Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
  • C07D493/16—Peri-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/20—Spiro-condensed systems

Definitions

• the present invention belongs to the field of natural medicines and medicinal chemistry and relates to novel homoharringtonine derivatives, in particular to aminated derivatives of high triterpene ester bases, and methods for preparing the same, compositions containing the compounds, and preparation thereof Use in anti-tumor drugs. Background technique
• HHT Homoharrington
• HHT is used in the induction of remission and post-remission treatment of acute myeloid leukemia, myeloproliferative disorders Syndrome (MDS), chronic myeloid leukemia and polycythemia vera and malignant lymphoma, especially for the treatment of acute non-lymphocytic leukemia (Zhang Zhixue, etc., HAG regimen in the treatment of high-risk myelodysplastic syndrome and acute marrow White blood Clinical study of the disease, Journal of Jinggangshan University, 2010, 31 (6), 108-110; Deng Jianqun et al.
• HHT can promote cell differentiation and apoptosis (Wang et al., homoharringtonine induces K562 and
• HHT human oral epidermoid carcinoma
• HHT pharmacological action of HHT mainly inhibits protein synthesis in eukaryotic cells and inhibits aminoacyl groups.
• -tR A binds to ribose and its formation of ribosomes and ⁇ chain, thus affecting the early stage of multimer formation, depolymerizing polyribosomes, interfering with protein ribosome function, and inhibiting intracellular DNA synthesis Role (Cai Zhen et al, apoptosis-related genes Survivin, Bcl-2 and bax expression in the apoptosis of myelodysplastic syndrome MUTZ-1 induced by homoharringtonine, Chinese Journal of Practical Oncology, 2003, 18 (3), 188-191; Cai Zhen et al.
• aminated or amidated small molecules have been widely used in the development and application of drugs, but the synthesis and application of aminated or amidated homoharringtonine derivatives have not been seen.
• One of the objects of the present invention is to provide an aminated or amidated derivative of the novel homoharringtonine characterized by the general formula ( ⁇ ) or a pharmaceutically acceptable adduct, complex or salt thereof:
• [eta] is selected, a substituted or unsubstituted C r C ls alkyl, substituted or unsubstituted C 2 - C 18 alkenyl group or a alkynyl group, a substituted or unsubstituted C 3 -C 7 cycloalkyl or cycloolefin A substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group or an aromatic heterocyclic group.
• the substituent is selected from the group consisting of halogen, amine, substituted amine, nitro, cyano, hydroxy, C 6 alkoxy, fluorenyl, dC 6 alkylthio. They can be the same or different, or they can be combined into one.
• a second object of the present invention is to provide a process for the preparation of an aminated or amidated derivative of a high triterpene ester of the formula (I) according to the invention:
• the aminated or amidated derivative (I) of the homoharringtonine of the present invention can be obtained by a two-step reaction as shown in the above formula.
• the homoharringtonine is gently hydrolyzed in the presence of an alkali or an alkaline reagent to form an acid intermediate of the homoharringtonine; and the acid intermediate of the high triterpene base and the corresponding organic amine have a condensing agent and Amination or amidation of the homoharringtonine in the presence of a base.
• Amination or amidation of the homoharringtonine base can also be obtained by one-step condensation amination of the homoharringtonine with the corresponding organic amine in the presence of a condensing agent or an alkaline agent.
• R p R 2 in the formula (I) is the same as defined above in the formula (I).
• a third object of the present invention is to provide a pharmaceutical composition comprising a compound of the present invention, the pharmaceutical composition comprising at least one compound of the present invention, and optionally a pharmaceutically acceptable excipient.
• a fourth object of the present invention is to provide a use of a compound of the present invention or a pharmaceutical composition comprising the same for the preparation of a medicament, particularly an antitumor medicament. Accordingly, the invention provides a method of treating a tumor patient comprising administering to a patient in need of treatment a therapeutically effective amount of at least one compound of the invention.
• the tumor is particularly selected from the group consisting of leukemia, multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, colon cancer, osteosarcoma, melanoma, human cervical cancer, glioma, Nasopharyngeal cancer, laryngeal cancer, esophageal cancer, middle ear tumor, prostate cancer, etc.
• the invention also relates to compounds of the invention for use in the treatment of tumors. detailed description
• the invention particularly relates to the following.
• heteroaryl group is a furyl group, a thiop group, a pyrrolyl group or a thiazolyl group, or a pharmaceutically acceptable salt thereof.
• oxazolyl isoxazolyl, pyrazolyl or pyridyl; preferably furyl, thiahaki or thiazolyl.
• the homoharringtonine aminated derivative or a pharmaceutically acceptable salt thereof according to any one of the above items 1 to 5, wherein the heterocyclic group or the nitrogen-containing heterocyclic ring is piperazinyl, morphine, Thiomorpholinyl, piperidinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, pyrazolidinyl.
• the substituent is selected from the group consisting of: a sulphate, an amino group, a dC 6 alkylamino group, a nitro group, Cyano, hydroxy d-Cs alkyl, dC 6 alkoxy, C r C 6 alkyl; preferably decyl, ethyl, isopropyl, me
• the homoharringtonine derivative or a pharmaceutically acceptable salt thereof according to any one of the above 1-8, wherein 1 and R 2 are independently selected from H, C 3 - C 7 cycloalkyl such as a ring hexyl group, a heteroaryl group such as furyl -OC4 furyl Yue or methyl group, or a 1? R and the nitrogen atom to which they are attached together form a nitrogen-containing heterocyclic groups such as pyrrole embankment, piperidinyl or di Yue Aminopiperidinyl or aryl-nitrogen-containing heterocycles such as 4-phenylpiperazine small group or 4-(4-fluorophenyl)-piperazine small group.
• the aminated or amidated derivatives of some of the homoharringtonines of the invention are shown below. These examples are only intended to further illustrate the present invention and are not intended to limit the scope of the invention.
• the present invention particularly preferably comprises the following compound of the formula (I):
• the present invention relates to compounds of formula (I) of the invention in the form of their salts, solvates, hydrates, adducts, complexes, polymorphs and prodrugs.
• mercapto refers to a straight or branched alkyl group containing the specified number of carbon atoms, such as C r C 18 alkyl, C r C 6 alkyl, C r C 4 alkyl, C r C 3 alkyl or the like.
• alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl, n-hexyl, n-octadecyl, and the like.
• olefin-based means a straight or branched hydrocarbon group containing at least one carbon-carbon double bond, for example, a C 2 -C 1S alkene group, a C 2 -C 1Q alkene group, a c 2 - group having a specified number of carbon atoms.
• Examples of olefinic groups include, but are not limited to, vinyl, allyl, and octadecenyl.
• alkynyl refers to a straight or branched chain hydrocarbon radical containing at least one carbon-carbon triple bond, for example: ( 2 - ⁇ 18 alkyne, Crd. alkyne, C 2 - C 8 An alkyne group, a c 2 -c 7 alkyne group, a c 2 - c 6 alkyne group, a c 2 -c 4 alkyne group and a c 2 -c 3 alkyne group.
• alkyne groups include, but are not limited to, ethynyl, propargyl, Octadecyl alkynyl
• C r C 7 cycloalkyl or cyclohydrocarbyl means a saturated or unsaturated 3-7 membered monocyclic hydrocarbon group, for example, a C 3 -C 7 cycloalkyl group may be cyclopropyl, cyclobutyl or cyclopentane.
• Base cyclohexyl, cyclodecyl, cyclopropenyl and cyclohexenyl.
• aryl refers to a monocarbocyclic aryl group having 6 to 14 carbon atoms or a fused or non-fused polycarbocyclic aryl group. In the case of a polycarbocyclic ring, as long as one carbocyclic ring is aromatic, can.
• the aryl group also includes an aryl group fused to a heterocyclic group. Examples of the aryl group are a phenyl group, a biphenyl group, a naphthyl group, a 5,6,7,8-tetrahydronaphthyl group, a 2.3-dihydrobenzofuranyl group and the like.
• heteroaryl refers to an aromatic ring group containing from 1 to 4 heteroatoms (eg 1, 2, 3 or 4 heteroatoms) as a ring atom in the ring. Heteroatoms refer to nitrogen, oxygen or sulfur
• the heteroaryl group may be a monocyclic heteroaryl group having 5 to 7 ring atoms, or a bicyclic heteroaryl group having 7 to 11 ring atoms. As long as one ring of the bicyclic aryl group is an aromatic heterocyclic ring, The other may be aromatic or non-aromatic, hetero atom-containing or hetero atom-free.
• heteroaryl groups are, for example, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, furan.
• Base thienyl, isoxazolyl, fluorenyl and the like.
• Heterocyclyl contains 1-4 heteroatoms (e.g. 1, 2, 3 or 4 heteroatoms) as non-aromatic cyclic groups of the ring atom. Heteroatoms refer to nitrogen, oxygen or sulfur.
• the heterocyclic group may be a monocyclic heterocyclic group having 4 to 8 ring atoms or a bicyclic heterocyclic group having 7 to 11 ring atoms. Heterocyclyl groups can be saturated or unsaturated but not aromatic.
• heterocyclic group examples include azacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, piperazinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl and the like.
• ! 3 ⁇ 4" means fluorine, chlorine, bromine or iodine.
• alkylamino refers to an amino group substituted with one or two alkyl groups having the specified number of carbon atoms, including cycloalkyl groups.
• alkoxy includes alkoxy and cycloalkyloxy.
• alkylthio alkylthio and cycloalkylthio.
• pharmaceutically acceptable adducts and complexes of the compounds of formula (I) refers to products in which the compounds of the invention are further combined with other small molecules or biomacromolecules by non-chemical or non-covalent inter- molecular forces.
• an example of the term "pharmaceutically acceptable pots of a compound of formula (I)" is an organic acid salt formed from an organic acid that forms a pharmaceutically acceptable anion; such organic acid salts include, but are not limited to, toluene Acid salts, methanesulfonate, malate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate and (X) -glycerol phosphate; suitable inorganic salts are also formed; these include, but are not limited to, hydrochlorides, sulfates, nitrates, bicarbonates and carbonates, phosphates, hydrobromides, hydroiodic acids Salt and so on.
• compositions can be obtained using standard procedures well known in the art. For example, it is produced by reacting a sufficient amount of a basic compound with a suitable acid which provides a pharmaceutically acceptable anion.
• polymorph refers to the solid crystalline form of a compound of the invention or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectral properties. Different physical properties include, but are not limited to, stability (eg, for heat or light), compressibility and density (important for formulation and product production), and dissolution rate (which can affect bioabsorbability and availability).
• Differences in stability can result in chemical reactivity (eg, differential oxidation, such that when formulated from one polymorph, fades faster than when formed from another polymorph) or mechanical properties (eg, as storage) Changes in the kinetically favorable polymorphic tablet granules converted to thermodynamically more stable polymorphs) or both (for example, tablets of one polymorph are more susceptible to breakage at high humidity) .
• the different physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form a solvate than the other or may be more difficult to filter or wash away than the other due to the different shape or size distribution of the particles.
• hydrate refers to a compound of the present invention or a salt thereof, which One step comprises stoichiometric or non-stoichiometric water bound by non-covalent intermolecular forces.
• prodrug refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs are only reactive under biological conditions to become active compounds, or they are active in their unreacted form. Prodrugs can generally be prepared using well-known methods, for example, 1 Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E.
• the four chiral centers of the high-ordered scutellaria® derivatives of the compounds of the present invention have the stereochemical structure shown by the formula (I).
• the definitions and conventions for stereochemistry used herein follow MCGRAW-HILL DICTIONARY OF CHEMICAL TERMS (SP Parker, Ed., McGraw-Hill Book Company, New York, 1984); ELIEL, E. and WILEN, S., STEREOCHEMISTRY OF ORGANIC COMPOUNDS (John Wiley & Sons, Inc., New York, 1994).
• Many organic compounds exist in optically active forms, i.e., they have the ability to rotate planes of plane polarization.
• treating generally refers to obtaining the desired pharmacological and/or physiological effects.
• the effect may be prophylactic according to the prevention of the disease or its symptoms in whole or in part; and/or may be therapeutic according to the partial or complete stabilization or cure of the disease and/or side effects due to the disease.
• treatment covers any treatment for a patient's condition, including:
• HHT HHT acid (I)
• the aminated derivative of the homoharringtonine of the formula (I) can be obtained by first hydrolyzing the homoharringtonine base (HHT) isolated by natural extraction and then reacting with the corresponding organic amine.
• R 2 in formula (I) is the same as defined above in formula (I).
• the above hydrolysis reaction is generally carried out in the presence of a base or an alkaline reagent.
• the base here may be, but is not limited to, an inorganic hydrazine.
• sodium hydroxide, potassium hydroxide, lithium hydroxide for example: sodium hydroxide, potassium hydroxide, lithium hydroxide.
• Solvents used include, but are not limited to, polar solvents.
• polar solvents For example, decyl alcohol, water, or a mixed solvent of decyl alcohol and water.
• the reaction temperature of the above hydrolysis reaction is usually from 0 °C to 40 °C.
• the reaction temperature varies depending on the base used or its concentration.
• the raw material for the hydrolysis reaction is homoharringtonine (HHT).
• HHT homoharringtonine
• the raw material is obtained by extracting and separating natural products, and can be purchased on the market. All of the organic amines for amination or amidation are commercially available.
• the amination or amidation reaction is generally carried out in the presence of a condensing agent.
• the condensing agent here may be, but not limited to, an organic condensing agent.
• 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexa-cerate (HATU) 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexa-cerate (HATU)
• HATU 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexa-cerate
• HBTU benzotriazole-oxime
• HBTU benzotriazole-1-yloxytris(didecylamino)phosphoryl hexafluorophosphate
• the amination or amidation reaction is generally carried out in the presence of a base.
• the base here may be, but not limited to, an organic base.
• DIPEA hydrazine, hydrazine-diisopropylethylamine
• TEA triethylamine
• pyridine 4-dimethylaminopyridine (DMAP).
• the amination or amidation reaction is generally carried out in a solvent or in the absence of a solvent.
• Solvents used include, but are not limited to, organic polar solvents. For example: dichlorodecane (DCM), tetrahydrofuran (THF), N, N-dimercaptocarboxamide (DMF), dimethyl sulfoxide (DMSO), and the like.
• the general operation of the amination or amidation reaction can be, but is not limited to, the addition of a suitable ratio of reactant starting materials, a base and a condensing agent to a dichloromethane solvent. After stirring at normal temperature for 24 hours, the resulting product was extracted with an organic solvent, washed with water and brine, dried and concentrated to give crude. It is then purified by high performance liquid chromatography to obtain pure product.
• Protecting groups are those groups which, once attached to an active moiety (e.g., a hydroxyl group or an amino group), prevent these moieties from being interfered by subsequent reactions and which can be removed by conventional methods after the reaction.
• hydroxy protecting groups include, but are not limited to, fluorenyl, benzyl, allyl, trityl (ie, triphenylmethyl), acyl (eg, benzoyl, acetyl or HOOC-X) -CO-,
• X" is an alkylene, alkenylene, cycloalkylene or arylene group, a silyl group (for example, trimethylsilyl, triethylsilyl and tert-butyldimethyl) Silyl), alkoxycarbonyl, aminocarbonyl (e.g., dimethylaminocarbonyl, methylethylaminocarbonyl, and phenylaminocarbonyl), alkoxyfluorenyl
• amino protecting group examples include, but are not limited to, an alkoxycarbonyl group, an alkanoyl group, an aryloxycarbonyl group, an aryl-substituted alkyl group, and the like. Hydroxy and amino protecting groups have been discussed in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons (1991). Both the hydroxy group and the amino protecting group can be removed by a conventional method after the reaction.
• the invention also provides a pharmaceutical composition comprising a compound of formula I of the invention.
• the present invention provides a pharmaceutical composition comprising at least one of the above A compound of formula I of the invention, and optionally a pharmaceutically acceptable excipient.
• a pharmaceutical composition comprising at least one of the above A compound of formula I of the invention, and optionally a pharmaceutically acceptable excipient.
• Methods of preparing the pharmaceutical compositions include the incorporation of suitable pharmaceutical excipients, carriers, diluents and the like.
• the pharmaceutical preparation of the present invention is produced by a known method, including a conventional mixing, dissolving or lyophilizing method.
• the compounds of the present invention can be formulated into pharmaceutical compositions and administered to a patient in a variety of routes suitable for the chosen mode of administration, e.g., orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).
• the compounds of the invention may be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an edible carrier. They can be enclosed in hard or soft gelatin capsules and can be compressed into tablets.
• a pharmaceutically acceptable carrier such as an inert diluent or an edible carrier.
• the active compound may be combined with one or more excipients and in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. Form use.
• Such compositions and preparations should contain at least 0.1% of active compound.
• the ratio of such compositions and formulations may of course vary and may range from about 1% to about 99% by weight of a given unit dosage form.
• the amount of active compound is such that an effective dosage level can be obtained.
• Tablets, lozenges, pills, capsules, and the like may also contain: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium sulphate; a disintegrating agent such as corn Starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose or aspartame; or flavorings such as mint, wintergreen or cherry.
• a binder such as tragacanth, acacia, corn starch or gelatin
• an excipient such as dicalcium sulphate
• a disintegrating agent such as corn Starch, potato starch, alginic acid, etc.
• lubricants such as magnesium stearate
• sweeteners such as sucrose, fructose, lactose or aspartame
• flavorings such as mint, wintergreen or cherry.
• the unit dosage form is
• any material used to prepare any unit dosage form The material should be pharmaceutically acceptable and substantially non-toxic in the amount applied.
• the active compound can be incorporated into a slow-setting formulation and a sustained release device.
• the active compound can also be administered intravenously or intraperitoneally by infusion or injection.
• An aqueous solution of the active compound or a salt thereof, optionally a miscible non-toxic surfactant can be prepared.
• Dispersing agents in glycerin, liquid polyethylene glycols, triacetin and mixtures thereof, and oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent microbial growth.
• the pharmaceutical dosage form suitable for injection or infusion may comprise a sterile aqueous solution or dispersion of the active ingredient (optionally encapsulated in a liposome) comprising a ready-to-use preparation suitable for sterile injectable or infusible solutions or dispersions. Or sterile powder.
• the final dosage form must be sterile, liquid, and stable under the conditions of manufacture and storage.
• the liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and suitable mixtures thereof.
• Appropriate fluidity can be maintained, for example, by liposome formation, by maintaining the desired particle size in the case of dispersing agents, or by the use of surfactants.
• Microbial action can be prevented by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).
• isotonic agents such as sugars, buffers or sodium chloride.
• Prolonged absorption of the injectable compositions can be brought about by the use of compositions which delay the absorbent (e.g., aluminum monostearate and gelatin).
• Sterile injectable solutions are prepared by combining the required active compound in a suitable solvent with the various other ingredients listed above, followed by filter sterilization.
• the preferred preparation methods are vacuum drying and lyophilization techniques which result in a powder of the active ingredient plus any additional ingredients present in the previously sterile filtration solution. .
• Useful solid carriers include comminuted solids (e.g., talc, clay, microcrystalline cellulose, silica, alumina, etc.).
• Useful liquid carriers include water, ethanol or ethylene glycol or a water-ethanol/ethylene glycol mixture, and the compounds of the present invention may be dissolved or dispersed in an effective amount, optionally with the aid of a non-toxic surfactant.
• Adjuvants such as fragrances
• additional antimicrobial agents can be added to optimize the properties for a given use.
• Thickeners (such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified inorganic materials) can also be used with liquid carriers to form coatable pastes, gels, ointments. , soap, etc., used directly on the user's skin.
• the therapeutic requirements of a compound or an active salt or derivative thereof depend not only on the particular salt selected, but also on the mode of administration, the shield of the disease to be treated, and the age and condition of the patient, ultimately depending on the attending physician or clinical The doctor's decision.
• unit dosage form is a unit dosage unit containing a physical dispersion unit suitable for administration to humans and other mammalian bodies.
• the unit dosage form can be a capsule or tablet, or a lot of capsules or tablets.
• the amount of unit dose of the active ingredient can vary or be adjusted from about 0.1 to about 1000 grams or more.
• the use of substances, especially anti-tumor drugs. Accordingly, the invention provides a method of treating a tumor patient comprising administering to a patient in need of treatment a therapeutically effective amount of at least one compound of the invention.
• the monoacylated and diacylated homoharringtonine derivatives of the present invention or a pharmaceutically acceptable salt thereof, for example, can be used for the treatment of leukemia, multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocarcinoma , pancreatic cancer, lung cancer, colorectal cancer, osteosarcoma, melanoma, human cervical cancer, glioma, nasopharyngeal carcinoma, laryngeal cancer, esophageal cancer, middle ear tumor, prostate cancer and other tumors.
• Homoharringtonine 11111 1 (2.5 ⁇ 4.58 11111101) was dissolved in methanol (18 1111, 1 M alkali solution (4.6 mL) was added, the base may be sodium hydroxide or lithium hydroxide, and stirred at room temperature for 7 hours.
• the pH of the reaction solution is adjusted to 5-7 with a 1 N acid solution.
• the acid may be hydrochloric acid or other inorganic acid, and the organic solvent is concentrated.
• the remaining aqueous solution is treated with toluene several times, and concentrated to give a white solid homoharrington.
• Alkaline acid (2.5 g) with a purity of 88%. Another 5% of the raw materials can be recovered. After the recovery, secondary hydrolysis can be carried out.
• HHT X01-1 BS-HH-043 Wherein XOl-1 : homoharringtonine; Zi: furan-2-ethylamine; HATU: 2-(7-azobenzotriazole) - ⁇ , ⁇ , ⁇ ', ⁇ '- Tetramethylurea hexafluoroantimonate; DIPEA: hydrazine, hydrazine-diisopropylethylamine.
• the homoharringtonine is hydrolyzed according to the general procedure described above. Then, the intermediate acid hydrazine 01-1 (106 mg, 0.2 mmol) and 2-aminofurfuryl furan (24 mg, 0.24 mmol) obtained by hydrolysis of homoharringtonine were dissolved in anhydrous N, N-dimethyl. Ammonium amide (2 mL), N,N-diisopropylethylamine (52 mg, 0.4 mmol) and 2-(7-azobenzotriazole)-N, N, ⁇ ', ⁇ '- Tetramethylurea hexahydrate (114 mg, 0.3 mmol) at 30. Stir under C conditions for 3 hours at 5-10. Water (6 mL) was added under EtOAc. EtOAc (EtOAc)EtOAc. Product BS-HH-043 (9 mg, 6%) 0
• Example 1 The procedure of Example 1 was carried out by reacting the intermediate acid X01-1 obtained by hydrolysis of homoharringtonine with 3-methylpiperidine using the same coupling reagent to obtain BS-HH-038: LC-MS: retention time: 1.57 Min (98.69%), m/z: 613.6 [M + H] + .
• Example 1 The procedure of Example 1 was carried out by reacting the intermediate acid X01-1 obtained by hydrolysis of homoharringtonine with 5-nonyl-2-aminomercaptofuran using the same coupling reagent to obtain BS-HH-054: LC-MS : Retention time: 1.23 min (63.39%), m/z: 625.8 [ ⁇ + ⁇ ]+ ⁇
• Example 2 Determination of anti-leukemia activity of the homoharringtonine aminated derivative of the present invention
• Leukemia cell lines K562/adr (resistant chronic myeloid leukemia, CML), NB4 (acute promyelocytic leukemia, AML), Kasumi-1 (acute myeloid leukemia M2,
• AML-M2 AML-M22
• Jurkat Acute lymphocytic leukemia, ALL
• H9 acute lymphocytic leukemia, ALL
• HHT Homoharringtonine
• 6000 well-grown leukemia cells were inoculated into the wells of a 96-well cell culture plate.
• the culture broth was a 1640 cell culture medium containing 10% fetal bovine serum.
• Different concentrations of homoharringtonine aminated derivatives were added, and after mixing, they were placed in a carbon dioxide (5% CO 2 ) cell incubator 37. C 72 hours of culture.
• the viable cell concentration was then determined by the MTT method. In the actual control group (without compound treatment), the cell viability was set to 100%, and the cell viability (%) after compound action and the half-growth inhibition concentration of 72-hour leukemia cells (72-hour IC 5Q value) were calculated.
• Table 1 shows that the homoharringtonine aminated derivatives of the present invention are capable of inducing cell death of human chronic myeloid leukemia, acute myeloid leukemia and acute lymphocytic leukemia and inhibiting the growth of these leukemia cells, wherein the homoharringtonine of the present invention
• Chemical derivatives BS-HH-012, BS-HH-042, BS-HH-050 and BS-HH-054 showed strong anti-K562/adr (resistant chronic myeloid leukemia, CML), NB4 (acute early) Myeloid leukemia, AML), Kasumi-1 (acute myeloid leukemia M2, AML-M2) and H9 (acute lymphoid leukemia, ALL) activity.
• Table 1 Determination of growth inhibition concentration of leukemia cells by homoharringtonine aminated derivatives (72 hours, IC 50 (g/mL) value and IC 90 ( ⁇ glmL ) value)
• Example 3 Determination of cell activity of anti-human multiple myeloma and lymphoma cells of the homoharringtonine aminated derivative of the present invention
• Myeloma and lymphoma cell line RPMI8226 (multiple myeloma), purchased from Shanghai Fuxiang Biotechnology Co., Ltd.
• Table 2 shows that the homoharringtonine aminated derivative of the present invention can induce human myeloma and lymphoma cell death and inhibit the growth of these tumor cells, wherein the homoharringtonine aminated derivative BS-HH-012 of the present invention , BS-HH-042, BS-HH-054 showed a strong anti-RPMI8226 (multiple myeloma) effect.
• Example 4 Determination of anti-human solid tumor effect of aminated derivative of homoharringtonine of the present invention
• Hep-2 human hepatocellular carcinoma, HCC
• A549 human lung cancer
• CaES-17 esophageal cancer cells
• PC-3 prostate cancer
• CNE nasopharyngeal carcinoma cells
• SK-OV-3 ovarian cancer cells
• RO human colon gland
• MGC 803 human gastric cancer cells
• MG6 3 osteosarcoma
• MG malignant glioma cells
• PANC-1 pancreatic cancer
• Huh7 human
• Becap37 human breast cancer cells
• Hela human cervical cancer cells
• the culture solution was a DMEM high glucose cell culture medium containing 10% fetal calf serum. Place in a carbon dioxide (5% C0 2 ) cell culture incubator 37. C was cultured for 24 hours, and then, various concentrations of homoharringtonine compound were added, and after mixing, the carbon dioxide (5% CO 2 ) cell incubator was further cultured at 37 ° C for 72 hours. Then, the concentration of the living cells was measured by the MTT method, and the cell viability (%) after the action of the drug was calculated. In this experiment, the cell viability of the control group (without compound treatment) was set to 100%.
• Table 2 shows that the aminated derivatives of the homoharringtonine of the present invention are capable of inducing death of human solid tumor cells and inhibiting the growth of these tumor cells, wherein the homoglycosylation derivative BS-HH-012 of the present invention, BS-HH-042, BS-HH-046, BS-HH-050 and BS-HH-054, showing strong anti-human solid tumor A549 (human lung cancer), PANC-1 (pancreatic cancer), Becap37 (human) Breast cancer cells), MG63 (osteosarcoma), anti-Huh7 (human liver cancer cells), RKO (human colon adenocarcinoma cells), Hela (human cervical cancer cells), CaES- (esophage cancer cells), CNE (nasopharyngeal carcinoma cells) ), Hep-2 (laryngeal cancer), PC-3 (prostate cancer), and SK-OV-3 (ovarian cancer cells) effects.
• the homoglycosylation derivative BS-HH-012 of the present invention showing strong anti-human solid tumor
• Table 2 Determination of growth inhibitory concentrations of homoharringtonine alkaloid derivatives against lymphoma and multiple myeloma and human solid tumor cells (72 hours, IC 5 Q (g/mL) values and IC 9 () (g/ mL) value).

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