WO2011054289A1 - 表阿霉素衍生物 - Google Patents
表阿霉素衍生物 Download PDFInfo
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- WO2011054289A1 WO2011054289A1 PCT/CN2010/078368 CN2010078368W WO2011054289A1 WO 2011054289 A1 WO2011054289 A1 WO 2011054289A1 CN 2010078368 W CN2010078368 W CN 2010078368W WO 2011054289 A1 WO2011054289 A1 WO 2011054289A1
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- 0 *CC([C@@](C[C@@](c1c(c(C(c2c(*)cccc22)=*)c3C2=O)O)OC(C2)OC(*)C(*)C2N2**2)(Cc1c3O)O)=O Chemical compound *CC([C@@](C[C@@](c1c(c(C(c2c(*)cccc22)=*)c3C2=O)O)OC(C2)OC(*)C(*)C2N2**2)(Cc1c3O)O)=O 0.000 description 2
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/044—Pyrrole radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
- A61K31/06—Phenols the aromatic ring being substituted by nitro groups
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- 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
- C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
Definitions
- This application relates to the field of medicinal chemistry. More specifically, the present application relates to epirubicin derivatives, methods for their preparation, and their use in treating tumors or cancer. Background
- Epirubicin is an anthracycline antitumor antibiotic synthesized by the Italian scholar Arcamone et al. in 1975 through a semi-synthetic pathway.
- the difference from doxorubicin is that the hydroxyl group at the 4-position of the amino sugar moiety is changed from cis to cis. In trans, the subtle changes in this three-dimensional structure lead to a significant reduction in heart and bone marrow toxicity.
- epirubicin The main role of epirubicin is to directly intercalate between DNA base pairs, interfere with the transcription process, and prevent the formation of mRNA.
- Epirubicin inhibits the synthesis of DNA and RNA, and therefore has a role in all phases of the cell cycle, and is a cell cycle non-specific drug.
- Epirubicin acts on both the cell membrane and the transport system, but the most important site of action is the nucleus.
- epirubicin also inhibits topoisomerase II.
- Epirubicin has equal or higher antitumor activity than doxorubicin (ADM), but its toxicity is especially low. Epirubicin has been shown to have a broad spectrum of effects against experimental tumors. Clinically, epirubicin is mainly used for the treatment of leukemia, malignant lymphoma, multiple myeloma, breast cancer, soft tissue sarcoma, gastric cancer, liver cancer, colorectal cancer, ovarian cancer and the like. Although the toxicity of epirubicin is relatively lower than that of doxorubicin, it still causes heart muscle damage and causes heart failure. Comparative studies have shown that the ratio of cumulative doses of epirubicin and doxorubicin to the same degree of cardiac dysfunction is 2:1.
- cardiac function should still be closely monitored during the treatment of epirubicin to reduce the risk of heart failure (this heart failure can occur even after a few weeks of termination of treatment and may not be effective for the corresponding medication).
- this heart failure can occur even after a few weeks of termination of treatment and may not be effective for the corresponding medication.
- the potential risk of epirubicin cardiotoxicity may increase; and there may be bone marrow suppression, gastrointestinal reactions such as nausea and vomiting, skin reactions such as dermatitis and pigmentation, and Venomitis, cellulitis and other toxic side effects.
- the present application relates to a solvate of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
- R 1 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 2 represents H or OH
- W represents 0 or NH
- R 3 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 4 represents F or OR 7 , wherein R 7 represents H or 2-pyranyl
- R 5 — R 6 represents a five-, six- or seven-membered optionally substituted saturated heterocyclic hydrocarbon group containing an N atom, an optionally substituted unsaturated heterocyclic hydrocarbon group or an optionally substituted aromatic heterocyclic group, or two five-membered groups.
- An optionally substituted fused ring group consisting of a six- or seven-membered ring.
- the present application is directed to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof Solvate:
- R 1 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 2 represents H or OH
- W represents 0 or NH
- R 3 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 4 represents F or OR 7 , wherein R 7 represents H or 2-pyranyl
- R 5 — R 6 represents a five-, six- or seven-membered optionally substituted saturated heterocyclic hydrocarbon group containing an N atom, an optionally substituted unsaturated heterocyclic hydrocarbon group or an optionally substituted aromatic heterocyclic group, or two five-membered groups.
- An optionally substituted fused ring group consisting of a six- or seven-membered ring.
- the present application relates to a process for the preparation of a solvate of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
- R 1 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 2 represents H or OH
- W represents 0 or NH
- R 3 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 4 represents F or OR 7 , wherein R 7 represents H or 2-pyranyl
- R 5 — R 6 represents a five-, six- or seven-membered optionally substituted saturated heterocyclic hydrocarbon group containing an N atom, an optionally substituted unsaturated heterocyclic hydrocarbon group or an optionally substituted aromatic heterocyclic group, or two five-membered groups.
- An optionally substituted fused ring group consisting of a six- or seven-membered ring,
- the method includes:
- R 1 , R 2 , R 3 , R 4 and W in the formula (VII) is the same as the group represented by R 1 , R 3 , R 4 and W in the formula (I);
- R 16 is the same as the group represented by R 16 in the formula (VI), and R 21 and R 22 each represent H or an optionally substituted hydrocarbon group;
- the compound of (X) is reacted under the action of a dehydrating agent to give a compound of the formula (I).
- the compound of formula 9 or formula 10 is reacted under the action of a dehydrating agent to give a compound of formula (I).
- R 15 and Q in the formula 8 is the same as the group represented by R 15 and Q in the formula (V).
- R 1 , R 3 , R 4 , R 2 and W represent the same groups.
- the group represented by R 15 and Q in the formula 10 is the same as the group represented by R 15 and Q in the formula (V), and the groups represented by RR 3 , R 4 , R 2 and W in the formula 7 are the same as the formula (VII).
- a method comprising administering to an individual in need of the method a therapeutically effective amount of a solvate of the compound shown, a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof: among them:
- R 1 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 2 represents H or OH
- W represents 0 or NH
- R 3 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 4 represents F or OR 7 , wherein R 7 represents H or 2-pyranyl
- R 5 — R 6 represents a five-, six- or seven-membered optionally substituted saturated heterocyclic hydrocarbon group containing an N atom, an optionally substituted unsaturated heterocyclic hydrocarbon group or an optionally substituted aromatic heterocyclic group, or two five-membered groups.
- An optionally substituted fused ring group consisting of a six- or seven-membered ring.
- references throughout this specification to "an embodiment” or “an embodiment” or “in another embodiment” or “in certain embodiments” means in at least one embodiment Specific reference elements, structures, or characteristics are described in connection with the embodiments. The appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment. Furthermore, the specific elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
- C 7 -C 12 alkyl describes an alkyl group as defined below having a total of from 7 to 12 carbon atoms
- a C 4 -C 12 cycloalkylalkyl group describes the following definition having a total of from 4 to 12 carbon atoms Cycloalkylalkyl.
- the total number of carbon atoms in the barrel symbol does not include carbon that may be present in the substituents of the group.
- hydrocarbyl refers to an aliphatic hydrocarbon group.
- the hydrocarbyl moiety can be a "saturated alkyl” group, meaning that it does not contain any alkene or alkyne moieties.
- the hydrocarbyl moiety may also be an "unsaturated alkyl” moiety, meaning that it contains at least one alkene or alkyne moiety.
- alkenyl refers to a group consisting of two to eight carbon atoms and at least one carbon-carbon double bond, and a straight or branched hydrocarbon chain group, such as a vinyl group, attached to the remainder of the molecule by a single bond.
- alkyne refers to two to eight carbon atoms and at least one a group consisting of a carbon-carbon triple bond, and a linear or branched hydrocarbon chain group bonded to the remainder of the molecule by a single bond.
- the hydrocarbyl moiety whether saturated or unsaturated, may be branched or linear.
- the hydrocarbyl group may have from 1 to 20 carbon atoms (in each occurrence of the present application, a numerical range such as “1 to 20” refers to each integer in a given range; as “1 to 20” means The hydrocarbyl group may be up to and including 20 carbon atoms from 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., although this definition also encompasses the occurrence of the term "hydrocarbyl group” in the unspecified range of values.
- the hydrocarbyl group may also be a medium-sized hydrocarbyl group having 1 to 10 carbon atoms.
- the hydrocarbyl group may also be a lower hydrocarbon group having 1 to 5 carbon atoms.
- the hydrocarbyl group of the compound of the present application can be designated as "d-hydrocarbyl” or the like.
- “d-hydrocarbyl” indicates the presence of from 1 to 4 carbon atoms in the hydrocarbyl chain, i.e., the hydrocarbyl chain is selected from the group consisting of decyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec. Butyl or tert-butyl.
- the hydrocarbyl group can be optionally substituted, that is, substituted or unsubstituted.
- the substituent group is one or more groups selected individually and independently from the group consisting of: cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, Sulfhydryl, hydrocarbylthio, arylthio, cyano, carbonyl, thiocarbonyl, 0-aminodecanoyl, N-aminodecanoyl, 0-thioaminodecanoyl, N-thioaminodecanoyl, C - acylamino, N-acylamino, S-azidoamido, N-azetido, C-carboxy, 0-carboxy, isocyanato, cyanide, isocalcocyanate Isothiocyanato), nitro, pyridinium, trihalodecanesulfonyl, -NR'R" or an amino group including a mono- and di-substitute
- Typical hydrocarbyl groups include, but are not limited to, mercapto, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, etc..
- substituent may be One of the substituents described below.
- dC 4 hydrocarbyl means a hydrocarbyl group as defined above containing one to four carbon atoms.
- the dc 4 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
- C r C 6 alkyl refers to a one to six carbon atoms in the hydrocarbyl group as defined above.
- the dc 6 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
- CC hydrocarbyl means a hydrocarbyl group as defined above containing one to twelve carbon atoms.
- the C r C 12 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
- C 2 -C 6 hydrocarbyl refers to a hydrocarbyl group as defined above containing two to six carbon atoms.
- the C 2 -C 6 hydrocarbyl group can be optionally substituted as defined for the hydrocarbyl group.
- the "c 3 -c 6 hydrocarbyl group” means a hydrocarbon group as defined above containing three to six carbon atoms.
- the c 3 -c 6 hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.
- the "c 3 -c 12 hydrocarbon group” means a hydrocarbon group as defined above containing three to twelve carbon atoms.
- the c 3 -c 12 hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.
- C 6 -C 12 hydrocarbon group means a hydrocarbon group as defined above containing six to twelve carbon atoms.
- the C 6 -C 12 hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.
- the "C 7 -C 12 hydrocarbon group” means a hydrocarbon group as defined above containing seven to twelve carbon atoms.
- the c 7 -c 12 hydrocarbyl group may be optionally substituted as defined for the hydrocarbyl group.
- hydrocarbyloxy refers to the formula -OR, wherein R is a hydrocarbyl group as defined above, such as decyloxy, ethoxy, n-propoxy, 1-decylethoxy (iso) Propyloxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy and the like.
- heterocycloalkyl refers to a stable three to twelve membered non-aromatic ring group consisting of a carbon atom and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- heterocyclyl groups include, but are not limited to, dioxocyclopentyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, VIII Hydroquinone, octahydroisoindolyl, 2-oxopiperizinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidine Base, piperidinyl, piperazinyl, 4-piperidinone, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, Thimorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.
- heterocycloalkyl is intended to include the above-defined cycloalkyl groups optionally substituted by one or more groups selected from the group consisting of cycloalkyl, aryl, heteroaryl.
- heteroalicyclic hydroxy, alkoxy, aryloxy, fluorenyl, thiol, arylthio, cyano, halo, carbonyl, thiocarbonyl, 0-aminodecanoyl, N-aminodecanoyl, 0-Thioaminodecanoyl, N-thioaminodecanoyl, C-amido, N-acylamino, S-sulfinylamino, N-azidoamido, C-carboxy, 0-carboxy, isocyanide Acidate, thiocyanyl, isothiocyanate, nitro, silane group, trihalodecanesulfonyl, -NR'R" (R, and R" are hydrocarbyl groups as defined in the present application) or include An amino group - and a di-substituted amino group, and a protected derivative thereof.
- heteroaryl refers to a 5 to 18 membered aromatic ring group consisting of a carbon atom and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- the nitrogen, carbon or sulfur atom in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized.
- Examples include, but are not limited to, azaindole, acridinyl, benzimidazolyl, benzothiazolyl, benzindenyl, benzothiadiazolyl, benzonaphthylfuranyl, benzoxazolyl, -benzodioxol-pentenyl group, a benzodioxin group, benzopyranyl, benzopyrone-yl, benzofuranyl, benzofuran keto, benzothiophen-yl points p (; phenyl P-phenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, oxazolyl, porphyrinyl, dibenzofuranyl, furyl, furanone Base, isothiazolyl, imidazolyl, fluorenyl, oxazolyl, isodecyl, indanyl, isoindoline, mes
- heteroaryl is intended to include a cyclic hydrocarbon group as defined above which is optionally substituted by one or more groups selected from the group consisting of cycloalkyl, aryl, heteroaryl.
- heteroalicyclic hydroxy, alkoxy, aryloxy, fluorenyl, thiol, arylthio, cyano, carbonyl, thiocarbonyl, 0-aminodecanoyl, N-aminodecanoyl, 0 -thioaminodecanoyl, N-thioaminodecanoyl, C-acylamino, N-acylamino, S-lamidoamido, N-sulfonamido, C-carboxy, 0-carboxy, isocyanate , thiocyano, isothiocyanate, nitro, silane, trioxanesulfonyl, -NR'R" (R, and R" are the hydrocarbyl groups defined in the present application) or include mono- and di - an amino group substituted with an amino group, and its protected neoplasm.
- “Arbitrary” or “arbitrarily” means that the condition of the subsequent description may or may not occur, and that the statement includes the occurrence or non-occurrence of the event or condition.
- “optionally substituted aryl” means that the aryl group may or may not be substituted, and the description includes substituted aryl groups and unsubstituted aryl groups.
- “Pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, antiseptic that has been approved by the U.S. Food and Drug Administration for use in humans or animals. Agents, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, etc., which have no side effects on the composition of the pharmaceutical composition. a.
- “Pharmaceutically acceptable salts” include “pharmaceutically acceptable acid addition salts” and “pharmaceutically acceptable base addition salts”.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are formed using inorganic or organic acids.
- the inorganic acid is, for example but not limited to, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, etc.
- the organic acid is, for example but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, Ascorbic acid, aspartic acid, benzoic acid, benzoic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, Cyclohexane-amino acid, dodecyl sulfate, ethane-1,2-di-cross-acid,
- “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, hexahydrate, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, Tridecylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimercaptoethanol, 2-diaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, refined ammonia Acid, histidine, caffeine, procaine, seabamin, choline, betaine, benzylamine, phenethylenediamine, ethylenediamine, glucosamine, decyl glucosamine, theobromine, triethanolamine , tromethamine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and
- Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, tridecylamine, dicyclohexylamine, choline and caffeine. Crystallization often produces solvates of the compounds of the present application.
- solvate refers to an aggregate comprising one or more molecules of a compound of the present application with one or more solvent molecules.
- the solvent may be water, and in this case, the solvate is a hydrate.
- the solvent may be an organic solvent.
- the compounds of the present application may exist in the form of hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as in the corresponding solvated forms.
- the compounds of the present application may be true solvates, but in other instances, the compounds of the present application may retain only amorphous water or the compound is a mixture of water and some indefinite solvent.
- “Pharmaceutical composition” refers to a formulation of a compound of the present invention and a medium which is generally accepted in the art for delivery of a biologically activating compound to a mammal such as a human.
- Such media include all pharmaceutically acceptable carriers, diluents or excipients.
- “Therapeutically effective amount” means that when administered to a mammal, preferably to a human, the compounds of the present invention are sufficient to effectively treat (as defined below) the amount of a disease or condition caused by abnormal cell proliferation in a mammal, preferably a human.
- the amount of the compound of the present application which constitutes a “therapeutically effective amount” will vary depending on the compound, the state of the disease and its severity, and the age of the mammal to be treated, but those skilled in the art will be able to rely on their own knowledge and the present disclosure.
- the formula determines the amount of the compound of the present application.
- treating encompasses a mammal having a related disease or condition, preferably a treatment-related disease or condition in a human, and includes:
- disease and “disease state” may be used interchangeably or may be different, as a particular disease or condition may not have a known causative agent (and therefore cannot be explained by etiology). Therefore, it is not recognized as a disease, but is considered to be an undesired disease state or condition in which the clinician has identified more or less specific series of symptoms.
- the present application relates to a solvate of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
- R 1 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 2 represents H or OH
- W represents 0 or NH
- R 3 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 4 represents F or OR 7 , wherein R 7 represents H or 2-pyranyl
- R 5 — R 6 represents a five-, six- or seven-membered optionally substituted saturated heterocyclic hydrocarbon group containing an N atom, an optionally substituted unsaturated heterocyclic hydrocarbon group or an optionally substituted aromatic heterocyclic group, or two five-membered groups.
- An optionally substituted fused ring group consisting of a six- or seven-membered ring.
- the C Cs hydrocarbyl group is selected from a dC 4 hydrocarbyl group or a dC 6 hydrocarbyl group.
- the C C8 hydrocarbyl group is selected from the group consisting of dC 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl.
- the C hydrocarbyl group is selected from the group consisting of dC 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl.
- the C C8 hydrocarbyl group is selected from the group consisting of d-C4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl.
- dC 8 hydrocarbon group or a hydrocarbon group selected from d- dC 6 hydrocarbon group is selected from d- dC 6 hydrocarbon group.
- the CC 8 alkoxy group is selected from the group consisting of CC 8 alkoxy, CC 6 alkoxy, or C r C 4 alkoxy.
- R 1 represents H, CH 3 or OCH 3 .
- R 3 represents H, F, CH 3 , CH 2 CH 3 , OH, OCH 3 Or OCH 2 CH 3 .
- R 3 represents H, CH 3 , OH or OCH 3 .
- R 3 represents CH 3 .
- the optionally substituted saturated heterocyclic hydrocarbon group, the optionally substituted unsaturated heterocyclic hydrocarbon group, the optionally substituted aromatic heterocyclic group or the optionally substituted fused ring group further contains 1-2 other identical or Different heteroatoms.
- the optionally substituted saturated heterocyclic hydrocarbon group, the optionally substituted unsaturated heterocyclic hydrocarbon group, the optionally substituted aromatic heterocyclic group or the optionally substituted fused ring group further contains 1-2 identical or different N, 0 or S atom.
- R 5 — R 6 is selected from the group of formula (II), the group of formula (V) or formula (;
- R 16 R 21 and R 22 represent 11, F, Cl, CN, OH, COOC 1-4 hydrocarbyl, OC 1-4 hydrocarbyl, C 1-4 hydrocarbyl or NR 18 R 19 respectively ;
- R 18 and R 19 represent H or C 1-6 hydrocarbyl, or NR 18 R 19 together represents pyrrolidin-1-yl, piperidin-1-yl or morphinolin-1-yl
- R 16 represents H, F, Cl, CN, OH, C3 ⁇ 4, CH 2 C3 ⁇ 4, CH 2 CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , COOCH 3 , COOCH 2 CH 3 , COOCH 2 CH 2 CH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , pyrrolidin-1-yl, piperidin-1-yl or Morpholine-1-yl.
- R 5 — R 6 represents 1-pyrrolyl, succinimide, glutarimide, butyrolactin-1-yl, valerolactam-1-yl, 3- Mercapto-pyrrol-1-yl, 3-decyloxy-pyrrol-1-yl, 3-mercapto-succinimidyl, 3-decyloxy-succinimide, 3-indenyl - glutarimide, 3-decyloxy-glutarimide, 3-mercapto-butyrolactam-1-yl, 3-methoxy-butyrolactam-1 -yl, 3- Mercapto-valerolactam-1-yl, 3-decyloxy-valerolactam-1 -yl, 4-mercapto-valerolactam-1-yl, 4-decyloxy-valerolactam-1- Base, 2-cyanomorpholine, 2-pyrroline-1-yl or phthalic acid imide.
- R 5 — R 6 represents 1-pyrrolyl, succinimide, glutarimide, butyrolactin-1-yl or valerolac-1-yl.
- the present application is directed to a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof Solvate:
- R 1 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 2 represents H or OH
- W represents 0 or NH
- R 3 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 4 represents F or OR 7 , wherein R 7 represents H or 2-pyranyl; N
- R 5 — R 6 represents a five-, six- or seven-membered optionally substituted saturated heterocyclic hydrocarbon group containing an N atom, an optionally substituted unsaturated heterocyclic hydrocarbon group or an optionally substituted aromatic heterocyclic group, or two five-membered groups.
- An optionally substituted fused ring group consisting of a six- or seven-membered ring.
- the pharmaceutical composition is formulated for oral, buccal, intravenous, intraperitoneal, subcutaneous, intramuscular, intranasal, eye drop, inhalation, intraoral, vaginal or epidermal
- the pharmaceutical dosage form to be administered is formulated for oral, buccal, intravenous, intraperitoneal, subcutaneous, intramuscular, intranasal, eye drop, inhalation, intraoral, vaginal or epidermal.
- the pharmaceutical composition is formulated into a solution, a water needle, a powder needle, a lyophilized powder, an oral solution, a syrup, a tablet, a pill, a capsule, a granule, a gel, a soft capsule. , suppositories, aerosols or creams.
- the pharmaceutical composition is formulated as a powder, a lyophilized powder, a water needle, an emulsion or a suspension.
- the pharmaceutical compositions further comprise excipients, lubricants, disintegrants, glidants, solubilizers, fillers, solvents, diluents, suspending agents, osmotic pressure adjusting agents, buffering agents, Analgesics, preservatives, antioxidants, sweeteners, colorants and/or binders.
- solubilizers that can be used in the present application include, but are not limited to, polyethylene glycol
- polyethylene glycol 400 polyethylene glycol 600 or polyethylene glycol 2000
- Tween including but not limited to Tween 20, Tween 40 or Tween 80
- polyoxyethylene Castor oil polyoxyethylene hydrogenated castor oil
- polyvinylpyrrolidone poloxamer
- lecithin soy lecithin
- cephalin phosphatidic acid
- dipalmitoyl phosphatidylcholine hydrogen phosphatidylethanolamine
- phosphatidylserine Cholesterol, diaminocholesterol, soy glucoside
- propylene glycol D-mannitol, trehalose
- benzyl benzoate ethanol, triamino decane, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, three Ethanolamine, soybean ⁇ sterol combined with ergosterol.
- excipients that can be used in the present application include, but are not limited to, lactose, sugar, D-mannitol, D-sorbitol, starch, alpha-starch, dextrin, crystalline cellulose, low substituted hydroxypropyl Cellulose, sodium carboxymethyl cellulose, gum arabic, amylopectin, light anhydrous silicic acid, synthetic aluminum silicate and magnesium aluminum silicate.
- lubricants that can be used in the present application include, but are not limited to, magnesium stearate, calcium stearate, talc, silica gel, and magnesium lauryl sulfate.
- binders that can be used in the present application include, but are not limited to, alpha-starch, sucrose, gelatin, gum arabic, decyl cellulose, ethyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose.
- disintegrants that can be used in the present application include, but are not limited to, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked carboxy-based fibers Sodium, croscarmellose sodium and treated agar.
- glidants that can be used in the present application include, but are not limited to, micronized silica gel,
- Cab-O-Sil (Cabot), Arosil (Degussa) and hydrated sodium aluminosilicate.
- Illustrative examples of the fillers of the present invention include, but are not limited to, lactose, sugar, starch, mannitol, erythritol, icing sugar, dextrin, and microcrystalline cellulose.
- solvents that can be used in the present application include, but are not limited to, water for injection, physiological saline, Ringer's solution, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.
- suspending agents that can be used in the present application include, but are not limited to: surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, phenylethyl chloride Ammonium, glyceryl monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinyl ropazine, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyl Propyl cellulose, etc.; polysolvate and polyoxyethylene hardened castor oil.
- surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, phenylethyl chloride Ammonium, glyceryl monostearate
- hydrophilic polymers such as polyvinyl alcohol, polyvinyl ropazin
- osmotic pressure adjusting agents that can be used in the present application include, but are not limited to, sodium chloride, glycerin, D-mannitol, D-sorbitol or glucose, and the like.
- buffers that can be used in the present application include, but are not limited to, phosphate, acetate, carbonate, and citrate buffers.
- analgesics that can be used in the present application include, but are not limited to, benzyl alcohol.
- preservatives that can be used in the present application include, but are not limited to, p-hydroxybenzophenone, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, and sorbic acid.
- antioxidants that can be used in the present application include, but are not limited to, sulfites and ascorbates.
- colorants that can be used in the present application include, but are not limited to: water soluble edible yellow dyes (food dyes such as Edible Red No. 2 or No. 3, Edible Yellow No. 4 or No. 5, edible blue No. l or No. 2); water-insoluble coloring dye (such as aluminum salt of water-soluble edible yellow dye), sunset yellow, tartrazine or carmine; and natural dyes (such as ⁇ -carotene, chlorophyll, iron and iron) ).
- water soluble edible yellow dyes food dyes such as Edible Red No. 2 or No. 3, Edible Yellow No. 4 or No. 5, edible blue No. l or No. 2
- water-insoluble coloring dye such as aluminum salt of water-soluble edible yellow dye
- sunset yellow tartrazine or carmine
- natural dyes such as ⁇ -carotene, chlorophyll, iron and iron
- natural or artificial sweeteners such as sodium saccharin, dipotassium glycyrrhetinate, xylitol, aspartame, sweet orange solid flavor, sweetness Vegetarian, sorbose, sucrose, glucose and stevia.
- the present application relates to a process for the preparation of a solvate of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
- R 1 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 2 represents H or OH
- W represents 0 or NH
- R 3 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 4 represents F or OR 7 , wherein R 7 represents H or 2-pyranyl
- R 5 — R 6 represents a five-, six- or seven-membered optionally substituted saturated heterocyclic hydrocarbon group containing an N atom, an optionally substituted unsaturated heterocyclic hydrocarbon group or an optionally substituted aromatic heterocyclic group, or two five-membered groups.
- An optionally substituted fused ring group consisting of a six- or seven-membered ring,
- the method comprises: a compound of the formula (VII) or a compound of the formula (VII) and one of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sulfonic acid, benzoic acid or p-toluene. Or a salt formed by one or more mixtures and a compound of the formula (VIII) are reacted in the presence of an acid or/and an alkaline reagent to give a compound of the formula (I),
- the salt of the compound of formula (VII) is selected from the group consisting of hydrochloride, sulfate, phosphate, citrate, acetate, sulfonate, ethanesulfonate, benzenesulfonate Or p-toluenesulfonate.
- the acidic agent is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, guanidinoic acid, citraic acid, benzoic acid, ruthenium Benzoic acid, citric acid, tartaric acid, lactic acid, malic acid, and mixtures thereof.
- the acidic reagent is used in an amount of from 0.05 to 500 times (molar amount) based on the compound of the formula (VII). In certain embodiments, the acidic reagent is used in an amount of from 0.2 to 50 moles per mole of the compound of formula (VII). In certain embodiments, the acidic reagent is used in the amount of formula (VII). 0.7 to 5 times (molar amount) of the compound is shown.
- the alkaline agent is selected from the group consisting of potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, sodium phosphate, potassium phosphate. , disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium lactate, potassium lactate, sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, sodium malate, potassium malate, sodium propionate, potassium propionate, sodium butyrate, Potassium butyrate, sodium succinate, potassium succinate, sodium valerate, potassium valerate, sodium glutarate, potassium pentoxide and mixtures thereof.
- the alkaline agent is used in an amount of from 0.05 to 500 times (molar amount) of the compound of formula (VII). In certain embodiments, the alkaline agent is used in an amount of from 0.2 to 50 moles (molar amount) of the compound of formula (VII). In certain embodiments, the alkaline agent is used in an amount of from 0.7 to 5 times (molar amount) of the compound of formula (VII). In certain embodiments, the reaction temperature is -10-150. C. In certain embodiments, the reaction temperature is from 0 to 100. C, In certain embodiments, the reaction temperature is from 10 to 80. C.
- the reaction is carried out in a solvent.
- solvents that can be used in the present application include, but are not limited to, dichlorodecane, trichlorodecane, hydrazine, hydrazine-dimercapto amide, disulfoxide, ethylene glycol dimethyl ether, ethanol, Sterol, isopropanol, tetrahydrofuran, ethyl acetate, decyl acetate, decyl propionate, ethyl propionate, ethylene glycol diethyl ether, hydrazine, hydrazine-diethyl hydrazide, 1,2-dichloroethane Alkane, acetonitrile, water and a compound of formula (VIII).
- an organic base is added to the reaction as an acid binding agent or catalyst.
- organic bases include, but are not limited to, triethylamine, tridecylamine, diisopropylethylamine, 4-diaminopyridine, 4-(1-pyrrolidinyl)pyridine, pyridine Or ⁇ -mercaptomorpholine.
- the base is used in an amount of from 0.5 to 10 times the molar amount of the compound of the formula (VII). In certain embodiments, when used as an acid binding agent, the base is used in an amount of from 1 to 5 times the molar amount of the compound of the formula (VII);
- the base is used in an amount of from 0.01 to 2 times the molar amount of the compound of the formula (VII). In certain embodiments, as the catalyst, the base is used in an amount of from 0.05 to 0.2 times the molar amount of the compound of the formula (VII).
- the compounding molar ratio of the compound of formula (VII) or a salt thereof to the compound of formula (VIII) is from 1:0.1 to 1:10,000. In certain embodiments, the molar ratio of the compound of formula (VII) or a salt thereof to the compound of formula (VIII) is from 1:0.5 to 1:1000. In some embodiments, the molar ratio of the compound of formula (VII) or a salt thereof to the compound of formula (VIII) is from 1 : 1:1 :500.
- the present application relates to a process for the preparation of a solvate of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
- R 1 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 2 represents H or OH
- W represents 0 or NH
- R 3 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 4 represents F or OR 7 , wherein R 7 represents H or 2-pyranyl
- R 5 — R 6 represents a five-, six- or seven-membered optionally substituted saturated heterocyclic hydrocarbon group containing an N atom, an optionally substituted unsaturated heterocyclic hydrocarbon group or an optionally substituted aromatic heterocyclic group, or two five-membered groups.
- An optionally substituted fused ring group consisting of a six- or seven-membered ring,
- the method comprises: a compound of the formula (VII) or a compound of the formula (VII) and one of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sulfonic acid, benzoic acid or p-toluene. Or a salt formed by one or more mixtures is reacted with a compound of the formula (IX) to give a compound of the formula (X), and the compound of the formula (X) is reacted under the action of a dehydrating agent to obtain a compound of the formula (I).
- R 10 , R", R 12 , R 13 and n in the formula (IX) is the same as the group represented by R 10 , R 11 R 12 , R 13 and n in the formula (II);
- the group represented by R 10 , R", R 12 , R 13 and n in X) is the same as the group represented by R 1G , R", R 12 , R 13 and n in the formula (II), in the formula (X) RR 2, R 3, R 4 and W represents a group of the formula RR (VII) 2, R 3, R 4 and W represent the same group.
- the reaction is in methylene chloride, trichloromethane, carbon tetrachloride, ethyl acetate, decyl acetate, decyl propionate, ethyl propionate, 1,2-dichloroethane , acetone, tetrahydrofuran, ethylene glycol dioxime ether, ethylene glycol diethyl ether, hydrazine, hydrazine-dihydrazinamide, hydrazine, hydrazine-diethyl hydrazide, dimethyl sulfoxide, acetonitrile, water or a mixture thereof In progress.
- a catalyst is added to the reaction.
- the catalyst is used in an amount of from 0.01 to 10 times the molar amount of the compound of the formula (VII). In certain embodiments, the catalyst is used in an amount of from 0.02 to 5 times the molar amount of the compound of formula (VII). In certain embodiments, the catalyst is used in an amount of from 0.05 to 1 times the molar amount of the compound of the formula (VII).
- an acid binding agent is added to the reaction.
- acid scavengers that can be used in the present application include, but are not limited to, triethylamine, tridecylamine, pyridine, diisopropylethylamine, fluorenyl-mercaptomorpholine, fluorenyl-hydrazinopiperidine, hydrazine- Ethyl piperidine, 4-diaminoguanidine, 4-diethylaminopyridine, 4-(pyrrolidin-1-yl)-pyridine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, cesium carbonate , sodium hydroxide and potassium hydroxide.
- the acid scavenger is used in an amount from 0.4 to 20 times the molar amount of the compound of formula (VII). In certain embodiments, the amount of acid binding agent is a compound of formula (VII) The molar amount is 0.8-10 times. In certain embodiments, the acid scavenger is used in an amount of from 1 to 5 times the molar amount of the compound of formula (VII).
- the reaction temperature is from -20 to 100. C. In certain embodiments, the reaction is suitably at a temperature of from -10-80. C. In certain embodiments, the optimum temperature for the reaction is from -5 to 80 °C.
- the molar ratio of the compound of formula (IX) to the compound of formula (VII) or a salt thereof is from 1:0.1 to 1:10. In certain embodiments, the molar ratio of the compound of formula (IX) to the compound of formula (VII) or a salt thereof is from 1:0.5 to 1:5. In certain embodiments, the molar ratio of the compound of formula (IX) to the compound of formula (VII) or a salt thereof is from 1:0.8 to 1:3.
- dehydrating agents that can be used in the present application include, but are not limited to, DCC (dicyclohexylcarbodiimide), EDC HC1 (1-ethyl-3-(3-dioxylpropyl)carbamate Imine hydrochloride), CDI (N,N,-carbonyldiimidazole) or DIC (N,N,-diisopropylcarbodiimide).
- DCC dicyclohexylcarbodiimide
- EDC HC1 (1-ethyl-3-(3-dioxylpropyl)carbamate Imine hydrochloride
- CDI N,N,-carbonyldiimidazole
- DIC N,N,-diisopropylcarbodiimide
- the dehydrating agent is used in an amount of from 0.1 to 10 times the molar amount of the compound of the formula (X). In certain embodiments, the dehydrating agent is used in an amount of from 0.5 to 5 times the molar amount of the compound of the formula (X). In certain embodiments, the dehydrating agent is used in an amount of from 1 to 3 times the molar amount of the compound of the formula (X).
- the reaction temperature is -10-120. C, in certain embodiments, the reaction temperature is from 0 to 100. C. In certain embodiments, the reaction temperature is from 20 to 100. C.
- the reaction is in dichloromethane, trichloromethane, ethyl acetate, decyl acetate, ethyl propionate, decyl propionate, acetone, tetrahydrofuran, ethylene glycol dioxime ether, ethylene It is carried out in the alcohol diethyl ether, hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-diethyl hydrazide, dimethyl sulfoxide, acetonitrile or a mixture thereof.
- the present application relates to a process for the preparation of a solvate of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
- R 1 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 2 represents H or OH
- W represents 0 or NH
- R 3 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 4 represents F or OR 7 , wherein R 7 represents H or 2-pyranyl
- R 5 — R 6 represents a five-, six- or seven-membered optionally substituted saturated heterocyclic hydrocarbon group containing an N atom, an optionally substituted unsaturated heterocyclic hydrocarbon group or an optionally substituted aromatic heterocyclic group, or two five-membered groups.
- An optionally substituted fused ring group consisting of a six- or seven-membered ring,
- the method comprises: a compound of the formula (VII) or a compound of the formula (VII) and one of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sulfonic acid, benzoic acid or p-toluene. Or a salt formed by one or more mixtures is reacted with a compound of formula 8 to give a compound of formula 9 or formula 10, and a compound of formula 9 or formula 10 is reacted under the action of a dehydrating agent to give a compound of formula (I).
- Q represents R 15 and the group represented by Q the same.
- R 1 , R 3 , R 4 , R 2 and W represent the same groups.
- the group represented by R 15 and Q in the formula 10 is the same as the group represented by R 15 and Q in the formula (V), and the groups represented by RR 3 , R 4 , R 2 and W in the formula 7 are the same as the formula (VII).
- the groups represented by RR 3 , R 4 , R 2 and W are the same.
- the reaction is in methylene chloride, trichloromethane, carbon tetrachloride, ethyl acetate, decyl acetate, decyl propionate, ethyl propionate, 1,2-dichloroethane , acetone, tetrahydrofuran, ethylene glycol dioxime ether, ethylene glycol diethyl ether, hydrazine, hydrazine-dihydrazinamide, hydrazine, hydrazine-diethyl hydrazide, dimethyl sulfoxide, acetonitrile, water or a mixture thereof In progress.
- a catalyst is added to the reaction.
- the catalyst is used in an amount of from 0.01 to 10 times the molar amount of the compound of the formula (VII). In certain embodiments, the catalyst is used in an amount of from 0.02 to 5 times the molar amount of the compound of formula (VII). In certain embodiments, the catalyst is used in an amount of from 0.05 to 1 times the molar amount of the compound of the formula (VII).
- an acid binding agent is added to the reaction.
- acid scavengers that can be used in the present application include, but are not limited to, triethylamine, tridecylamine, pyridine, diisopropylethylamine, fluorenyl-mercaptomorpholine, fluorenyl-hydrazinopiperidine, hydrazine- Ethyl piperidine, 4-diaminoguanidine, 4-diethylaminopyridine, 4-(pyrrolidin-1-yl)-pyridine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, cesium carbonate , sodium hydroxide and potassium hydroxide.
- the acid scavenger is used in an amount of from 0.4 to 20 times the molar amount of the compound of formula (VII). In certain embodiments, the acid scavenger is used in an amount from 0.8 to 10 times the molar amount of the compound of formula (VII). In certain embodiments, the acid scavenger is used in an amount of from 1 to 5 times the molar amount of the compound of formula (VII).
- the reaction temperature is from -20 to 100. C. In certain embodiments, the reaction temperature is -10-80. C. In certain embodiments, the reaction temperature is from 0 to 80. C.
- the molar ratio of the compound of formula (VII) or a salt thereof to the compound of formula 8 is: 1: 0.2-1:10. In certain embodiments, the molar ratio of the compound of formula (VII) or a salt thereof to the compound of formula 8 is: 1: 0.5-1:5. In certain embodiments, the molar ratio of the compound of formula (VII) or a salt thereof to the compound of formula 8 is: 1: 0.8-1:3.
- dehydrating agents that can be used in the present application include, but are not limited to, DCC (dicyclohexylcarbodiimide), EDC HC1 (1-ethyl-3-(3-dioxylpropyl)carbamate Imine hydrochloride), CDI (N,N,-carbonyldiimidazole) and DIC (N,N,-diisopropylcarbodiimide).
- the amount of dehydrating agent is from 0.1 to 10 times the molar amount of the compound of Formula 9 or 10.
- the amount of dehydrating agent is from 0.5 to 5 times the molar amount of the compound of formula 9 or 10.
- the dehydrating agent is used in an amount of from 1 to 3 times the molar amount of the compound of Formula 9 or 10.
- the reaction temperature is -10-120. C. In certain embodiments, the reaction temperature is from 0 to 100. C. In certain embodiments, the reaction temperature is from 20 to 100. C.
- the reaction is in dichloromethane, trichloromethane, ethyl acetate, decyl acetate, ethyl propionate, decyl propionate, acetone, tetrahydrofuran, ethylene glycol dioxime ether, ethylene It is carried out in the alcohol diethyl ether, hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-diethyl hydrazide, dimethyl sulfoxide, acetonitrile or a mixture thereof.
- a catalyst is added to the reaction.
- the catalyst is used in an amount of from 0.01 to 1 times the molar amount of the compound of formula 9 or 10. In certain embodiments, the catalyst is used in an amount of from 0.02 to 0.8 times the molar amount of the compound of formula 9 or 10. In certain embodiments, the catalyst is used in an amount of from 0.03 to 0.5 times the molar amount of the compound of Formula 9 or 10.
- R 1 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 2 represents H or OH
- W represents 0 or NH
- R 3 represents H, F, OH, an optionally substituted hydrocarbon group or an optionally substituted alkoxy group
- R 4 represents F or OR 7 , wherein R 7 represents H or 2-pyranyl
- R 5 — R 6 represents a five-, six- or seven-membered optionally substituted saturated heterocyclic hydrocarbon group containing an N atom, an optionally substituted unsaturated heterocyclic hydrocarbon group or an optionally substituted aromatic heterocyclic group, or two five-membered groups.
- An optionally substituted fused ring group consisting of a six- or seven-membered ring.
- the disease or condition resulting from abnormal cell proliferation is cancer.
- the cancer is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, liver cancer, gastric cancer, small cell lung cancer, non-small cell lung cancer, colon cancer, colon cancer, Hodgkin's disease, non-Hodgkin's lymph Tumor, rectal cancer, brain cancer, urinary tract cancer, kidney cancer, bladder cancer, uterine cancer, pancreatic cancer, head and neck cancer, melanoma, various blood cancers, lymphoma and multiple myeloma.
- Illustrative examples of compounds in the state include, but are not limited to, other types of anticancer drugs, immunopotentiators, anticancer synergists, hormones, and traditional Chinese medicine preparations.
- the combined use may be used simultaneously or sequentially.
- compounds include, but are not limited to, paclitaxel, cyclophosphamide, 5-fluorouracil, salidolamine, cisplatin, revimid, HKI272, tarceva, Irresa, Actimid, BIBW2992, revlimid (lenalidomide), triazine Derivatives such as hexamethylene melamine; enzymes such as asparaginase; antibacterial agents such as bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubicin, mitomycin, epirubicin Or pucamycin; alkylating agents such as busulfan, carboplatin, carmustine,
- the fluorouracil used in combination with a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate thereof Etoposide, cyclophosphamide, cisplatin, carboplatin, vincristine, gemcitabine, vinorelbine, chlorambucil, doxorubicin, melphalan, osmolalol, and mixtures thereof.
- a second method for the preparation of this compound 100 mg of a single-neck round bottom bottle was added with 100 mg of epirubicin hydrochloride, dissolved in 3 ml of DMF, and 63 ⁇ l of DIEA (diisopropylethylamine) and 2 mg of DMAP (4-di) were added.
- the amidinopyridine was stirred for 10 min, 21 mg of succinic anhydride was added, and the mixture was stirred at room temperature for 1 hour under argon atmosphere.
- the reaction mixture was sparged, and the obtained residue was added with 20 ml of distilled water and 10 ml of chloroform, and filtered to give a cake.
- HePG-2 human liver cancer cell line
- A549 Human lung cancer fine-packed strain
- A431 Epidermoid cell line
- THP-1 human leukemia cell line
- U937 human lymphatic cancer cell line
- NCI-H460 human lung cancer cell line
- NCI-H446 human lung cancer packet
- DU-145 human prostate cancer cell line
- HL-60 human leukemia fine-package strain
- K562 human leukemia cell line
- PC-3 human prostate cancer cell line
- MTT tetrazolium blue
- DMSO disulfoxide
- the cells were seeded in RPMI 1640 cell culture medium containing 10% fetal calf serum (100 ku/L for each of penicillin and streptomycin), and the incubator was placed at 37. In a cell culture incubator containing 5% CO 2 , the cells were changed once every 2-3 days, digested with 0.25% trypsin solution, and passaged and collected.
- the logarithmic growth phase cells were prepared into a cell suspension of the desired concentration with RPMI 1640 medium containing 10% fetal bovine serum, and added to a 96-well cell culture plate at a dose of 3000-5000 cells per well (, ⁇ ) for 24 hours. Different concentrations of the test substance ⁇ were added to each well, and each concentration had 4 parallel holes. After culturing for 72 hr-120 hr, the supernatant was discarded, and a freshly prepared serum-free medium of 0.5 mg/ml MTT was added to each well, 37. C was incubated for 4 hr and the supernatant was discarded.
- the yttrium was dissolved in 200 ⁇ l DMSO, and after lightly shaking for 15 minutes, the light absorption value (OD-value) was measured by a microplate reader at a detection wavelength of 570 nm and a reference wavelength of 450 nm.
- inhibition rate (OD-value of control group - OD-value of administration group) / OD-value of control group x l00%; expressed by maximum inhibition rate I max and half effective concentration (IC 5 ) Anticancer effect.
- the micro-Cal Origin software was used to map, and the four-parameter Logistic program in the software was used to fit the inhibition curve of the test object on tumor cell growth, and the half effective concentration (IC 5 :: g/ml) for inhibiting tumor cell proliferation was determined.
- test subjects were exposed to concentrations of 0.001 g/ml, 0.003 g/ml, and 0.009 g/ml.
- Doxorubicin (positive drug) exposure concentration is 1.25 g/ml, 5 g/ml, 20 g/ml.
- Table 1 lists the growth inhibition rates of the compounds on HL-60 cells at a concentration of ⁇ , and Table 2 lists the inhibitory activities of the compounds on various tumor cells. Growth inhibition rate of test compound against HL-60 cells at ⁇ concentration Compound inhibition rate (%) Example 1 80
- Example 8 Inhibitory activity of test compounds on tumor cells
- the compounds disclosed herein have inhibitory activity against human cancer cells, and wherein the activity of the compound of Example 1 is comparable to or better than that of epirubicin, and against a variety of human tumor cell lines.
- Cell lines such as human leukemia K562, human prostate cancer PC-3, lymphoma U937, kidney cancer 786-0, lung cancer A549 have very strong growth inhibition effects.
- the compounds of the invention have a broad spectrum of anti-tumor activity.
- Example 1 compound solution preparation method Weigh 4.53 of the compound of Example 1, weigh 4 ( ⁇ L DMSO (dimercapto sulfoxide) dissolved, then add 340 ⁇ RH40 (polyoxyethylene castor oil), mix well, add 4.156 mL of normal saline. After mixing evenly, pass 0.45 ⁇ After filtration of the filter, a solution of 1 mg/ml of the compound of Example 1 was obtained.
- DMSO dimercapto sulfoxide
- RH40 polyoxyethylene castor oil
- mice Mortality of mice after a single intravenous injection of the compound of Example 1
- the compound of Example 1 was administered to the tail vein of the mice at a dose of 20 mg/kg, and the administration volume was 20 ml/kg.
- a total of 9 mice were observed for 14 days. There was no significant change in the body weight of the animals, and no animal death occurred. No significant abnormalities were found in the indicators. No obvious abnormalities were found in the anatomy at the end of the experiment.
- the above results indicate that the compound of the present invention is well tolerated in mice. It will be understood that the various embodiments of the present invention are described in the foregoing, and the various modifications may be made without departing from the spirit and scope of the invention. Therefore, the application is limited only by the accompanying claims.
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Description
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PCT/CN2010/078368 WO2011054289A1 (zh) | 2009-11-03 | 2010-11-03 | 表阿霉素衍生物 |
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US (1) | US8877720B2 (zh) |
CN (1) | CN102050856B (zh) |
WO (1) | WO2011054289A1 (zh) |
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WO2014059740A1 (zh) * | 2012-03-06 | 2014-04-24 | 天津和美生物技术有限公司 | 四环蒽醌衍生物 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59212484A (ja) * | 1983-05-17 | 1984-12-01 | フア−ミタリア・カルロ・エルバ・ソシエタ・ペル・アツイオ−ニ | アントラサイクリン誘導体 |
WO1990010639A2 (en) * | 1989-03-13 | 1990-09-20 | Farmitalia Carlo Erba S.R.L. | New 3'-(4-morpholinyl)- and 3'-(2-methoxy-4-morpholinyl)- anthracycline derivatives |
CN101555264A (zh) * | 2008-04-11 | 2009-10-14 | 天津和美生物技术有限公司 | 具有高活性的四环蒽醌类抗生素的衍生物及其制备和应用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2140006A (en) | 1983-05-17 | 1984-11-21 | Erba Farmitalia | Anthracycline derivatives |
US5843903A (en) * | 1995-11-27 | 1998-12-01 | The Administrators Of The Tulane Educational Fund | Targeted cytotoxic anthracycline analogs |
EP1572242B1 (en) * | 2002-12-13 | 2014-04-16 | Immunomedics, Inc. | Immunoconjugates with an intracellularly-cleavable linkage |
-
2009
- 2009-11-03 CN CN200910071116.3A patent/CN102050856B/zh active Active
-
2010
- 2010-11-03 WO PCT/CN2010/078368 patent/WO2011054289A1/zh active Application Filing
- 2010-11-03 US US13/508,035 patent/US8877720B2/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59212484A (ja) * | 1983-05-17 | 1984-12-01 | フア−ミタリア・カルロ・エルバ・ソシエタ・ペル・アツイオ−ニ | アントラサイクリン誘導体 |
WO1990010639A2 (en) * | 1989-03-13 | 1990-09-20 | Farmitalia Carlo Erba S.R.L. | New 3'-(4-morpholinyl)- and 3'-(2-methoxy-4-morpholinyl)- anthracycline derivatives |
CN101555264A (zh) * | 2008-04-11 | 2009-10-14 | 天津和美生物技术有限公司 | 具有高活性的四环蒽醌类抗生素的衍生物及其制备和应用 |
Also Published As
Publication number | Publication date |
---|---|
CN102050856B (zh) | 2014-04-30 |
US20130131001A1 (en) | 2013-05-23 |
US8877720B2 (en) | 2014-11-04 |
CN102050856A (zh) | 2011-05-11 |
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