WO2022089589A1 - Sel double de glycoside flavonoïde-organoamine inhibiteur de dpp-4, son procédé de préparation et application associée - Google Patents

Sel double de glycoside flavonoïde-organoamine inhibiteur de dpp-4, son procédé de préparation et application associée Download PDF

Info

Publication number
WO2022089589A1
WO2022089589A1 PCT/CN2021/127466 CN2021127466W WO2022089589A1 WO 2022089589 A1 WO2022089589 A1 WO 2022089589A1 CN 2021127466 W CN2021127466 W CN 2021127466W WO 2022089589 A1 WO2022089589 A1 WO 2022089589A1
Authority
WO
WIPO (PCT)
Prior art keywords
double salt
dpp
baicalin
inhibitor
salt compound
Prior art date
Application number
PCT/CN2021/127466
Other languages
English (en)
Chinese (zh)
Inventor
王化录
王鹿荧
Original Assignee
杭州拉林智能科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州拉林智能科技有限公司 filed Critical 杭州拉林智能科技有限公司
Publication of WO2022089589A1 publication Critical patent/WO2022089589A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the application relates to the technical field of medicinal chemistry, in particular to a flavonoid glycoside-organic amine DPP-4 inhibitor double salt compound and a preparation method and application thereof.
  • Diabetes mellitus is a common metabolic disease mainly characterized by hyperglycemia caused by both genetic and environmental factors.
  • the basic pathological feature is absolute (type 1 diabetes) or relative insufficient insulin secretion (type 2 diabetes).
  • Diabetes can lead to endocrine and metabolic disorders such as sugar, protein, secondary water and electrolyte metabolism disorders, acid-base balance disorders, and long-term complications such as blindness, renal failure, heart attack, stroke, vascular disease, and even foot damage.
  • Neurodegeneration and central nervous system dysfunction is the main form of diabetes, accounting for 90% of the incidence of diabetes, and insulin resistance is common in type 2 diabetes.
  • Dipeptidyl peptidase 4 (DPP-4) inhibitors have become an important measure for the treatment of type 2 diabetes, such as sitagliptin, saxagliptin, alogliptin, which can inhibit glucagon-like peptide Inactivation of -1 (GLP-1) and glucose-dependent insulin secretion-stimulating polypeptide (GIP) increases the levels of endogenous GLP-1 and GIP, promotes insulin release from islet ⁇ cells, and inhibits islet ⁇ cells from secreting glucagon It increases insulin levels, lowers blood sugar, and is less likely to induce hypoglycemia and weight gain.
  • GLP-1 glucagon-like peptide Inactivation of -1
  • GIP glucose-dependent insulin secretion-stimulating polypeptide
  • Baicalin and baicalin are both flavonoid glycosides (flavonoid glycosides for short), which have rich pharmacological activities, such as improving antioxidant capacity by resisting lipid peroxidation, scavenging free radicals and superoxide anions, improving blood circulation and increasing blood flow. , Anti-platelet aggregation, inhibit virus infection, enhance immunity, anti-cell hypoxia, neuroprotection, inhibit tumor cell growth, etc.
  • the flavonoid glycoside-organic amine DPP-4 inhibitor double salt has higher inhibitory activity on DPP-4.
  • a double salt compound which is a double salt of a flavone glycoside and an organic amine DPP-4 inhibitor, and the flavone glycoside has the general structural formula shown in the following formula (1):
  • R 1 to R 9 are each independently selected from -H, -OH, C 1 -C 6 alkyl, alkoxy or substituted alkyl, and at least one of R 1 and R 2 is selected from -OH.
  • R 1 and R 2 are both selected from -OH.
  • the flavonoid glycoside is baicalin or baicalin.
  • the organic amine DPP-4 inhibitor contains at least one amino group, and the amino groups are each independently selected from -NH 2 , -NR'H or -NR' 2 , the R' for electron donating groups.
  • the organic amine DPP-4 inhibitor is selected from any one of sitagliptin, saxagliptin and alogliptin.
  • this application also provides a kind of preparation method of described double salt compound, comprising the following steps:
  • the mixed solution is reacted to obtain a reaction solution
  • the solvent was removed from the reaction solution.
  • the polar aprotic organic solvent is one or more of N,N-dimethylformamide, dimethylsulfoxide or acetonitrile.
  • Another aspect of the present application further provides a pharmaceutical composition, which contains a therapeutically effective amount of the double salt compound or its optical isomer, enantiomer, diastereomer, racemate or racemate mixture, and a pharmaceutically acceptable carrier, excipient or diluent.
  • the DPP-4 inhibitor drug is used for the treatment of diabetes and complications.
  • the DPP-4 inhibitor is used for the treatment of type 2 diabetes and its complications.
  • a double salt nanoparticle is provided, wherein the double salt nanoparticle is obtained by nano-grinding the double salt compound.
  • Another aspect of the present application provides the application of the double salt nanoparticles in the preparation of DPP-4 inhibitor drugs.
  • the DPP-4 inhibitor drug is used for the treatment of diabetes and complications.
  • the DPP-4 inhibitor is used for the treatment of type 2 diabetes and its complications.
  • Organic amine DPP-4 inhibitors are alkaline and can form salts with inorganic acids or small-molecule organic acids to increase their stability and improve physical properties. Salts formed by molecular organic acids and organic amine DPP-4 inhibitors did not improve the biological activity of these drugs.
  • the double salt compound provided by this application uses a specific structure of flavonoid glycosides and an organic amine DPP-4 inhibitor to form a double salt.
  • the molecular structure of the flavonoid glycoside contains a carboxyl group and a phenolic hydroxyl group, which can inhibit the organic amine DPP-4.
  • the amine group in the agent is bonded, and the binding effect between the two is stronger than that of the general drug salt.
  • the double salt exhibits higher inhibitory activity on DPP-4.
  • Natural compounds such as flavonoid glycosides have poor water solubility, but because there are carboxyl groups and phenolic hydroxyl groups in the molecular structure, they are easily soluble in alkalis, and form salts with small molecular organic bases to enhance their water solubility. Further, the double salt compound provided by the present application is ground by nano-grinding technology to reduce the particle size of the material so that the particle size reaches the nanometer level, so that the double salt compound has better water solubility.
  • Fig. 1 ⁇ Fig. 4 is the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 1 of the application;
  • Figures 9 to 12 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 3 of the application;
  • 13 to 16 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 4 of the application;
  • 17 to 20 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 5 of the application;
  • 21 to 24 are the hydrogen nuclear magnetic resonance spectrum, infrared spectrum, DSC test chart and XRD chart of the double salt compound prepared in Example 6 of the present application.
  • DPP-4 (Dipeptidyl Peptidase-4)
  • alkyl refers to a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, for example, "C 1 -C 6 alkyl” refers to an alkyl group containing 1 to 6 carbon atoms, and each occurrence may independently be a C 1 alkyl, C 2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl .
  • Suitable examples include, but are not limited to: methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n - propyl, -CH2CH2CH ) 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ) , 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 ) )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 ) CH 2 CH 2 CH 3 ), 2-p
  • alkoxy refers to a group having an -O-alkyl group, ie an alkyl group as defined above is attached to the core structure via an oxygen atom.
  • Suitable examples include, but are not limited to: methoxy (-O- CH3 or -OMe), ethoxy (-O- CH2CH3 or -OEt) and tert-butoxy (-OC( CH3 ) 3 or -OtBu).
  • Ammonia refers to a derivative of ammonia, non-limiting classes of amino groups include -NH2 , -N(alkyl) 2 , -NH(alkyl), -N(cycloalkyl) 2 , -NH(cycloalkane) base), -N(heterocyclyl) 2 , -NH(heterocyclyl), -N(aryl) 2 , -NH(aryl), -N(alkyl)(aryl), -N(alkane (heterocyclyl), -N(cycloalkyl)(heterocyclyl), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), and the like.
  • “Pharmaceutically acceptable” refers to those ligands, materials, compositions and/or dosage forms suitable for administration to a patient within the scope of sound medical judgment and commensurate with a reasonable benefit/risk ratio.
  • Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch, potato starch and substituted or unsubstituted beta-cyclodextrins; (3) cellulose and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; Formulations such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyvalent Alcohols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers such as magnesium hydroxide and hydrogen
  • Substituted in reference to a group means that one or more hydrogen atoms attached to member atoms within the group are replaced with a substituent selected from defined or suitable substituents.
  • the term “substituted” should be understood to include the implied condition that such substitution is consistent with the permissible valences of the substituted atoms and substituents and that the substitution results in a stable compound.
  • a group may contain one or more substituents, one or more of the member atoms within the group may be substituted.
  • a single member atom within the group may be substituted with more than one substituent, so long as the substitution is consistent with the permissible valence of the atom.
  • a "member atom” refers to an atom or atoms that form a chain or ring. Where more than one member atom is present in a chain and within a ring, each member atom is covalently bound to an adjacent member atom in the chain or ring. The atoms that make up a substituent on a chain or ring are not member atoms in the chain or ring.
  • IC50 refers to the half-maximal inhibitory concentration of a compound relative to inhibition of a given activity, eg, influenza A virus, DNA polymerase, RNA polymerase. The smaller the IC50 value, the stronger the inhibitory activity of the compound for a given activity.
  • the application relates to a double salt compound, which is a double salt of a flavone glycoside and an organic amine DPP-4 inhibitor, and the flavone glycoside has the general structural formula shown in the following formula (1):
  • R 1 to R 9 are each independently selected from -H, -OH, C 1 -C 6 alkyl, alkoxy or substituted alkyl, and at least one of R 1 and R 2 is selected from -OH.
  • the flavonoid glycosides, the carboxyl hydrogen in the gluconic acid unit in the molecular structure, and the phenolic hydroxyl hydrogen (the hydrogen in R 1 or R 2 ) in the flavonoid unit together form a hydrogen ion-rich region and are proton donors.
  • the nitrogen atom of the organic amine in the organic amine DPP-4 inhibitor contains a lone pair of electrons and is a proton acceptor. The two are combined to form the flavonoid glycoside-organic amine DPP-4 inhibitor double salt.
  • the carboxyl hydrogen in the gluconic acid unit and the phenolic hydroxyl hydrogen in the flavonoid unit in the flavonoid glycosides are located on both sides of the sugar ring, respectively.
  • the carboxyl hydrogen and the phenolic hydroxyl hydrogen on both sides of the sugar ring are converted to the same side, as shown in formula (2), to form a proton nest (proton shown in the dotted box in formula 2). structure), carboxyl oxygen electrons and nitrogen lone pair electrons.
  • the hydrogen proton and amine in the proton nest can form a very stable ammonium salt; from the analysis of molecular orbital theory, the empty orbital of hydrogen in the proton nest and the lone pair of electrons of amine can be perfectly combined; from quantum chemistry and quantum entanglement
  • Theoretical analysis shows that hydrogen electrons in the proton nest, carboxyl oxygen electrons and lone electron pairs of nitrogen in organic amines are entangled in the salt-forming region. After dissociating from the organic base, the quantum entanglement formed during its salt formation continued to exist, which improved the biological activity of the flavonoid glycoside-organic amine DPP-4 inhibitor double salt.
  • R3 is selected from -H or -OCH3 .
  • R 5 , R 6 , R 9 are all selected from -H.
  • R 7 , R 8 are each independently selected from -H or -OH.
  • R8 is selected from -H.
  • R7 is selected from -OH. In other embodiments, R7 is selected from -H.
  • the flavone glycoside can be any one of apigenin flavone glycoside, baicalin, scutellarin, chrysin flavone glycoside or wogonin, optionally, the flavone glycoside is baicalin or Baicalin.
  • the organic amine DPP-4 inhibitor contains at least one amino group, the amino groups are each independently selected from -NH 2 , -NR'H or -NR' 2 , and the R' is an electron donating group.
  • R' alkyl or alkoxy In some embodiments, R' alkyl or alkoxy.
  • the organic amine DPP-4 inhibitor is selected from any one of sitagliptin, saxagliptin and alogliptin.
  • Sitagliptin a dipeptidyl peptidase-4 (DPP-4) inhibitor
  • DPP-4 dipeptidyl peptidase-4
  • the structural formula of sitagliptin is shown below:
  • Saxagliptin a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor, can increase endogenous glucagon-like peptide-1 by selectively inhibiting DPP-4 (Glucagon-like Peptide-1, GLP-1) and glucose-dependent insulinotropic polypeptide (Glucose-dependent Insulinotropic Peptide, GIP) levels, thereby regulating blood sugar.
  • DPP-4 Glucagon-like Peptide-1, GLP-1
  • GIP glucose-dependent insulinotropic polypeptide
  • Alogliptin chemical name is 2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxopyrimidin-1-yl]methyl ] Benzonitrile, a selective inhibitor of DPP-4 with antidiabetic effects.
  • the structural formula of alogliptin is shown below:
  • the application also relates to a preparation method of a described double salt compound, comprising the following steps:
  • the molar ratio of the flavonoid glycoside to the organic amine DPP-4 inhibitor can be any ratio between 1:3 and 3:1, for example, it can also include 1:2, 1:1.5, 1:1, 1.5 :1, 2:1, optional 1:1.
  • the polar aprotic organic solvent may be one or more of N,N-dimethylformamide, dimethylsulfoxide or acetonitrile.
  • step S10 there are various methods for mixing and dissolving the flavonoid glycoside, the organic amine DPP-4 inhibitor and the polar aprotic organic solvent to obtain a mixed solution.
  • the following steps can be included
  • the concentration of the flavonoid glycosides in the first solution is 0.1 mol/L to 1.0 mol/L, optionally 0.33 mol/L.
  • the concentration of the organic amine DPP-4 inhibitor in the second solution is 0.1 mol/L to 1.0 mol/L, optionally 0.33 mol/L.
  • the reaction temperature may be 30°C to 100°C, optionally 50°C to 70°C, and more optionally 70°C.
  • the method for removing the solvent may be concentration under reduced pressure, and the temperature of the concentration under reduced pressure may be 40°C to 70°C, optionally 60°C.
  • Step S30 also includes a purification step.
  • the method of purification can be beating.
  • the solvent used in the beating can be ethyl acetate.
  • the dosage of ethyl acetate is 1:1 to 1:5 according to acid (baicalin or scutellarin) mol/L, and 1:3 is the best; the temperature of beating can be 5°C ⁇ 50°C, and 20 °C ⁇ 30°C, time is 20 minutes ⁇ 40 minutes.
  • the purification also includes filtering the solution after beating, and further drying the filter cake after filtering.
  • the drying method can be freeze drying or vacuum drying.
  • the temperature of the vacuum drying may be 20°C to 60°C, optionally 30°C, and the drying time may be 8 hours to 48 hours, optionally 24 hours.
  • the temperature of the freeze-drying is less than 0°C, and the drying time can be 3 hours to 12 hours, optionally 6 hours.
  • the present application relates to a compound containing a therapeutically effective amount of the above-mentioned double salt compound or its optical isomer, enantiomer, diastereomer, racemate or racemic mixture, and a pharmaceutically acceptable carrier , excipient or diluent composition.
  • the present application relates to the application of the double salt compound in the preparation of DPP-4 inhibitor drugs.
  • the DPP-4 inhibitor medicament prepared according to the double salt compound of the present application is used for the treatment of diabetes and complication diseases, optionally type 2 diabetes and its complications.
  • the application further relates to a method of treating a neurodegenerative disease, the method optionally comprising administering to a patient suffering from a neurodegenerative disease in need thereof an appropriate amount of a double salt as defined above, comprising a double salt according to the application composition of compounds.
  • the average particle size of the double salt nanoparticles ranges from 50 nm to 500 nm.
  • the application also relates to a method for preparing the double salt nanoparticles, comprising:
  • the compound salt compound, the suspending agent and the solvent are mixed and ground by a nano-grinder.
  • the suspending agent is Tween, hypromellose, polyethylene glycol, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, fatty acid glycerides, polyol type nonionic Surfactant, polyoxyethylene type nonionic surface cleanser, poloxamer, vitamin E polyethylene glycol succinate, phospholipids, gelatin, xanthan gum, sodium lauryl sulfate and sodium deoxycholate one or more of them.
  • the suspending agent is a combination of Tween, hypromellose and polyethylene glycol.
  • the mass ratio of the double salt compound and the suspending agent is 1000:(0.5-3).
  • the rotation speed of the grinding is 1000 rpm to 3000 rpm, and the grinding time is 20 minutes to 60 minutes.
  • the diameter of the working chamber of the nano-grinder used in the grinding is 85 mm. If the diameter of the working chamber of the nano-grinder changes, the speed should be adjusted accordingly.
  • the present application also relates to the application of the double salt nanoparticles in the preparation of DPP-4 inhibitor drugs.
  • the antimicrobial drug is used for the treatment of viral diseases
  • the DPP-4 inhibitor drug is used for the treatment of diabetes and complications, optionally type 2 diabetes and its complications.
  • the compounds of the present application useful in therapy according to the present application may be administered in the form of the original chemical compound, optionally in combination with one or more adjuvants, excipients, carriers, buffers, diluents and/or
  • the active ingredient is introduced into the pharmaceutical composition along with other conventional pharmaceutical excipients.
  • Such salts of the compounds of the present application may be anhydrous or solvated.
  • the application provides a medicament comprising a compound usable according to the application or a pharmaceutically acceptable derivative thereof and one or more pharmaceutically acceptable carriers and optionally other Therapeutic and/or prophylactic ingredients.
  • the carrier or carriers must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient.
  • the medicament of the present application may be suitable for oral, rectal, bronchial, nasal, topical, buccal, sublingual, transdermal, vaginal or parenteral (including dermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral) , intraocular injection or infusion), or in a form suitable for administration by inhalation or insufflation (including powder and liquid aerosol administration) or by sustained release systems.
  • sustained release systems include semipermeable matrices of solid hydrophobic polymers containing the compounds of the present application, which matrices may be in the form of shaped articles such as films or microcapsules.
  • the compounds usable according to the present application can thus be placed in the form of medicaments and unit dosages thereof together with conventional auxiliaries, carriers or diluents.
  • Such forms include: solids, in particular tablets, filled capsules, powders and pellets; and liquids, in particular aqueous or non-aqueous solutions, suspensions, emulsions, elixirs and fillings therewith capsules, all forms for oral administration, suppositories for rectal administration and sterile injectable solutions for parenteral use.
  • These medicaments and unit dosage forms thereof may contain conventional ingredients in conventional proportions, with or without other active compounds or components, and such unit dosage forms may contain any suitable effective amount corresponding to the intended daily dosage range to be used. the active ingredient.
  • the compounds useful in accordance with the present application can be administered in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may include one or more compounds useful in accordance with the present application as active ingredients.
  • pharmaceutically acceptable carriers can be solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material .
  • the carrier is a finely divided solid in admixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter Wait.
  • the term "preparation” is intended to include the formulation of the active compound with an envelope material as a carrier, providing a capsule in which the active component, with or without carriers, is surrounded by and thus associated with a carrier.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active ingredient is uniformly dispersed therein, eg, by stirring.
  • the molten homogeneous mixture is then poured into appropriately sized molds, allowed to cool and thereby solidify.
  • Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams containing in addition to the active ingredient suitable carriers known in the art agent or spray.
  • Liquid preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions.
  • liquid preparations for parenteral injection can be formulated as aqueous polyethylene glycol solutions.
  • the chemical compounds according to the present application may be formulated for parenteral administration (eg, by injection, eg, bolus injection or continuous infusion), and may be presented in unit dosage form in ampoules with an added preservative, Prefilled syringes, small volume infusions or in multi-dose containers.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • solid form preparations that are intended to be converted shortly before use to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • These formulations can contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweetening agents, dispersing agents, thickening agents, solubilizers, and the like.
  • the drug is administered locally or systemically or by a combination of both routes.
  • 0.001% to 70% by weight of the compound alternatively 0.01% to 70% by weight of the compound, even more alternatively
  • the compounds of the present application are administered in formulations of the compounds.
  • a suitable amount of compound administered is in the range of 0.01 mg/kg body weight to 1 g/kg body weight.
  • compositions suitable for administration also include: lozenges comprising the active agent in a flavoured base (usually sucrose and acacia or tragacanth), lozenges comprising the active agent in an inert base such as gelatin and glycerol or sucrose and acacia Pastilles of the ingredients and mouthwashes containing the active ingredient in a suitable liquid carrier.
  • a flavoured base usually sucrose and acacia or tragacanth
  • lozenges comprising the active agent in an inert base such as gelatin and glycerol or sucrose and acacia Pastilles of the ingredients and mouthwashes containing the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are administered directly to the nasal cavity by conventional means such as with a dropper, pipette or spray.
  • Compositions may be presented in single or multiple dose form. In the latter case of a dropper or pipette, this can be accomplished by the patient administering a suitable predetermined volume of the solution or suspension. In the case of a nebulizer, this can be achieved, for example, by means of a metered atomizing spray pump.
  • Administration to the respiratory tract can also be accomplished by means of an aerosol with a suitable propellant such as a chlorofluorocarbon (CFC) (eg dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), Carbon dioxide or other suitable gas provides the active ingredient in a pressurized pack.
  • a suitable propellant such as a chlorofluorocarbon (CFC) (eg dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane)
  • CFC chlorofluorocarbon
  • the aerosol may also conveniently contain a surfactant, such as lecithin.
  • the dose of the drug can be controlled by setting the metering valve.
  • the active ingredient may be provided in dry powder form, eg, a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose, and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose, and polyvinylpyrrolidone (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • Powder compositions may be presented in unit dosage forms, eg, capsules or cartridges such as gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compounds In compositions intended for administration to the respiratory tract, including intranasal compositions, the compounds generally have a small particle size, eg, about 5 microns or less. Such particle sizes can be obtained by means known in the art, for example by micronization.
  • compositions suitable for sustained release of the active ingredient can be used.
  • the pharmaceutical formulations may optionally be presented in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are optional compositions.
  • Sitagliptin 4.07 grams (0.01mol) was suspended in 15ml DMF, 4.46 grams (0.01mol) of baicalin was added to 30ml DMF, the above-mentioned sitagliptin DMF solution was added to the baicalin DMF solution, and the reaction was stirred at 70 ° C for 15 hours , the reaction solution was concentrated to dryness under reduced pressure at 60°C to obtain a crude product.
  • the crude product was slurried with 30 ml of ethyl acetate at room temperature for 20 minutes, filtered, and the filter cake was divided into two equal parts.
  • the first part was suspended in 15 ml of water, and freeze-dried for 6 hours to remove the solvent to obtain a pale yellow solid product.
  • the second filter cake was dried under vacuum at 30°C for 24 hours to obtain a pale yellow solid product.
  • 3.67 g of baicalin sitagliptin salt was obtained, and the yield was 85.92%.
  • the second part 3.65 g of baicalin sitagliptin salt was obtained, and the yield was 85.86%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figures 1 to 4. Compared with the simple mixture of baicalin and sitagliptin, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with sitagliptin-NH 2 , and the infrared spectrum also showed this feature, and the thermal weight loss showed that the product had peaks at 193 °C and 336 °C. Compared with baicalin and sitagliptin, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the crude product was slurried with 30 ml of ethyl acetate at room temperature for 20 minutes, filtered, and the filter cake was divided into two equal parts.
  • the first part was suspended in 15 ml of water, and freeze-dried for 6 hours to remove the solvent to obtain a pale yellow solid product.
  • the second filter cake was dried under vacuum at 30°C for 24 hours to obtain a pale yellow solid product.
  • the first part obtained 2.80 grams of scutellarin sitagliptin salt with a yield of 64.47%, and the second part obtained 2.85 grams of scutellarin sitagliptin salt with a yield of 65.45%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 5 to Figure 8. Compared with the simple mixture of baicalin and sitagliptin, the product is more soluble. The chemical shifts show that the carboxyl hydrogen of baicalin forms a salt with sitagliptin-NH 2 , and the infrared spectrum also shows this feature. The thermal weight loss shows that the product has peaks at 198°C, 273°C, 312°C, 335°C, and 363°C. . Compared with baicalin and sitagliptin, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method is basically the same as that of Example 1, except that sitagliptin is replaced by 3.15 g (0.01 mol) of saxagliptin.
  • the first part obtained 3.60 g of baicalin saxagliptin salt with a yield of 96.49%, and the second part obtained 3.68 g of baicalin saxagliptin salt with a yield of 97.15%.
  • the product was characterized by 1H NMR, IR, DSC and XRD. The results are shown in Figures 9 to 12. Compared with the simple mixture of baicalin and saxagliptin, the product is more soluble, and the chemical shift of 1H NMR It shows that the carboxyl hydrogen of baicalin forms a salt with saxagliptin-NH 2 , and the infrared spectrum also presents this feature, and the thermal weight loss shows that the product has peaks at 192 °C and 349 °C. Compared with baicalin and saxagliptin, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method is basically the same as that of Example 2, except that sitagliptin is replaced by 3.15 g (0.01 mol) of saxagliptin.
  • the first part obtained 2.44 g of saxagliptin salt with a yield of 62.68%, and the second part obtained 2.5 g of saxagliptin salt with a yield of 63.45%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 13 to Figure 16. Compared with the pure mixture of baicalin and saxagliptin, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with saxagliptin-NH 2 , and the infrared spectrum also showed this feature, and the thermal weight loss showed that the product had peaks at 117°C, 147°C, 195°C, and 356°C. Compared with baicalin and saxagliptin, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • the preparation method is basically the same as that of Example 1, except that sitagliptin is replaced by 3.39 g (0.01 mol) of alogliptin.
  • the first part obtained 3.44 g of baicalin alogliptin salt with a yield of 87.50%, and the second part obtained 3.50 g of baicalin alogliptin salt with a yield of 88.48%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 17 to Figure 20. Compared with the simple mixture of baicalin and alogliptin, the product is more soluble. The shift showed that the carboxyl hydrogen of baicalin formed a salt with alogliptin-NH 2 , and the infrared spectrum also showed this feature, and the thermal weight loss showed that the product had peaks at 197°C, 220°C, and 303°C. Compared with baicalin and alogliptin, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has been formed into a salt.
  • the preparation method was basically the same as that of Example 2, except that sitagliptin was replaced by 3.39 g (0.01 mol) of alogliptin.
  • the first part obtained 3.33 g of scutellarin alogliptin salt with a yield of 83.19%, and the second part obtained 3.40 g of scutellarin alogliptin salt with a yield of 83.26%.
  • the product was characterized by hydrogen NMR, infrared spectroscopy, DSC and XRD. The results are shown in Figure 21 to Figure 24. Compared with the simple mixture of baicalin and alogliptin, the product is more soluble. The chemical shifts showed that the carboxyl hydrogen of baicalin formed a salt with alogliptin-NH 2 , and the infrared spectrum also showed this feature. The thermal weight loss showed that the product had peaks at 196°C and 365°C. Compared with baicalin and alogliptin, the physical properties, spectral characteristics and thermodynamic properties of the product have changed, indicating that it has become a salt.
  • Each compound salt compound was prepared into different concentrations of the test sample, and the activity of the compound was determined by the chromogenic substrate method. Using glycylproline-p-nitroaniline as the substrate, under slightly alkaline conditions, the different concentrations were determined. The inhibitory effect of the concentration compound on DPP-4 was calculated, and the IC50 was calculated.
  • the inhibitory activity of the baicalin-sitagliptin compound salt compound and the baicalin-sitagliptin compound salt compound to DPP-4 is stronger than the inhibitory activity of sitagliptin to DPP-4;
  • the inhibitory activity of baicalin saxagliptin compound salt compound and saxagliptin compound salt compound on DPP-4 is stronger than that of oseltamivir on DPP-4;
  • baicalin alogliptin compound salt compound and baicalin alogliptin compound salt compound on DPP-4 was stronger than that of lamivudine on DPP-4.
  • the obtained nanosuspension of baicalin and sitagliptin double salt is dried in a fluidized bed drying equipment, and the drying air inlet temperature is 65° C., and dried to a moisture content of about 3% to prepare the baicalin and sitagliptin double salt.
  • the solubility of the prepared baicalin-sitagliptin double-salt compound at 20° C. for 10 minutes increased by 2.2 times.
  • the preparation method is basically the same as that of Example 8, except that the baicalin and sitagliptin double salt compound is replaced by the baicalin and sitagliptin double salt compound.
  • the particle size distribution of baicalin and sitagliptin double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-sitagliptin double-salt nanoparticles have a 2.0-fold increase in solubility at 20° C. for 10 minutes.
  • the preparation method is basically the same as that of Example 8, except that the baicalin-sitagliptin double-salt compound is replaced by the baicalin-saxagliptin double-salt compound.
  • the particle size distribution of the baicalin-saxagliptin compound salt nanoparticles is in the range of 50 nm to 500 nm.
  • the solubility of the prepared baicalin-dasatinib double-salt compound at 20° C. for 10 minutes increased by 1.8 times.
  • the preparation method is basically the same as that of Example 10, except that the baicalin saxagliptin double salt compound is replaced with the baicalin saxagliptin double salt compound.
  • the particle size distribution of the saxagliptin double salt nanoparticles of baicalin is in the range of 50 nm to 500 nm.
  • the prepared saxagliptin-saxagliptin double-salt nanoparticles have a 1.6-fold increase in solubility at 20° C. for 10 minutes compared to the saxagliptin-saxagliptin compound without nano-milling.
  • the preparation method is basically the same as that of Example 8, except that the baicalin sitagliptin double salt compound is replaced by the baicalin alogliptin double salt compound.
  • the particle size distribution of baicalin alogliptin double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared baicalin-alogliptin double-salt nanoparticles have a 1.6-fold increase in solubility at 20° C. for 10 minutes.
  • the preparation method is basically the same as that of Example 12, except that the baicalin alogliptin double salt compound is replaced by the baicalin alogliptin double salt compound.
  • the particle size distribution of scutellarin and alogliptin double salt nanoparticles is in the range of 50nm to 500nm.
  • the prepared scutellarin-alogliptin double-salt nanoparticles have a 1.8-fold increase in solubility at 20° C. for 10 minutes.
  • the blank control group, baicalin group, baicalin group, sitagliptin group, alogliptin group, dasatinib group, baicalin-sitagliptin compound salt nanosuspension group (baicalin west Refer to Example 8 for the preparation method of the gliptin double salt nanosuspension, and the scutellarin and sitagliptin double salt nanosuspension group (the preparation method of the scutellarin and sitagliptin double salt nanosuspension refers to the example).
  • baicalin alogliptin double salt nanosuspension group (baicalin alogliptin double salt nanosuspension preparation method refers to Example 12), baicalin alogliptin double salt nanosuspension Group (refer to Example 13 for the preparation method of the baicalin alogliptin double salt nanosuspension).
  • mice C57BL/6 nitric oxide synthase deficient mice, 6-8 weeks old. All mice had free access to food and water, and were kept at room temperature (23 ⁇ 2)°C.
  • mice with diabetic nephropathy were established, and the qualified mice were randomly divided into groups of 10.
  • the dosing schedule was as follows:
  • Blank control group only given normal saline.
  • Baicalin group baicalin was formulated into a dosing solution with sterile PBS, and the dose was 8 mg/kg by gavage, once a day, for 6 weeks.
  • Baicalin group scutellarin was formulated into a dosing solution with sterile PBS, and the dose was 8 mg/kg by gavage, once a day, for 6 weeks.
  • Sitagliptin group Sitagliptin was formulated into a dosing solution with sterile PBS, and the dosage was 7.2 mg/kg, administered by gavage, once a day, for 6 weeks.
  • Sitagliptin group Sitagliptin was formulated into a dosing solution with sterile PBS, and the dose was 4.3 mg/kg by gavage, once a day, for 6 weeks.
  • Baicalin and sitagliptin compound salt nanosuspension group Baicalin and sitagliptin compound salt nanosuspension was used as the dosing solution, and the dosage was 15 mg/kg, intragastrically, once a day, for 6 consecutive administrations. week.
  • Baicalin and sitagliptin compound salt nanosuspension group scutellarin and sitagliptin compound salt nanosuspension was used as the dosing solution, according to the dosage of 15 mg/kg, intragastrically, once a day, continuously given medicine for 6 weeks.
  • Baicalin-Alogliptin Compound Salt Nanosuspension Group Baicalin-Alogliptin Compound Salt Nanosuspension was used as the dosing solution, 10 mg/kg dose, intragastrically, once a day, for 6 consecutive administrations week.
  • Baicalin alogliptin compound salt nanosuspension group scutellarin alogliptin compound salt nanosuspension was used as the dosing solution, and the dosage was 10 mg/kg, intragastrically, once a day, continuously given medicine for 6 weeks.
  • proteinuria inhibition rate (average proteinuria content of blank control group-average proteinuria content of each administration group)/average proteinuria content of blank control group*100% ), the result is as follows:
  • the inhibition rate of proteinuria in the baicalin group was 25.4%
  • the inhibition rate of proteinuria in the baicalin group was 24.8%
  • the inhibition rate of proteinuria in the sitagliptin group was 32.6%
  • the inhibition rate of proteinuria in the alogliptin group was 34.8%
  • the inhibition rate of proteinuria in the baicalin and sitagliptin compound salt 15mg/kg) nanosuspension group was 81.6%
  • the inhibition rate of proteinuria was 80.8% in the group of Ting compound salt (15mg/kg) nanosuspension group
  • the inhibition rate of proteinuria in the group of baicalin alogliptin compound salt (10mg/kg) nanosuspension group was 79.8%
  • the inhibition rate of baicalin alogliptin group was 79.8%.
  • the inhibition rate of proteinuria in the Lipin compound salt (10mg/kg) nanosuspension group was 79.6%. Compared with the blank group, the natural product group and the small molecule group, each compound salt nanosuspension group had a significant improvement in urinary protein.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un sel double de glycoside flavonoïde-organoamine inhibiteur de DPP-4. Le glycoside flavonoïde présente la formule développée telle que représentée dans la formule (1), dans laquelle R1-R9 sont indépendamment choisis dans un groupe constitué par -H, -OH, un alkyle, un alcoxy ou un alkyle substitué en C1-C6, et au moins un élément parmi R1 et R2 est choisi parmi -OH. L'invention concerne également un procédé de préparation du sel double, une composition pharmaceutique contenant une quantité thérapeutique de principes actifs et une application associée. L'invention concerne en outre des nanoparticules de sel double obtenues par nano-broyage du composé de sel double et une application associée.
PCT/CN2021/127466 2020-10-30 2021-10-29 Sel double de glycoside flavonoïde-organoamine inhibiteur de dpp-4, son procédé de préparation et application associée WO2022089589A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011190989.9 2020-10-30
CN202011190989 2020-10-30

Publications (1)

Publication Number Publication Date
WO2022089589A1 true WO2022089589A1 (fr) 2022-05-05

Family

ID=79014744

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/127466 WO2022089589A1 (fr) 2020-10-30 2021-10-29 Sel double de glycoside flavonoïde-organoamine inhibiteur de dpp-4, son procédé de préparation et application associée

Country Status (2)

Country Link
CN (1) CN113880900B (fr)
WO (1) WO2022089589A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113880900B (zh) * 2020-10-30 2023-07-07 杭州拉林智能科技有限公司 黄酮苷-有机胺类dpp-4抑制剂复盐化合物及其制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101732417A (zh) * 2010-02-09 2010-06-16 曾建国 博落回总生物碱离子对混合物的制备方法和用途
CN102086172A (zh) * 2011-01-13 2011-06-08 廖国超 沙格列汀的药用盐及其制备方法
WO2013046229A1 (fr) * 2011-09-26 2013-04-04 Hetero Research Foundation Nouveaux sels de l'alogliptine
CN103649090A (zh) * 2011-10-14 2014-03-19 劳乐斯实验室私营有限公司 新的西他列汀盐、其制备方法及其药物组合物
CN110314233A (zh) * 2019-08-12 2019-10-11 浙江养生堂天然药物研究所有限公司 包含柠檬苦素类化合物和dpp-4抑制剂的组合产品
CN113880900A (zh) * 2020-10-30 2022-01-04 杭州拉林智能科技有限公司 黄酮苷-有机胺类dpp-4抑制剂复盐化合物及其制备方法和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101732417A (zh) * 2010-02-09 2010-06-16 曾建国 博落回总生物碱离子对混合物的制备方法和用途
CN102086172A (zh) * 2011-01-13 2011-06-08 廖国超 沙格列汀的药用盐及其制备方法
WO2013046229A1 (fr) * 2011-09-26 2013-04-04 Hetero Research Foundation Nouveaux sels de l'alogliptine
CN103649090A (zh) * 2011-10-14 2014-03-19 劳乐斯实验室私营有限公司 新的西他列汀盐、其制备方法及其药物组合物
CN110314233A (zh) * 2019-08-12 2019-10-11 浙江养生堂天然药物研究所有限公司 包含柠檬苦素类化合物和dpp-4抑制剂的组合产品
CN113880900A (zh) * 2020-10-30 2022-01-04 杭州拉林智能科技有限公司 黄酮苷-有机胺类dpp-4抑制剂复盐化合物及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SOKAR SAMIA SALEM; EL-SAYAD MAGDA EL-SAYED; GHONEIM MAI EL-SAYED; SHEBL ABDELHADI MOHAMED: "Combination of Sitagliptin and Silymarin ameliorates liver fibrosis induced by carbon tetrachloride in rats", BIOMEDICINE & PHARMACOTHERAPY, vol. 89, 20 February 2017 (2017-02-20), FR , pages 98 - 107, XP029987163, ISSN: 0753-3322, DOI: 10.1016/j.biopha.2017.02.010 *

Also Published As

Publication number Publication date
CN113880900A (zh) 2022-01-04
CN113880900B (zh) 2023-07-07

Similar Documents

Publication Publication Date Title
EP3445749B1 (fr) Composés et compositions destinés au traitement d'états associés à une activité de nlrp
CA2802733C (fr) Promedicaments de composes nh-acides : derives esters, carbonates, carbamates et phosphonates
JP2015518891A (ja) 抗ウイルス化合物の固体形態
TWI458481B (zh) ３－戊基苯乙酸的鹽及其藥學用途
US9249106B2 (en) Substituted hydrazide compounds and use thereof
CN101674823A (zh) 用于与增强的5-脂氧合酶和/或白三烯活性有关的疾病（例如哮喘）的r-齐留通
WO2022089589A1 (fr) Sel double de glycoside flavonoïde-organoamine inhibiteur de dpp-4, son procédé de préparation et application associée
JP2018510138A (ja) Ｏｌｉｇ２活性の阻害
KR102605329B1 (ko) Olig2 활성의 억제
CN114340643A (zh) 用于car-t细胞治疗的脂质-荧光素缀合物的设计和有效合成
WO2013071693A1 (fr) Composé d'oxadiazole et son procédé de préparation, composition pharmaceutique et utilisation de celle-ci
WO2022089598A1 (fr) Composé de sel double de glycoside flavonoïde-amine organique neuroagoniste, son procédé de préparation et son application
WO2022089593A1 (fr) Composé de sel double d'un agent anti-tumoral à base de glycoside de flavone amine organique, son procédé de préparation et son utilisation
TW202024038A (zh) 靶向突變哺乳動物蛋白質之小分子
WO2022089600A1 (fr) Composé de sel double d'agent antimicrobien à base de flavonoïde glycoside amine organique, son procédé de préparation et son utilisation
CN102731488A (zh) 苯并咪唑类衍生物、及其制法和药物组合物与用途
WO2009033396A1 (fr) Composés dithiolopyrrolones, leur préparation et leur utilisation
WO2022089590A1 (fr) Composé de sel du complexe flavonoïde glycoside-inhibiteur de tyrosine kinase amine organique, son procédé de préparation et son utilisation
JP6363192B2 (ja) トリグリセリド、総コレステロール、及び低密度リポタンパク質の血中濃度を低減する方法
CN116209673A (zh) 用于治疗sars的化合物
KR102640385B1 (ko) 고혈압 및/또는 폐 섬유증 치료용 조성물
CH641775A5 (fr) N-(1-methyl 2-pyrrolidinyl methyl) 2,3-dimethoxy 5-methylsulfamoyl benzamide et ses derives, son procede de preparation et composition le renferment.
CN113797218A (zh) 药物组合物及其制备方法和应用
CN111138282A (zh) 绿原酸l-精氨酸盐及其用途
CN110938001A (zh) 绿原酸乙醇胺盐及用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21885315

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 25/10/2023)