CN117500808A - Anthracene compound, preparation method and medical application thereof - Google Patents

Anthracene compound, preparation method and medical application thereof Download PDF

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Publication number
CN117500808A
CN117500808A CN202280042744.2A CN202280042744A CN117500808A CN 117500808 A CN117500808 A CN 117500808A CN 202280042744 A CN202280042744 A CN 202280042744A CN 117500808 A CN117500808 A CN 117500808A
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compound
formula
phenyl
cancer
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胡范
方丽
谭芳
肖黎
刘克楠
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D491/02—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 two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms

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  • Organic Chemistry (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to an anthracene compound of a formula A, a preparation method and medical application thereof, wherein the anthracene compound has the effect of inhibiting the growth of tumor cells and has the potential of being used as an anti-tumor drug. The invention also relates to a method for quality control of a sample.

Description

Anthracene compound, preparation method and medical application thereof Technical Field
The invention relates to the technical field of medicines, in particular to an anthracene compound with anti-tumor activity, a pharmaceutically acceptable salt thereof, a preparation method and application thereof.
Background
With the development of molecular biology technology and the further understanding of pathogenesis from cellular and molecular level, the discovery of high-efficiency and low-toxicity anticancer drugs by taking key enzymes in tumorigenesis and development signal paths as targets has become an important research direction. The molecular targeting treatment of tumor is different from traditional tumor treatment method, and is based on the research of tumor molecular biology, and the key path for tumor growth is blocked by small molecular compound, so as to achieve the effect of blocking tumor cell growth.
CN102378574a discloses azo anthracene derivatives represented by formula B and uses thereof for modulating glucagon-like peptide-1 receptor:
the inventors of the present application studied the degradation process of such anthracene compounds, and found that they are easily degraded under a suitable acidic environment, and the degradation products thereof are generally more stable. CN102378574a indicates that these azo anthracene derivatives have an effect of modulating glucagon-like peptide-1 (GLP-1) receptors. Further activity studies on degradation products of such compounds are necessary, and potential medical uses thereof are found.
Disclosure of Invention
In one aspect, the invention provides an anthracene compound of formula a:
and the pharmaceutically acceptable salts thereof,
wherein:
x is independently selected from oxygen, hydrogen, nitrogen;
R 1 selected from COOH or-COOCH 3 ；
R 2 is-Y 1 –L–Y 2 ；
L is selected from- (CH) 2 ) a -or-O-, wherein a is 0 or 1;
Y 1 is phenylene, which is 1, 3-phenylene or 1, 4-phenylene;
Y 2 selected from phenyl, pyridyl, diazaaryl or imidazolyl, and Y 2 Optionally independently with hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, CF 3 、–CH 2 F、–CH 2 CF 3 、CN、–CH 2 CN、–OCH 3 、–O–C(CH 3 ) 3 、–OCH 2 CH 3 、–OCH(CH 3 ) 2 、–OCF 3 、–OCH 2 CF 3 、NH 2 、–SO 2 –CH 3 、–NHCH 3 、–CO–NHCH 3 、–NHCH 2 CH 3 、–N(CH 3 ) 2 、–CO–CH 3 、–CO–NHCH 3 Substituted 1-3 times;
R 3 selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, furyl, thienyl, oxazolyl, pyridyl, thiazolyl, pyrimidinyl, epoxypentacyclic, epoxyhexacyclic, -sulfonyl-thiazolyl, -sulfonyl-oxazolyl, -sulfonyl-pyridyl, -carbonyl-oxazolyl, -carbonyl-pyridyl; optionally independently from each other with halogen, amino, OH, COOH, CN, -CH 2 CN、CF 3 、–CH 2 F、–CH 2 CF、–C(CH 3 ) 3 、–O–C(CH 3 ) 3 、–OCH 3 、C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl substituted 1-3 times.
In some embodiments, each X is independently oxygen.
In some embodiments, R 1 COOH.
In some embodiments, L is selected from- (CH) 2 ) a -or-O-, wherein a is 0 or 1. When a is 0, L is a direct bond. When a is 1, L is-CH 2 -. In some preferred embodiments, L is a direct bond.
In some embodiments, Y 1 Is 1, 4-phenylene.
In some embodiments, when each X is independently O, R 1 Is COOH, L is a direct bond, Y 1 In the case of 1, 4-phenylene, the compound has the formula A 1 The structure shown:
in some embodiments, Y 2 When phenyl, it is optionally substituted with H, F, cl, CN, -CH 2 CN、–OCH 3 、CF 3 、CH 3 Any one of them is substituted 1 time.
In some embodiments, Y 2 In the case of pyridyl, it is optionally substituted with H, C 1-4 Alkyl, -OCH 3 、 –N(CH 3 ) 2 、F、CN、NH 2 、CH 2 F、–CO–NHCH 3 、–CO–CH 3 1-2 times of any one of the substitutions. Preferably Y 2 For the pyridyl group substituted 2 times by methyl group, preferably 4-pyridyl group substituted 2 times by methyl group, more preferably
In some embodiments, R 3 Is C substituted by phenyl 1-4 An alkyl group; preferably, R 3 Is 1-phenyl-propyl-, including (R) -1-phenyl-propyl-or (S) -1-phenyl-propyl-.
The present invention further provides a compound of formula I: (2S) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) -2- ((8S) -3- (4-hydroxyphenyl) -7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carboxamide) propionic acid and pharmaceutically acceptable salts thereof:
the present invention also provides a process for preparing the compound (2S) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) -2- ((8S) -3- (4-hydroxyphenyl) -7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carboxamide) propionic acid of formula I comprising the steps of:
a) The compound shown in the formula II is hydrolyzed to generate a compound shown in the formula III, and the specific reaction is as follows:
and
b) Reacting compound III to produce a compound of formula I, which is specifically reacted as follows:
in some embodiments, steps a and b are reacted in the corresponding solvent; the solvent is independently selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetone, dichloromethane, acetonitrile, methanol or ethanol.
In some embodiments, the compound of formula II in step a is subjected to a hydrolysis reaction with an acidic reagent; the acidic reagent is selected from boron trifluoride, boron trichloride, aluminum trichloride or sulfur trioxide, preferably boron trichloride.
In some embodiments, the reaction of step b is performed in an aqueous base.
In some embodiments, the reaction described in step a is subjected to a post-treatment step before being put into the next reaction step; the post-treatment step is selected from one or more of dilution, filtration, pH adjustment, washing, extraction, concentration, crystallization and drying; the post-treatment step may be performed one or more times as desired.
In some embodiments, the post-treatment of step a is as follows: after the compound of the formula I is prepared, the crude product of the compound I is obtained through pH adjustment, liquid separation, 2-methyltetrahydrofuran extraction and concentration.
Pharmaceutically acceptable salts described herein include acid addition salts and base salts.
The compounds provided herein and pharmaceutically acceptable salts thereof may exist in chiral form, i.e., in the S or R configuration. The compounds provided herein and pharmaceutically acceptable salts thereof may exist in an achiral form. The expression compounds of the invention, when exemplified in one configuration, also means that the structure of another configuration or achiral form thereof is disclosed.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., an amine group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., amine-to-carbamate formation).
The compounds of the present invention include stereoisomers of the compounds. Stereoisomers according to the present invention are enantiomers which occur when asymmetric carbon atoms are present in a compound of formula I; when the compound has a carbon-carbon double bond or a cyclic structure, a cis-trans isomer is produced; tautomers can occur when compounds exist as ketones or oximes; as a specific embodiment, stereoisomers described herein include, but are not limited to: enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
Pharmaceutically acceptable salts of the present invention can exist in unsolvated and solvated forms.
The compounds provided herein, and pharmaceutically acceptable salts thereof, may be used in therapy alone or in combination with at least one other therapeutic agent.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula a or a pharmaceutically acceptable salt thereof, and one or more additional therapeutically active ingredients.
In another aspect, the present invention provides a pharmaceutical formulation comprising a compound of formula a or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical preparation is any preparation formulation which is clinically acceptable.
The compound and the pharmaceutically acceptable salt thereof provided by the invention can be formed into solid dosage forms, such as capsules, tablets, pills, troches, sugar-coated agents, granules, powders, ointments, creams, drops and the like; the compounds and pharmaceutically acceptable salts thereof provided herein may be in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, suspensions, solutions, sprays and the like.
The pharmaceutically acceptable carrier and/or pharmaceutically acceptable diluent useful in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the pharmaceutical formulation art.
In another aspect, the invention also provides a pharmaceutical composition comprising (2S) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) -2- ((8S) -3- (4-hydroxyphenyl) -7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carboxamide) propionic acid or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable adjuvants, carriers, excipients.
Pharmaceutical compositions of the compounds of formula I of the present invention may be prepared according to methods well known in the art.
The compound of formula I of the present invention or the pharmaceutical composition containing it may be administered in a liquid dosage form, a solid dosage form. For example, the liquid dosage form may be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
The compound of the formula I or the pharmaceutical composition containing the same can be prepared into common preparations, and can also be sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
The inventors have found that the compounds of formula I have anti-tumor activity and are capable of inhibiting the growth of, for example, cervical cancer cells.
Thus, in a further aspect, the present invention provides the use of a compound of formula a, and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of tumours.
In yet another aspect, the present invention provides the use of a compound of formula I and pharmaceutically acceptable salts thereof for the preparation of an antitumor drug.
In some embodiments, the tumor is a malignancy, including, but not limited to, breast cancer, cervical cancer, rectal cancer, pancreatic cancer, prostate cancer, kidney cancer, ovarian cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, or glioblastoma.
In yet another aspect, the present invention also provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula a, preferably formula I, and pharmaceutically acceptable salts thereof. In some embodiments, the disease is a tumor, particularly a malignancy, including, but not limited to, breast cancer, cervical cancer, rectal cancer, pancreatic cancer, prostate cancer, renal cancer, ovarian cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, glioma, and glioblastoma.
Method for quality control
CN102378574a discloses the free base of the azo anthracene derivative (S) -2- { [ (3S, 8S) -3- [4- (3, 4-dichloro-benzyloxy) -phenyl ] -7- ((S) -1-phenyl-propyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carbonyl ] -amino } -3- [4- (2, 3-dimethyl-pyridin-4-yl) -phenyl ] -propionic acid (hereinafter abbreviated as "OAD 2"), and the dihydrochloride (S) -2- { [ (3S, 8S) -3- [4- (3, 4-dichloro-benzyloxy) -phenyl ] -7- ((S) -1-phenyl-propyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carbonyl ] -amino } -3- [4- (2, 3-dimethyl-pyridin-4-yl) -phenyl ] -propionic acid 2 (hereinafter abbreviated as "OAD2 HCl"). They have the effect of modulating GLP-1 receptors and have the potential to treat type 2 diabetes. The structures of OAD2 and oad2.2hcl are as follows:
the researchers of the present invention found that in the preparation of oad2.2hcl, the ether linkage is easily broken to give the compound of formula I described above due to the strong acidity of the salification process and the temperature influence of the drying process. During the stepwise scale-up, researchers found that there was a trend towards increasing compounds of formula I with increasing batches, which was not seen in the pilot production of oad2.2hcl before. The compound of formula I can be used as a reference compound for quality control of OAD2.2HCl and pharmaceutical compositions or formulations containing OAD2.2HCl.
In one aspect, the invention provides a method for quality control of a sample, wherein the sample is a starting material, pharmaceutical composition or formulation comprising the starting material, associated with a compound of formula a, formula A1 or formula I described herein, the method comprising: taking the corresponding compound of formula A, formula A1 or formula I as a reference compound, and determining the level of the reference compound in the sample.
In some embodiments, the method further optionally comprises comparing the determined level of the reference compound to a desired level of the reference compound in the sample.
The starting materials related to the compounds of formula a, formula A1 or formula I mean compounds which are capable of forming the compounds of formula a, formula A1 or formula I by degradation.
In some embodiments, the reference compound is a compound of formula a. In some embodiments, the reference compound is a compound of formula A1. In some preferred embodiments, the reference compound is the compound of formula I.
In some embodiments, the sample is a starting material associated with the compound of formula I, preferably OAD2, preferably oad2.2hcl. In some embodiments, the sample is a pharmaceutical composition or formulation comprising OAD2 or preferably oad2.2hcl.
In some preferred embodiments, the invention provides a method for quality control of a sample that is OAD2, oad2.2hcl, or a pharmaceutical composition or formulation containing OAD2 or oad2.2hcl, the method comprising: taking the compound of the formula I as a reference compound, and determining the level of the reference compound in the sample. In some embodiments, the method further optionally comprises comparing the determined level of the reference compound to a desired level of the reference compound in the sample. In some such embodiments, the desired level of the compound of formula I is less than 1.0%, such as less than 0.9%, or less than 0.8%, or less than 0.7%, or less than 0.6%, or less than 0.5%, or less than 0.4%, or less than 0.3%, or less than 0.2%, or less than 0.1%, or less than 0.09%, or less than 0.08%, or less than 0.07%, or less than 0.06%, or less than 0.05%, or less than 0.04%, or less than 0.03%, or less than 0.02%, or less than 0.01%, based on the total weight of the compound of formula I and OAD2 or preferably oad2.2 HCl. In other embodiments, the desired level of the compound of formula I in a pharmaceutical composition or formulation containing OAD2 or preferably oad2.2hcl is less than 1.0%, or less than 0.9%, or less than 0.8%, or less than 0.7%, or less than 0.6%, or less than 0.5%, or less than 0.4%, or less than 0.3%, or less than 0.2%, or preferably less than 0.1%, or less than 0.09%, or less than 0.08%, or less than 0.07%, or less than 0.06%, or less than 0.05%, or less than 0.04%, or less than 0.03%, or less than 0.02%, or less than 0.01% based on the total weight of the pharmaceutical composition or formulation.
The method for determining the level of the reference compound may be a method conventionally used in the art, such as High Performance Liquid Chromatography (HPLC).
Definition of the definition
The compounds described in the present invention are named according to the chemical structural formula. If the nomenclature of the compounds does not match the chemical formula when the same compound is represented, the chemical formula is used.
In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the definitions of some terms are provided below. When the definition and interpretation of terms provided by the present invention are different from the meanings commonly understood by those skilled in the art, the definition and interpretation of terms provided by the present invention is intended.
Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.
Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers of a molecule having two or more chiral centers and having a non-mirror relationship between the molecules.
Unless otherwise indicated, "(+)" means dextrorotation, "(-)" means levorotatory, "(±)" means racemization.
Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keysAnd straight dotted line keyRepresenting the spatial centre as absolute configuration, but not necessarily in particular a wedge-shaped solid keyOr a wedge-shaped dotted key
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., an amine group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., amine-to-carbamate formation).
The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" herein refers to salts of the compounds of the present disclosure, prepared from the compounds of the present disclosure having a particular substituent with a relatively non-toxic acid or base. When the compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, and the like. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or basic group by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The term "optional" or "optionally" herein refers to the subsequently described event or circumstance that may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" herein means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, and may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable.
The term "optionally substituted" herein means both "substituted" and "unsubstituted".
The term "halogen" herein means fluorine, chlorine, bromine and iodine.
The term "C" herein 1～4 Alkyl "is a straight or branched chain alkyl having 1 to 4 carbons including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and 1-methylpropyl.
The term "C" herein 3～6 Cycloalkyl "means a monovalent group derived from the removal of any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 6 carbons, i.e., a cycloalkyl of 3 to 6 carbons. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Drawings
Fig. 1: MS diagram of compound I.
Fig. 2: H-NMR chart of Compound I.
Advantageous effects
The anthracene compound of the invention can be used as a reference compound for quality control of raw materials related thereto, pharmaceutical compositions or preparations containing the raw materials. Surprisingly, while their source compounds have activity in modulating GLP-1 receptor and thus can be used for the treatment of type 2 diabetes, the anthracene compounds of the invention have very different antitumor activity, with potential for use as antitumor agents.
Detailed Description
The present invention will be explained in more detail with reference to examples or experimental examples, which are only for illustrating the technical aspects of the present invention, and do not limit the spirit and scope of the present invention.
The experimental methods in the examples of the present invention, in which specific conditions are not specified, are generally conventional conditions or conditions according to the recommended conditions of the raw materials or commercial manufacturers. Reagents of unspecified origin are typically conventional reagents commercially available.
The methyl (S) -2- ((3S, 8S) -3- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carboxamide) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) propanoate of formula II used in the present invention can be prepared as described with reference to CN 102378574A.
Example 1: preparation of (2S) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) -2- ((8S) -3- (4-hydroxyphenyl) -7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carboxamide) propionic acid
Step a:
to a 1000 ml reaction flask were added 30 g of methyl (S) -2- ((3S, 8S) -3- (4- ((3, 4-dichlorobenzyl) oxy) phenyl) -7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carboxamide) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) propionate (34.48 mmol) and 350 ml of dichloromethane, dissolved with stirring, nitrogen protected, and cooled to 0 ℃. 150 ml of a 1mol/L solution of boron trichloride in methylene chloride was slowly added, and the reaction was carried out at 0℃for 18 hours after completion of the addition. 150 ml of methylene chloride and 500 ml of 5% sodium bicarbonate solution were added, stirred for 30 minutes, and the solution was separated. The aqueous phase was extracted with 250 ml of dichloromethane and the dichloromethane phases were combined and concentrated under reduced pressure at 30 ℃ to give 30 g of crude methyl (S) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) -2- ((3S, 8S) -3- (4-hydroxyphenyl) -7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carboxamido) propanoate which was used directly in the next reaction.
Step b:
to a 500 ml reaction flask were added 30 g of methyl (S) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) -2- ((3S, 8S) -3- (4-hydroxyphenyl) -7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carboxamide) propionate crude product and 150 ml of 2-methyltetrahydrofuran, and the mixture was dissolved with stirring. A75 ml aqueous solution of 6 g sodium hydroxide was added thereto, and the reaction was stirred at room temperature for 18 hours. After termination of the reaction, ph=3-4 was adjusted with 1N diluted hydrochloric acid. The aqueous phase was separated, extracted with 100ml of 2-methyltetrahydrofuran, the organic phases were combined and concentrated under reduced pressure to give 12 g of (2S) -3- (4- (2, 3-dimethylpyridin-4-yl) phenyl) -2- ((8S) -3- (4-hydroxyphenyl) -7- ((S) -1-phenylpropyl) -2,3,6,7,8, 9-hexahydro- [1,4] dioxino [2,3-g ] isoquinoline-8-carboxamide) propionic acid.
Example 2: detection of Compounds of formula I
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS); NMR shift (. Delta.) is in units of 10-6 (ppm); NMR was performed using a Bruker DMX-500 nuclear magnetic instrument with deuterated pyridine as the solvent and Tetramethylsilane (TMS) as the internal standard. MS was determined using a Bruker Esquire 3000plus mass spectrometer. Mass Spectrometry (MS): the detection method comprises the following steps: a Bruker Esquire 3000plus mass spectrometer; an ESI source; and (5) detecting positive ions.
The results were as follows:
MS profile: HRMS (ESI) C 43 H 43 N 3 O 6 Theoretical value: 697.32+1.00[ M+H ]]Measurement value: 698.32
1 H-NMR spectrum: 1 H-NMR(400MHz,Py-d5):δ8.71(d,1H),8.55(d,1H),7.18-7.59(m,13H),7.13(s,1H),7.06(s,1H),7.04(d,1H),4.55(m,1H),5.24(d,1H),4.45(dd,1H),4.11(dd,1H),4.09(d,1H),3.94(dd,1H),3.78(dd,1H),3.66(dd,1H),3.56(dd,1H),3.47(dd,2H),3.08(dd,1H),2.60(s,3H),2.15(m,4H),2.01(m,1H),1.40(m,1H),0.75(t,3H).
example 3: evaluation of biological Activity of Compounds of formula I
Test instrument and reagent
MTT method for investigating anti-tumor activity of compound of formula I
Weighing 0.5 g of MTT (sigma), dissolving in 100ml of Phosphate Buffer Solution (PBS), filtering to remove bacteria in the solution by using a 0.22 mu m filter membrane, and placing the solution in a 4 ℃ light-shielding place for preservation, wherein in the preparation and preservation processes, the container is wrapped by aluminum foil paper, and the light-shielding treatment is performed as much as possible in the process of adding the MTT solution.
The experimental method comprises the following steps:
1. the logarithmic phase of Hela cells (from ATCC) was collected, the cell suspension concentration was adjusted, the cells were inoculated into 96-well flat plates, 100. Mu.l each was added to the wells to give a cell density of about 1000-3000 cells/well (all edge wells were filled with sterile PBS), and the cells were concentrated in 5% CO 2 Incubate at 37℃for 12 hours.
2. The original medium was discarded, 200. Mu.l of the prepared medium containing the compound of formula I and the blank (concentration gradients of the compound of formula I are 2.5, 5, 10, 20, 40, 80, 160. Mu. Mol/L; all the medium contains one thousandth of dimethyl sulfoxide) was added, and 3 to 4 multiplex wells were made.
3.5％CO 2 Incubation was continued for 48 hours at 37℃and observed under an inverted microscope (Nikon Ti-S).
4. The original medium was discarded, 200. Mu.l of medium free of compound and dimethyl sulfoxide and 20. Mu.l of the prepared MTT solution (5 mg/ml, i.e., 0.5% MTT solution) were added to each well, and after further incubation for 4 hours, the culture was terminated.
5. The culture medium in the wells was carefully aspirated, 150. Mu.l of dimethyl sulfoxide was added to each well, the mixture was shaken on a shaking table at a low speed for 10 minutes to dissolve the crystals sufficiently, and the absorbance of each well was measured at OD490nm on a microplate reader (BioTek, synergy H1).
Experimental analysis: at different concentrations of drug and cell viability (OD) on cell lines 490 ) The dose response curve was plotted to determine the median inhibitory concentration (IC 50 )。
Experimental results: half Inhibitory Concentration (IC) of Compounds of formula I on cervical cancer cell lines 50 ) 27.24nM.
Example 4: detection of Compounds of formula I as reference Compounds for OAD2.2HCl samples
Reagent and reagent: acetonitrile (HPLC), methanol (HPLC), trifluoroacetic acid (HPLC), purified water
Instrument and appliance: electronic analytical balance, liquid chromatograph, amido hexadecyl silica gel column, measuring flask and beaker
Chromatographic column: amide hexadecyl silica gel column (Supleco Ascentis Express RP-Amide, 3.0X105 mm,2.7 um)
Detection wavelength: 280nm of
Flow rate: 0.425ml/min
Sample injection amount: 2 μl
A diluent: 0.05% aqueous trifluoroacetic acid-0.05% acetonitrile trifluoroacetic acid solution (40:60)
Mobile phase a:0.05% aqueous trifluoroacetic acid solution
Mobile phase B:0.05% acetonitrile solution of trifluoroacetic acid: 0.05% methanol solution of trifluoroacetic acid=1:2 (V/V)
The elution gradient was as follows:
Time mobile phase a (%) Mobile phase B (%)
0 50 50
10 45 55
35 15 85
36 1 99
38 1 99
38.1 50 50
45 50 50
Assay:
an appropriate amount of oad2.2hcl was placed in a measuring flask, dissolved in a diluent (0.05% acetonitrile solution of trifluoroacetic acid: 0.05% aqueous solution of trifluoroacetic acid=60:40 (V/V)) and diluted to a solution of about 0.5mg/ml, and shaken well.
An appropriate amount of the compound of formula I was placed in a measuring flask, dissolved in a diluent (0.05% acetonitrile solution of trifluoroacetic acid: 0.05% aqueous solution of trifluoroacetic acid=60:40 (V/V)) and diluted to a solution of about 0.5mg/ml, and shaken well.
Each 10 μl of the above prepared solution was precisely measured, and the solution was injected into a liquid chromatograph to record a chromatogram.
Results:
the retention time of the compound of formula I was 3.567, the retention time of oad2.2 HCl was 22.059, the relative retention time was: 0.161.
various modifications of the invention, in addition to those described herein, are intended to fall within the scope of the appended claims in light of the foregoing description. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims (21)

  1. A compound of formula a and pharmaceutically acceptable salts thereof:
    and the pharmaceutically acceptable salts thereof,
    wherein:
    x is independently selected from oxygen, hydrogen, nitrogen;
    R 1 selected from COOH or-COOCH 3 ；
    R 2 is-Y 1 –L–Y 2 ；
    L is selected from- (CH) 2 ) a -or-O-, wherein a is 0 or 1;
    Y 1 is phenylene, which is 1, 3-phenylene or 1, 4-phenylene;
    Y 2 selected from phenyl, pyridyl, diazaaryl or imidazolyl, and Y 2 Optionally independently with hydrogen, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, CF 3 、–CH 2 F、–CH 2 CF 3 、CN、–CH 2 CN、–OCH 3 、–O–C(CH 3 ) 3 、–OCH 2 CH 3 、–OCH(CH 3 ) 2 、–OCF 3 、–OCH 2 CF 3 、NH 2 、–SO 2 –CH 3 、–NHCH 3 、–CO–NHCH 3 、–NHCH 2 CH 3 、–N(CH 3 ) 2 、–CO–CH 3 、–CO–NHCH 3 Substituted 1-3 times;
    R 3 selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl, furyl, thienyl, oxazolyl, pyridyl, thiazolyl, pyrimidinyl, epoxypentacyclic, epoxyhexacyclic, -sulfonyl-thiazolyl, -sulfonyl-oxazolyl, -sulfonyl-pyridyl, -carbonyl-oxazolyl, -carbonyl-pyridyl; optionally independently from each other with halogen, amino, OH, COOH, CN, -CH 2 CN、CF 3 、–CH 2 F、–CH 2 CF、–C(CH 3 ) 3 、–O–C(CH 3 ) 3 、–OCH 3 、C 1-4 Alkyl, C 3-6 Cycloalkyl, phenyl substituted 1-3 times.
  2. The compound of claim 1, wherein X is independently oxygen.
  3. The compound of claim 1 or 2, wherein Y 1 Is 1, 4-phenylene.
  4. A compound according to any one of claims 1 to 3 wherein R 1 COOH.
  5. The compound of any one of claims 1 to 4, wherein L is a direct bond or-CH 2 -preferably a direct bond.
  6. The compound of any one of claims 1 to 5, wherein the compound has the formula a 1 The structure shown:
  7. any one of claims 1 to 6The compound of item, wherein Y 2 Is phenyl, optionally substituted 1 time with substituents as follows: H. f, cl, CN, -CH 2 CN、–OCH 3 、CF 3 、CH 3 。
  8. The compound of any one of claims 1 to 6, wherein Y 2 Is 4-pyridinyl, which are optionally substituted 1 to 2 times by the following substituents alone: H. CH (CH) 3 、–OCH 3 、–N(CH 3 ) 2 、F、CN、NH 2 、–CH 2 CH 3 、–CH 2 CH 2 CH 3 、–CH 2 F、–CO–NHCH 3 、–CO–CH 3 The method comprises the steps of carrying out a first treatment on the surface of the Preferably 4-pyridyl substituted 2 times with methyl, more preferably
  9. The compound of any one of claims 1 to 8, R 3 is-C substituted by phenyl 1-4 An alkyl group; preferably 1-phenyl-propyl-, including (R) -1-phenyl-propyl-or (S) -1-phenyl-propyl-.
  10. The compound of claim 1 having the structure of formula I:
  11. a process for preparing a compound of formula I as defined in claim 10, comprising the steps of:
    a. reacting a compound represented by formula II to produce a compound of formula III:
    and
    b. Reacting compound III to give a compound of formula I as shown in claim 10:
  12. the process of claim 11, wherein steps a and b are reacted in a suitable solvent independently selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetone, dichloromethane, acetonitrile, methanol, or ethanol.
  13. The process of claim 11 or 12, wherein the compound of formula II in step a undergoes a hydrolysis reaction with an acidic reagent selected from one of boron trifluoride, boron trichloride, aluminum trichloride or sulfur trioxide.
  14. The production process according to any one of claims 11 to 13, wherein the reaction of step b is carried out in alkaline water.
  15. A pharmaceutical composition comprising an effective amount of a compound of formula I as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients, carriers or excipients.
  16. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 15 for the preparation of an anti-tumour agent.
  17. The use of claim 16, wherein the tumor is selected from breast cancer, cervical cancer, rectal cancer, pancreatic cancer, prostate cancer, kidney cancer, ovarian cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, glioma or glioblastoma.
  18. A method for quality control of a sample, wherein the sample is a starting material, pharmaceutical composition or formulation comprising the starting material, associated with a compound according to any one of claims 1 to 10, the method comprising: taking the corresponding compound of any one of claims 1 to 10 as a reference compound and determining the level of the reference compound in the sample, and optionally comparing the determined level of the reference compound with a desired level of the reference compound in the sample.
  19. The method of claim 18, wherein the reference compound is a compound of formula A1 according to claim 6, preferably a compound of formula I according to claim 10.
  20. The method of claim 18 or 19, wherein the sample is OAD2 or preferably oad2.2hcl, or a pharmaceutical composition or formulation comprising OAD2 or preferably oad2.2hcl.
  21. The method of claim 20, wherein:
    the desired level of the compound of formula I is less than 1.0%, such as less than 0.9%, or less than 0.8%, or less than 0.7%, or less than 0.6%, or less than 0.5%, or less than 0.4%, or less than 0.3%, or less than 0.2%, or less than 0.1%, or less than 0.09%, or less than 0.08%, or less than 0.07%, or less than 0.06%, or less than 0.05%, or less than 0.04%, or less than 0.03%, or less than 0.02%, or less than 0.01%, based on the total weight of the compound of formula I and OAD2 or preferably oad2.2 HCl; and/or
    The desired level of the compound of formula I is less than 1.0%, or less than 0.9%, or less than 0.8%, or less than 0.7%, or less than 0.6%, or less than 0.5%, or less than 0.4%, or less than 0.3%, or less than 0.2%, or preferably less than 0.1%, or less than 0.09%, or less than 0.08%, or less than 0.07%, or less than 0.06%, or less than 0.05%, or less than 0.04%, or less than 0.03%, or less than 0.02%, or less than 0.01% based on the total weight of the pharmaceutical composition or formulation containing OAD2 or preferably oad2.2 HCl.
CN202280042744.2A 2021-06-17 2022-06-07 Anthracene compound, preparation method and medical application thereof Pending CN117500808A (en)

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