, their own weight content is generally
1mg to 2g, preferably 100mg are to 800mg, such as containing times Si Fuwei compounds about 150mg shown in Formula II (in terms of Si Fuwei again)
With L-carnitine or derivatives thereof about 600mg (in terms of levocarnitine), wherein " about " refers to ± 5% scope.
Preferably, present embodiment provides following composition or preparation：
A kind of pharmaceutical composition or preparation, it includes two kinds of active components and pharmaceutic adjuvant, and one of which active component is
Phosphoric acid times Si Fuwei (1:3), citric acid times Si Fuwei (1:3), phosphoric acid times Si Fuwei (1:2), carbonic acid times Si Fuwei (1:2) it is, careless
Acid times Si Fuwei (1:2), malonic acid times Si Fuwei (1:2), butanedioic acid times Si Fuwei (1:2), L MALIC ACID times Si Fuwei (1:
2), D-malic acid times Si Fuwei (1:2), racemization malic acid times Si Fuwei (1:2), L-TARTARIC ACID times Si Fuwei (1:2), D- winestones
Acid times Si Fuwei (1:2), racemic tartaric acid times Si Fuwei (1:2), mesotartaric acid times Si Fuwei (1:2), fumaric acid times
Si Fuwei (1:2), citric acid times Si Fuwei (1:2), pamoic acid times Si Fuwei (1:2), sulfuric acid times Si Fuwei (1:2)、1,2-
Ethionic acid times Si Fuwei (1:2), 1,4- fourths disulfonic acid times Si Fuwei (1:2), naphthalene -1,5- disulfonic acid times Si Fuwei (1:2), phosphorus
Acid times Si Fuwei (1:1), carbonic acid times Si Fuwei (1:1), acetic acid times Si Fuwei (1:1), propionic acid times Si Fuwei (1:1), Pfansteihl
Times Si Fuwei (1:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (1:1), racemic lactic acid times Si Fuwei (1:1), palmitic acid times Si Fuwei (1:1)、
Stearic acid times Si Fuwei (1:1), oxalic acid times Si Fuwei (1:1), malonic acid times Si Fuwei (1:1), butanedioic acid times Si Fuwei (1:
1), L MALIC ACID times Si Fuwei (1:1), D-malic acid times Si Fuwei (1:1), racemization malic acid times Si Fuwei (1:1), L- winestones
Acid times Si Fuwei (1:1), D- tartaric acid times Si Fuwei (1:1), racemic tartaric acid times Si Fuwei (1:1), mesotartaric acid
Times Si Fuwei (1:1), fumaric acid times Si Fuwei (1:1), citric acid times Si Fuwei (1:1), benzoic acid times Si Fuwei (1:1)、L-
Mandelic acid times Si Fuwei (1:1), D- mandelic acids times Si Fuwei (1:1), racemic mandelic acid times Si Fuwei (1:1), nicotinic acid takes charge of good fortune again
Wei (1:1), hydroxyl naphthoic acid times Si Fuwei (1:1), pamoic acid times Si Fuwei (1:1), hippuric acid times Si Fuwei (1:1), hydrochloric acid times
Si Fuwei (1:1), sulfuric acid times Si Fuwei (1:1), thiocyanic acid times Si Fuwei (1:1), hydrobromic acid (1:1) times Si Fuwei, nitric acid times
Si Fuwei (1:1), taurine times Si Fuwei (1:1), 1,2- ethionic acids times Si Fuwei (1:1), 1,4- fourths disulfonic acid takes charge of good fortune again
Wei (1:1), benzene sulfonic acid times Si Fuwei (1:1), 2,5- dihydroxy benzenes sulfonic acids times Si Fuwei (1:1), phosphoric acid times Si Fuwei (2:1)、
Carbonic acid times Si Fuwei (2:1), acetic acid times Si Fuwei (2:1), propionic acid times Si Fuwei (2:1), Pfansteihl times Si Fuwei (2:1)、D-
Lactic acid times Si Fuwei (2:1), racemic lactic acid times Si Fuwei (2:1), palmitic acid times Si Fuwei (2:1), stearic acid times Si Fuwei (2:
1), oxalic acid times Si Fuwei (2:1), malonic acid times Si Fuwei (2:1), butanedioic acid times Si Fuwei (2:1), L MALIC ACID times Si Fuwei
(2:1), D-malic acid times Si Fuwei (2:1), racemization malic acid times Si Fuwei (2:1), L-TARTARIC ACID times Si Fuwei (2:1)、D-
Tartaric acid times Si Fuwei (2:1), racemic tartaric acid times Si Fuwei (2:1), mesotartaric acid times Si Fuwei (2:1), rich horse
Acid times Si Fuwei (2:1), citric acid times Si Fuwei (2:1), benzoic acid times Si Fuwei (2:1), L- mandelic acids times Si Fuwei (2:
1), D- mandelic acids times Si Fuwei (2:1), racemic mandelic acid times Si Fuwei (2:1), nicotinic acid times Si Fuwei (2:1), hydroxyl naphthoic acid is taken charge of again
Fu Wei (2:1), pamoic acid times Si Fuwei (2:1), hippuric acid times Si Fuwei (2:1), hydrochloric acid times Si Fuwei (2:1), sulfuric acid times
Si Fuwei (2:1), thiocyanic acid times Si Fuwei (2:1), hydrobromic acid times Si Fuwei (2:1), nitric acid times Si Fuwei (2:1), taurine
Times Si Fuwei (2:1), ethionic acid times Si Fuwei (2:1), fourth disulfonic acid times Si Fuwei (2:1), benzene sulfonic acid times Si Fuwei (2:
1), 2,5- dihydroxy benzenes sulfonic acids times Si Fuwei (2:1), phosphoric acid times Si Fuwei (3:1), carbonic acid times Si Fuwei (3:1), acetic acid is taken charge of again
Fu Wei (3:1), propionic acid times Si Fuwei (3:1), Pfansteihl times Si Fuwei (3:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (3:1), racemic lactic acid
Times Si Fuwei (3:1), palmitic acid times Si Fuwei (3:1), stearic acid times Si Fuwei (3:1), oxalic acid times Si Fuwei (3:1), the third two
Acid times Si Fuwei (3:1), butanedioic acid times Si Fuwei (3:1), L MALIC ACID times Si Fuwei (3:1), D-malic acid times Si Fuwei (3:
1), racemization malic acid times Si Fuwei (3:1), L-TARTARIC ACID times Si Fuwei (3:1), D- tartaric acid times Si Fuwei (3:1), racemic
Tartaric acid times Si Fuwei (3:1), mesotartaric acid times Si Fuwei (3:1), fumaric acid times Si Fuwei (3:1), citric acid is taken charge of again
Fu Wei (3:1), benzoic acid times Si Fuwei (3:1), L- mandelic acids times Si Fuwei (3:1), D- mandelic acids times Si Fuwei (3:1), disappear
Revolve mandelic acid times Si Fuwei (3:1), nicotinic acid times Si Fuwei (3:1), hydroxyl naphthoic acid times Si Fuwei (3:1), pamoic acid times Si Fuwei
(3:1), hippuric acid times Si Fuwei (3:1), hydrochloric acid times Si Fuwei (3:1), sulfuric acid times Si Fuwei (3:1), thiocyanic acid times Si Fuwei
(3:1), hydrobromic acid times Si Fuwei (3:1), nitric acid times Si Fuwei (3:1), taurine times Si Fuwei (3:1), 1,2- ethionic acids
Times Si Fuwei (3:1), 1,4- fourths disulfonic acid times Si Fuwei (3:1), benzene sulfonic acid times Si Fuwei (3:1), 2,5- dihydroxy benzenes sulfonic acids
Times Si Fuwei (3:1) one kind in, another active component is levocarnitine, acetyl levocarnitine, chloracetyl levocarnitine, third
The left card Buddhist nun of acyl levocarnitine, chlorine propionyl-L-carnitine, Acetyl-L-carnitine hydrochloride, ST 261, hydrochloric acid chloracetyl
One kind in spit of fland or hydrochloric acid chlorine propionyl-L-carnitine.It is preferred that oral formulations, more preferably tablet and capsule；In unit composition or
In preparation, their own weight content is generally 1mg to 2g, preferably 100mg to 800mg, and such as above-mentioned times Si Fuwei is combined
Thing about 150mg (in terms of Si Fuwei again) and levocarnitine or derivatives thereof about 600mg (in terms of levocarnitine), wherein " about " refer to ±
5% scope.
Aforementioned pharmaceutical compositions or preparation can be prepared according to the conventional production process of pharmaceutical field, such as by times Si Fuwei
Compound and levocarnitine or derivatives thereof are mixed with one or more pharmaceutic adjuvants, are then made into required formulation.
Above-mentioned composition is not only stable in chemistry, and also has synergy and/or can reduce individually
Times Si Fuwei side effect.
To realize the purpose of the present invention, another further aspect, the invention provides times Si Fuwei compounds shown in Formula II, or institute
Times Si Fuwei compounds made from preparation method are stated, or described pharmaceutical composition is preparing prevention and/or is treating virus infection
Application in medicine.
In one embodiment, preparing prevention the invention provides above-mentioned times of Si Fuwei compound and/or treating B-mode
Application in hepatitis viruse (HBV) and/or the medicine of human immunodeficiency virus (HIV) infection.
In one embodiment, the invention provides the above-mentioned times of Si Fuwei compound comprising therapeutically effective amount and medicinal auxiliary
The pharmaceutical composition of material is preparing prevention and/or treatment hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV)
Application in the medicine of infection.
In one embodiment, the invention provides above-mentioned times of Si Fuwei compounds, Zuo Kani comprising therapeutically effective amount
The pharmaceutical composition of spit of fland or derivatives thereof and pharmaceutic adjuvant is preparing prevention and/or treatment hepatitis type B virus (HBV) and/or people
Application in the medicine of para-immunity defective virus (HIV) infection.
It the experiment proved that, times Si Fuwei compounds that the present invention is provided have following advantage：
(1) preparation method is easy, and the product of high-purity can be made.
(2) there is physical behavior, chemical stability or preparation adaptability good or improve.
Embodiment
The embodiment of form, does further specifically to foregoing invention content of the invention by the following examples
It is bright, but should not be construed as the content of the invention of the present invention and be only limitted to following examples, it is all to be made based on the above of the present invention
Invention belongs to the scope of the present invention.
Embodiment 1
Oxalic acid times Si Fuwei (1:1) preparation
At 40~45 DEG C, times Si Fuwei 5.0g (9.48mmol) and oxalic acid 0.85g (9.44mmol) are dissolved in isopropanol
In 200mL, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration；Filter cake depressurizes dry at 30~35 DEG C
It is dry, obtain oxalic acid times Si Fuwei (1:1).Yield 95.2%.HPLC purity is 99.6%.
Embodiment 2
Oxalic acid times Si Fuwei (1:2) preparation
At 45~50 DEG C, times Si Fuwei 5.0g (9.48mmol) and oxalic acid 0.43g (4.78mmol) are dissolved in isopropanol
In 200mL, stirring is cooled to 15~20 DEG C after dissolving completely, continues stirring and crystallizing；Suction filtration；Filter cake depressurizes dry at 30~35 DEG C
It is dry, obtain oxalic acid times Si Fuwei (1:2).Yield 92.8%.HPLC purity is 99.4%.
Embodiment 3~10
The preparation method of each times of Si Fuwei compound in embodiment 3~10, except medicinal acid used, solvent are different with rate of charge
Outside, other operations are carried out by the operation described in embodiment 1.
Embodiment 11
1,4- fourth disulfonic acid times Si Fuwei (1:1) preparation
It is at 45~50 DEG C, times Si Fuwei 5.0g (9.48mmol) and Isosorbide-5-Nitrae-fourth disulfonic acid 2.05g (9.48mmol) is molten
In after methanol/ethanol (volume ratio 1/1) 100mL in the mixed solvent, dissolving completely, isopropyl is added dropwise at 45~50 DEG C of temperature in control
Stirring is cooled to 15~20 DEG C after ether 50mL, completion of dropping, continues stirring and crystallizing；Suction filtration；Filter cake depressurizes dry at 35~40 DEG C
It is dry, obtain fourth disulfonic acid times Si Fuwei (1:1).Yield 94.3%.HPLC purity is 99.4%.
Embodiment 12
Citric acid times Si Fuwei (1:3) preparation
At 50~55 DEG C, times Si Fuwei 5.0g (9.48mmol) and citric acid 0.61g (3.17mmol) are dissolved in methanol
In 50mL solvent, it is added dropwise after methyl tertiary butyl ether(MTBE) 15mL, completion of dropping and stirs at 45~50 DEG C of temperature after dissolving completely, in control
15~20 DEG C are cooled to, continues stirring and crystallizing；Suction filtration；Filter cake is dried under reduced pressure at 30~35 DEG C, obtains citric acid times Si Fuwei (1:
3).Yield 92.8%.HPLC purity is 99.89%.
Embodiment 13~19
The preparation method of each times of Si Fuwei compound in embodiment 13~19, except medicinal acid used, solvent and rate of charge not
With outside, other operations are carried out by the operation described in embodiment 11.
Embodiment 20
Hydrobromic acid times Si Fuwei (2:1) preparation of salt
At 40~45 DEG C, times Si Fuwei 5.0g (9.48mmol) and hydrobromic acid 1.53g (18.91mmol) are dissolved in ethanol
In 250mL, when being concentrated into original volume half after dissolving completely, stirring is cooled to 15~20 DEG C, continues stirring and crystallizing；Suction filtration；Filter
Cake is dried under reduced pressure at 30~35 DEG C, obtains hydrobromic acid times Si Fuwei (2:1).Yield 91.3%.HPLC purity is 99.0%.
Embodiment 21~27
The preparation method of each times of Si Fuwei compound in embodiment 21~27, except medicinal acid used, solvent and rate of charge not
With outside, other operations are carried out by the operation described in embodiment 20.
Embodiment 28
Stability study
A times Si Fuwei monoethyl maleates (being prepared by the method disclosed in patent document CN101616674A), oxalic acid is taken to take charge of again
Fu Wei (1:1) (preparing as described in Example 1), 1,4- fourth disulfonic acid times Si Fuwei (1:1) (make as described in Example 11
It is standby), carbonic acid times Si Fuwei (1:1) (preparing as described in Example 3), propionic acid times Si Fuwei (2:1) (the method for pressing embodiment 22
Prepare) tested respectively under the conditions of high temperature (60 DEG C ± 2 DEG C), detected after 10 days, it is as a result as follows：
| Sample | 0 day HPLC purity | 10 days HPLC purity |
| Times Si Fuwei monoethyl maleates | 99.2% | 98.1% |
| Oxalic acid times Si Fuwei (1:1) | 99.6% | 99.4% |
| 1,4- fourth disulfonic acid times Si Fuwei (1:1) | 99.4% | 99.1% |
| Carbonic acid times Si Fuwei (1:1) | 99.7% | 90.1% |
| Propionic acid times Si Fuwei (2:1) | 99.8% | 96.5% |
The studies above shows：The oxalic acid times Si Fuwei (1 that the present invention is provided:1) with 1,4- fourth disulfonic acid times Si Fuwei (1:1)
Good thermal stability.
Embodiment 29
Solubility studies
A times Si Fuwei monoethyl maleates (being prepared by the method disclosed in patent document CN101616674A), oxalic acid is taken to take charge of again
Fu Wei (1:1) (prepare as described in Example 1) and 1,4- fourth disulfonic acid times Si Fuwei (1:1) (make as described in Example 11
It is standby), determine their dissolubilities in different pH medium respectively at 25 DEG C, it is as a result as follows：
The studies above shows：The oxalic acid times Si Fuwei (1 that the present invention is provided:1) with 1,4 fourth disulfonic acid times Si Fuwei (1:1)
Dissolubility be significantly increased compared with a times Si Fuwei monoethyl maleates.
Embodiment 30
Oxalic acid times Si Fuwei (1:1) thin membrane coated tablet and its preparation
| Component | Content (mg/ pieces) |
| Label： | |
| Oxalic acid times Si Fuwei (1:1) | 175.6 |
| Microcrystalline cellulose | 150.0 |
| Lactose monohydrate | 120.0 |
| Pregelatinized starch | 50.0 |
| Cross-linked carboxymethyl cellulose sodium | 20.0 |
| Magnesium stearate | 10.0 |
| Thin film coating material： | |
| Opadry II | 20.0 |
Concrete operations：
Weighed according to each supplementary material in upper table, pregelatinized starch and cross-linked carboxymethyl cellulose sodium are mixed together 5 minutes, plus
Enter lactose monohydrate to mix 10 minutes, add oxalic acid times Si Fuwei (1:1) mixed 10 minutes with microcrystalline cellulose.Plus purified water is suitable
Amount, is pelletized using efficient wet granulator, is dried at 60 DEG C or so, then through 24 mesh perforated screen whole grains, additional magnesium stearate is mixed
Even 10 minutes, tabletting；Then coating material is made into suspension with the stirring of 75% ethanol, using high-efficiency coating machine, makes piece bed temperature
Degree is coated at 45 DEG C or so, is produced.
Embodiment 31
1,4- fourth disulfonic acid times Si Fuwei (1:1) capsule and its preparation
| Component | Content (mg/ pieces) |
| 1,4- fourth disulfonic acid times Si Fuwei (1:1) | 211.5 |
| Microcrystalline cellulose | 150.0 |
| Lactose monohydrate | 65.0 |
| Sodium carboxymethyl starch | 15.0 |
| Magnesium stearate | 1.5 |
Concrete operations：
Weighed according to each supplementary material in upper table, sodium carboxymethyl starch and lactose monohydrate are mixed together 5 minutes, add crystallite
Cellulose is mixed 10 minutes, adds Isosorbide-5-Nitrae-fourth disulfonic acid times Si Fuwei (1:1) mix 10 minutes.Plus Purified Water q. s, use
Efficient wet granulator is pelletized, and is dried at 60 DEG C or so, then through 24 mesh perforated screen whole grains, additional magnesium stearate mixes 10 points
Clock, is packed into hypromellose cellulose capsule, produces.
Embodiment 32
Sulfuric acid times Si Fuwei (1:2) thin membrane coated tablet and its preparation
| Component | Content (mg/ pieces) |
| Label： | |
| Sulfuric acid times Si Fuwei (1:2) | 164.0 |
| Microcrystalline cellulose | 200.0 |
| Lactose monohydrate | 120.0 |
| Pregelatinized starch | 50.0 |
| Cross-linked carboxymethyl cellulose sodium | 20.0 |
| Magnesium stearate | 10.0 |
| Thin film coating material： | |
| Opadry II | 20.0 |
Concrete operations：
Weighed according to each supplementary material in upper table, pregelatinized starch and cross-linked carboxymethyl cellulose sodium are mixed together 5 minutes, plus
Enter lactose monohydrate to mix 10 minutes, add sulfuric acid times Si Fuwei (1:2) mixed 10 minutes with microcrystalline cellulose.Plus purified water is suitable
Amount, is pelletized using efficient wet granulator, is dried at 60 DEG C or so, then through 24 mesh perforated screen whole grains, additional magnesium stearate is mixed
Even 10 minutes, tabletting；Then coating material is made into suspension with the stirring of 75% ethanol, using high-efficiency coating machine, makes piece bed temperature
Degree is coated at 45 DEG C or so, is produced.
Embodiment 33
Citric acid times Si Fuwei (1:3) thin membrane coated tablet and its preparation
| Component | Content (mg/ pieces) |
| Label： | |
| Citric acid times Si Fuwei (1:3) | 168.2 |
| Microcrystalline cellulose | 200.0 |
| Lactose monohydrate | 120.0 |
| Pregelatinized starch | 50.0 |
| Cross-linked carboxymethyl cellulose sodium | 20.0 |
| Magnesium stearate | 10.0 |
| Thin film coating material： | |
| Opadry II | 20.0 |
Concrete operations：
Weighed according to each supplementary material in upper table, pregelatinized starch and cross-linked carboxymethyl cellulose sodium are mixed together 5 minutes, plus
Enter lactose monohydrate to mix 10 minutes, add citric acid times Si Fuwei (1:3) mixed 10 minutes with microcrystalline cellulose.Plus purified water
In right amount, pelletized, dried with fluid bed at 60 DEG C or so using efficient wet granulator, then through 24 mesh perforated screen whole grains, it is additional
Magnesium stearate is mixed 10 minutes, tabletting；Then coating material is made into suspension with the stirring of 75% ethanol, using high-efficiency coating
Machine, makes piece bed tempertaure be coated at 45 DEG C or so, produces.
Embodiment 34
Hydrobromic acid times Si Fuwei (2:1) thin membrane coated tablet and its preparation
Concrete operations：
Weighed according to each supplementary material in upper table, pregelatinized starch and cross-linked carboxymethyl cellulose sodium are mixed together 5 minutes, plus
Enter lactose monohydrate to mix 10 minutes, add hydrobromic acid times Si Fuwei (2:1) mixed 10 minutes with microcrystalline cellulose.Plus purified water
In right amount, pelletized, dried at 60 DEG C or so using efficient wet granulator, then through 24 mesh perforated screen whole grains, additional magnesium stearate
Mix 10 minutes, tabletting；Then coating material is made into suspension with the stirring of 75% ethanol, using high-efficiency coating machine, makes piece bed
Temperature is coated at 45 DEG C or so, is produced.
Embodiment 35
Hydrochloric acid times Si Fuwei (3:1) thin membrane coated tablet and its preparation
| Component | Content (mg/ pieces) |
| Label： | |
| Hydrochloric acid times Si Fuwei (3:1) | 181.1 |
| Microcrystalline cellulose | 200.0 |
| Lactose monohydrate | 120.0 |
| Pregelatinized starch | 50.0 |
| Cross-linked carboxymethyl cellulose sodium | 20.0 |
| Magnesium stearate | 10.0 |
| Thin film coating material： | |
| Opadry II | 20.0 |
Concrete operations：
Weighed according to each supplementary material in upper table, pregelatinized starch and cross-linked carboxymethyl cellulose sodium are mixed together 5 minutes, plus
Enter lactose monohydrate to mix 10 minutes, add hydrochloric acid times Si Fuwei (3:1) mixed 10 minutes with microcrystalline cellulose.Plus purified water is suitable
Amount, is pelletized using efficient wet granulator, is dried at 60 DEG C or so, then through 24 mesh perforated screen whole grains, additional magnesium stearate is mixed
Even 10 minutes, tabletting；Then coating material is made into suspension with the stirring of 75% ethanol, using high-efficiency coating machine, makes piece bed temperature
Degree is coated at 45 DEG C or so, is produced.
Embodiment 36
Oxalic acid times Si Fuwei (1:1), levocarnitine thin membrane coated tablet and its preparation
| Component | Content (mg/ pieces) |
| Label： | |
| Oxalic acid times Si Fuwei (1:1) | 175.6 |
| Levocarnitine | 600.0 |
| Microcrystalline cellulose | 300.0 |
| Lactose monohydrate | 120.0 |
| Pregelatinized starch | 50.0 |
| Cross-linked carboxymethyl cellulose sodium | 20.0 |
| Magnesium stearate | 10.0 |
| Thin film coating material： | |
| Opadry II | 20.0 |
Concrete operations：
Weighed according to each supplementary material in upper table, pregelatinized starch and cross-linked carboxymethyl cellulose sodium are mixed together 5 minutes, plus
Enter lactose monohydrate to mix 10 minutes, add oxalic acid times Si Fuwei (1:1) mix 10 minutes, add levocarnitine and microcrystalline cellulose
Element mixing 10 minutes.Plus Purified Water q. s, pelletized, dried with fluid bed at 60 DEG C or so to moisture using efficient wet granulator
Less than 1.5%, then through 24 mesh perforated screen whole grains, additional magnesium stearate is mixed 10 minutes, tabletting；Then coating material is used
The stirring of 75% ethanol is made into suspension, using high-efficiency coating machine, piece bed tempertaure is coated at 45 DEG C or so, produces.
The foregoing is only a specific embodiment of the invention, but protection scope of the present invention is not limited thereto, any
Those skilled in the art disclosed herein technical scope in, the change that can expect without creative work or
Replace, should all be included within the scope of the present invention.Therefore, protection scope of the present invention should be limited with claims
Fixed protection domain is defined.
Claims (11)
1. times Si Fuwei compounds shown in Formula II,
Wherein, n=1/3,1/2,1,2 or 3, B are selected from：Hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid,
Nitric acid, carbonic acid, dodecyl sulphate, phosphoglycerol, 2- ethylenehydrinsulfonic acids, taurine, camphorsulfonic acid, cyclamic acid, amino
Sulfonic acid, 1,2- ethionic acids, 1,4- fourths disulfonic acid, benzene sulfonic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2,5- dihydroxy benzenes
Sulfonic acid, p-aminobenzene sulfonic acid, saccharin, naphthalene -1,5- disulfonic acid, formic acid, acetic acid, glycolic, 2,2- dichloroacetic acid, propionic acid, L- breasts
Acid, D-ALPHA-Hydroxypropionic acid, racemic lactic acid, pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, octanoic acid, n-nonanoic acid, capric acid, undecenoic acid, the moon
Cinnamic acid, palmitic acid, stearic acid, oleic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D-malic acid, racemization malic acid, L- wine
Stone acid, D- tartaric acid, racemic tartaric acid, mesotartaric acid, fumaric acid, 1,5- glutaric acids, 2- oxo -1,5- glutaric acids,
1,6- adipic acids, 1,10- decanedioic acid, citric acid, benzoic acid, P-methoxybenzoic acid, 4- acetaminobenzoic acids, salicylic acid,
Acetylsalicylic acid, gentianic acid, 4-ASA, phenylacetic acid, L- mandelic acids, D- mandelic acids, racemic mandelic acid, 3- phenyl third
Acid, cinnamic acid, caffeic acid, benzenebutanoic acid, picric acid, nicotinic acid, orotic acid, chinic acid, ascorbic acid, glucuronic acid, glucose
Acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactosaccharic acid, tannic acid, alginic acid, 1- hydroxyl -2- naphthalene first
Acid, 4,4'- methylene two (3- hydroxy-2-naphthoic acids), acetylgiycine, hippuric acid, asparatate, glutamic acid, burnt paddy ammonia
Acid, glutamine or asparagine.
2. according to claim 1 times of Si Fuwei compound, wherein,
N=1/3, B are selected from：Phosphoric acid, citric acid, tannic acid or alginic acid；Or,
N=1/2, B are selected from：Sulfuric acid, persulfuric acid, phosphoric acid, carbonic acid, phosphoglycerol, 1,2- ethionic acids, 1,4- fourths disulfonic acid, naphthalene-
1,5- disulfonic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D-malic acid, racemization malic acid, L-TARTARIC ACID, D- tartaric acid,
Racemic tartaric acid, mesotartaric acid, fumaric acid, 1,5- glutaric acids, 2- oxo -1,5- glutaric acids, 1,6- adipic acids, 1,
10- decanedioic acid, citric acid, camphoric acid, galactosaccharic acid, tannic acid, the alginic acid, (3- hydroxyl -2- naphthalene first of 4,4'- methylene two
Acid), asparatate or glutamic acid；Or,
N=1,2 or 3, B are selected from：Hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, ten
Dialkyl group sulfuric acid, phosphoglycerol, 2- ethylenehydrinsulfonic acids, taurine, camphorsulfonic acid, cyclamic acid, sulfamic acid, 1,2- second two
Sulfonic acid, 1,4- fourths disulfonic acid, benzene sulfonic acid, p-hydroxybenzenyl sulfonate, o hydroxybenzenesulfonic acid, 2,5- dihydroxy benzenes sulfonic acids, p-aminophenyl
Sulfonic acid, saccharin, naphthalene -1,5- disulfonic acid, formic acid, acetic acid, glycolic, 2,2- dichloroacetic acid, propionic acid, Pfansteihl, D-ALPHA-Hydroxypropionic acid, racemization
It is lactic acid, pentamethylene propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, octanoic acid, n-nonanoic acid, capric acid, undecenoic acid, laurate, palmitic acid, hard
Resin acid, oleic acid, oxalic acid, malonic acid, butanedioic acid, L MALIC ACID, D-malic acid, racemization malic acid, L-TARTARIC ACID, D- tartaric acid,
Racemic tartaric acid, mesotartaric acid, fumaric acid, 1,5- glutaric acids, 2- oxo -1,5- glutaric acids, 1,6- adipic acids, 1,
10- decanedioic acid, citric acid, benzoic acid, P-methoxybenzoic acid, 4- acetaminobenzoic acids, salicylic acid, acetylsalicylic acid, dragon
Cholic acid, 4-ASA, phenylacetic acid, L- mandelic acids, D- mandelic acids, racemic mandelic acid, 3- phenylpropionic acids, cinnamic acid, coffee
Acid, benzenebutanoic acid, picric acid, nicotinic acid, orotic acid, chinic acid, ascorbic acid, glucuronic acid, gluconic acid, galacturonic acid,
Glucoheptonic acid, lactobionic acid, camphoric acid, galactosaccharic acid, tannic acid, alginic acid, 1- hydroxy-2-naphthoic acids, 4,4'- methylene two
(3- hydroxy-2-naphthoic acids), acetylgiycine, hippuric acid, asparatate, glutamic acid, pyroglutamic acid, glutamine or Tianmen
Winter acid amides.
3. according to claim 2 times of Si Fuwei compound, wherein, described times of Si Fuwei compound is selected from：
Phosphoric acid times Si Fuwei (1:Or citric acid times Si Fuwei (1 3):3)；
Phosphoric acid times Si Fuwei (1:2), carbonic acid times Si Fuwei (1:2), oxalic acid times Si Fuwei (1:2), malonic acid times Si Fuwei (1:
2), butanedioic acid times Si Fuwei (1:2), L MALIC ACID times Si Fuwei (1:2), D-malic acid times Si Fuwei (1:2), racemization malic acid
Times Si Fuwei (1:2), L-TARTARIC ACID times Si Fuwei (1:2), D- tartaric acid times Si Fuwei (1:2), racemic tartaric acid takes charge of good fortune again
Wei (1:2), mesotartaric acid times Si Fuwei (1:2), fumaric acid times Si Fuwei (1:2), citric acid times Si Fuwei (1:2)、4,
4'- methylene two (3- hydroxy-2-naphthoic acids) times Si Fuwei (1:2), sulfuric acid times Si Fuwei (1:2), 1,2- ethionic acids are taken charge of again
Fu Wei (1:2), 1,4- fourths disulfonic acid times Si Fuwei (1:Or naphthalene -1,5- disulfonic acid times Si Fuwei (1 2):2)；
Phosphoric acid times Si Fuwei (1:1), carbonic acid times Si Fuwei (1:1), acetic acid times Si Fuwei (1:1), propionic acid times Si Fuwei (1:1)、
Pfansteihl times Si Fuwei (1:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (1:1), racemic lactic acid times Si Fuwei (1:1), palmitic acid times Si Fuwei
(1:1), stearic acid times Si Fuwei (1:1), oxalic acid times Si Fuwei (1:1), malonic acid times Si Fuwei (1:1), butanedioic acid takes charge of good fortune again
Wei (1:1), L MALIC ACID times Si Fuwei (1:1), D-malic acid times Si Fuwei (1:1), racemization malic acid times Si Fuwei (1:1)、
L-TARTARIC ACID times Si Fuwei (1:1), D- tartaric acid times Si Fuwei (1:1), racemic tartaric acid times Si Fuwei (1:1), meso
Tartaric acid times Si Fuwei (1:1), fumaric acid times Si Fuwei (1:1), citric acid times Si Fuwei (1:1), benzoic acid times Si Fuwei (1:
1), L- mandelic acids times Si Fuwei (1:1), D- mandelic acids times Si Fuwei (1:1), racemic mandelic acid times Si Fuwei (1:1), nicotinic acid times
Si Fuwei (1:1), 1- hydroxy-2-naphthoic acids times Si Fuwei (1:1), 4,4'- methylene two (3- hydroxy-2-naphthoic acids) times takes charge of good fortune
Wei (1:1), hippuric acid times Si Fuwei (1:1), hydrochloric acid times Si Fuwei (1:1), sulfuric acid times Si Fuwei (1:1), thiocyanic acid takes charge of good fortune again
Wei (1:1), hydrobromic acid times Si Fuwei (1:1), nitric acid times Si Fuwei (1:1), taurine times Si Fuwei (1:1), the sulphur of 1,2- second two
Acid times Si Fuwei (1:1), 1,4- fourths disulfonic acid times Si Fuwei (1:1), benzene sulfonic acid times Si Fuwei (1:Or 2,5- dihydroxy benzenes sulphurs 1)
Acid times Si Fuwei (1:1)；
Phosphoric acid times Si Fuwei (2:1), carbonic acid times Si Fuwei (2:1), acetic acid times Si Fuwei (2:1), propionic acid times Si Fuwei (2:1)、
Pfansteihl times Si Fuwei (2:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (2:1), racemic lactic acid times Si Fuwei (2:1), palmitic acid times Si Fuwei
(2:1), stearic acid times Si Fuwei (2:1), oxalic acid times Si Fuwei (2:1), malonic acid times Si Fuwei (2:1), butanedioic acid takes charge of good fortune again
Wei (2:1), L MALIC ACID times Si Fuwei (2:1), D-malic acid times Si Fuwei (2:1), racemization malic acid times Si Fuwei (2:1)、
L-TARTARIC ACID times Si Fuwei (2:1), D- tartaric acid times Si Fuwei (2:1), racemic tartaric acid times Si Fuwei (2:1), meso
Tartaric acid times Si Fuwei (2:1), fumaric acid times Si Fuwei (2:1), citric acid times Si Fuwei (2:1), benzoic acid times Si Fuwei (2:
1), L- mandelic acids times Si Fuwei (2:1), D- mandelic acids times Si Fuwei (2:1), racemic mandelic acid times Si Fuwei (2:1), nicotinic acid times
Si Fuwei (2:1), 1- hydroxy-2-naphthoic acids times Si Fuwei (2:1), 4,4'- methylene two (3- hydroxy-2-naphthoic acids) times takes charge of good fortune
Wei (2:1), hippuric acid times Si Fuwei (2:1), hydrochloric acid times Si Fuwei (2:1), sulfuric acid times Si Fuwei (2:1), thiocyanic acid takes charge of good fortune again
Wei (2:1), hydrobromic acid times Si Fuwei (2:1), nitric acid times Si Fuwei (2:1), taurine times Si Fuwei (2:1), the sulphur of 1,2- second two
Acid times Si Fuwei (2:1), 1,4- fourths disulfonic acid times Si Fuwei (2:1), benzene sulfonic acid times Si Fuwei (2:Or 2,5- dihydroxy benzenes sulphurs 1)
Acid times Si Fuwei (2:1)；
Phosphoric acid times Si Fuwei (3:1), carbonic acid times Si Fuwei (3:1), acetic acid times Si Fuwei (3:1), propionic acid times Si Fuwei (3:1)、
Pfansteihl times Si Fuwei (3:1), D-ALPHA-Hydroxypropionic acid times Si Fuwei (3:1), racemic lactic acid times Si Fuwei (3:1), palmitic acid times Si Fuwei
(3:1), stearic acid times Si Fuwei (3:1), oxalic acid times Si Fuwei (3:1), malonic acid times Si Fuwei (3:1), butanedioic acid takes charge of good fortune again
Wei (3:1), L MALIC ACID times Si Fuwei (3:1), D-malic acid times Si Fuwei (3:1), racemization malic acid times Si Fuwei (3:1)、
L-TARTARIC ACID times Si Fuwei (3:1), D- tartaric acid times Si Fuwei (3:1), racemic tartaric acid times Si Fuwei (3:1), meso
Tartaric acid times Si Fuwei (3:1), fumaric acid times Si Fuwei (3:1), citric acid times Si Fuwei (3:1), benzoic acid times Si Fuwei (3:
1), L- mandelic acids times Si Fuwei (3:1), D- mandelic acids times Si Fuwei (3:1), racemic mandelic acid times Si Fuwei (3:1), nicotinic acid times
Si Fuwei (3:1), 1- hydroxy-2-naphthoic acids times Si Fuwei (3:1), 4,4'- methylene two (3- hydroxy-2-naphthoic acids) times takes charge of good fortune
Wei (3:1), hippuric acid times Si Fuwei (3:1), hydrochloric acid times Si Fuwei (3:1), sulfuric acid times Si Fuwei (3:1), thiocyanic acid takes charge of good fortune again
Wei (3:1), hydrobromic acid times Si Fuwei (3:1), nitric acid times Si Fuwei (3:1), taurine times Si Fuwei (3:1), the sulphur of 1,2- second two
Acid times Si Fuwei (3:1), 1,4- fourths disulfonic acid times Si Fuwei (3:1), benzene sulfonic acid times Si Fuwei (3:Or 2,5- dihydroxy benzenes sulphurs 1)
Acid times Si Fuwei (3:1).
4. the preparation method of according to any one of claims 1 to 3 times of Si Fuwei compound, the preparation method includes：
(1) in suitable solvent, a kind of solution for including times Si Fuwei and acid B is formed；
(2) solid is separated out；
(3) separated out solid is separated；
(4) alternatively, the solid of separation is dried, or rear re-dry is further purified.
5. the preparation method of according to claim 4 times of Si Fuwei compound, wherein,
In step (1), the suitable solvent is selected from water, ethanol, methanol, propyl alcohol, isopropanol, n-butanol, ethylene glycol, formic acid second
Ester, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ether, isopropyl ether, n-butyl ether, glycol monoethyl ether, second two
Diethylene glycol dimethyl ether, t-butyl methyl ether, tetrahydrofuran, petroleum ether, acetonitrile, dichloromethane, chloroform, n-hexane, hexamethylene, third
Ketone, butanone, pentanone, cyclohexanone, toluene, dimethylbenzene, dimethyl acetamide, dimethylformamide or their mixture；
The sour B is selected from the acid representated by B in Formula II；
The sour B and times Si Fuwei molar ratio is 0.2:1~4:1, when n answers for 1/3 times Si Fuwei in formula II
During compound, sour B and times Si Fuwei molar ratio is 0.2:1~0.4:1；When n answers for 1/2 times Si Fuwei in formula II
During compound, sour B and times Si Fuwei molar ratio is 0.5:1~0.7:1；When n is combined for 1 times Si Fuwei in formula II
During thing, sour B and times Si Fuwei molar ratio is 0.8:1~1.5:1；When n is 2 times Si Fuwei compounds in formula II
When, sour B and times Si Fuwei molar ratio is 1.7:1~2.5:1；When n is 3 times Si Fuwei compounds in formula II
When, sour B and times Si Fuwei molar ratio is 2.7:1~3.5:1.
6. a kind of pharmaceutical composition, its according to any one of claims 1 to 3 times of Si Fuwei comprising therapeutically effective amount is combined
Thing, or times Si Fuwei compounds made from preparation method described in claim 4 or 5, and pharmaceutic adjuvant.
7. pharmaceutical composition according to claim 6, it is also comprising levocarnitine or derivatives thereof.
8. pharmaceutical composition according to claim 7, wherein the levocarnitine derivative is selected from acetyl levocarnitine, chlorine
Acetyl levocarnitine, propionyl-L-carnitine, chlorine propionyl-L-carnitine or their officinal salt, the officinal salt is, for example, hydrochloric acid
Acetyl levocarnitine, ST 261, hydrochloric acid chloracetyl levocarnitine or hydrochloric acid chlorine propionyl-L-carnitine.
9. the pharmaceutical composition according to any one of claim 6~8, wherein, described pharmaceutical composition is with preparation shape
Formula is present.
10. according to any one of claims 1 to 3 times of Si Fuwei compound, or the preparation method described in claim 4 or 5
Obtained times of Si Fuwei compound, or pharmaceutical composition any one of claim 6~9 are preparing prevention and/or controlled
Treat the application in the medicine of virus infection.
11. application according to claim 10, wherein the virus infection is exempted from for the hepatitis b virus infected and/or mankind
Epidemic disease defective virus infects.
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| CN201610035611 | 2016-01-19 | ||
| CN2016100356119 | 2016-01-19 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002057288A1 (en) * | 2001-01-19 | 2002-07-25 | Lg Life Sciences Ltd. | Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same |
| CN101616674A (en) * | 2007-01-17 | 2009-12-30 | 株式会社Lg生命科学 | The maleic acid monosalt of antiviral agent and comprise its pharmaceutical composition |
| CN105085571A (en) * | 2014-05-20 | 2015-11-25 | 四川海思科制药有限公司 | Tenofovir alafenamide compound, preparation method and purpose thereof |
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2017
- 2017-01-16 CN CN201710033868.5A patent/CN106977548A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002057288A1 (en) * | 2001-01-19 | 2002-07-25 | Lg Life Sciences Ltd. | Novel acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same |
| CN101616674A (en) * | 2007-01-17 | 2009-12-30 | 株式会社Lg生命科学 | The maleic acid monosalt of antiviral agent and comprise its pharmaceutical composition |
| CN105085571A (en) * | 2014-05-20 | 2015-11-25 | 四川海思科制药有限公司 | Tenofovir alafenamide compound, preparation method and purpose thereof |
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