WO2021203938A1 - 一种治疗痛风的化合物及其制备方法和用途 - Google Patents

一种治疗痛风的化合物及其制备方法和用途 Download PDF

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WO2021203938A1
WO2021203938A1 PCT/CN2021/081519 CN2021081519W WO2021203938A1 WO 2021203938 A1 WO2021203938 A1 WO 2021203938A1 CN 2021081519 W CN2021081519 W CN 2021081519W WO 2021203938 A1 WO2021203938 A1 WO 2021203938A1
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compound
human
racemate
prodrug
enantiomer
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PCT/CN2021/081519
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English (en)
French (fr)
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李青松
姚林山
高金胜
苑菲
陈磊
张洪洋
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北京诺康达医药科技股份有限公司
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Priority to JP2022549391A priority Critical patent/JP7466670B2/ja
Priority to EP21784541.1A priority patent/EP4134374A4/en
Priority to US17/800,029 priority patent/US20230159583A1/en
Publication of WO2021203938A1 publication Critical patent/WO2021203938A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0016—Oximes
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0007—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa
    • C07J5/0023—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16
    • C07J5/003—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes
    • C07J5/0038—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond not substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group including 16-alkylidene substitutes by an alkyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
    • C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17

Definitions

  • the present invention relates to a compound for the treatment of gout.
  • the compound can be used for the treatment of gout, and has a significant therapeutic effect especially for acute gout.
  • the invention also provides a preparation method and application of the compound.
  • Gout is a clinical syndrome caused by sodium urate or sodium urate crystals deposited in tissues or organs from supersaturated extracellular fluid. Long-term increase in blood uric acid leads to precipitation of urate crystals in soft tissues, which is one of the main causes of gout.
  • Western medicines currently on the market for the treatment of gout can treat gout through different mechanisms, but there are problems of greater toxicity and poor efficacy.
  • colchicine can cause diarrhea, abdominal pain, liver damage, and dose-dependent adverse reactions; non-steroidal anti-inflammatory drugs include sodium salicylate, aspirin, ibuprofen, indomethacin, naproxen, rofecoxib It is easy to cause cardiovascular diseases; the development cost of cytokine antagonists is relatively high and the medication has limitations.
  • glucocorticoid drugs treat gout with prednisone and methylprednisolone (intermediate-acting glucocorticoids, their glucose-increasing and anti-inflammatory effects are not optimal, but the side effects are also small, and they have a negative feedback effect on the HPA axis.
  • the effects on water and electrolytes are still within the acceptable range), suitable for acute gout in patients who cannot tolerate non-steroidal anti-inflammatory drugs, colchicine or renal insufficiency.
  • Methylprednisolone has a fast clinical onset time, can quickly inhibit the activity of enzymes, and saturate the hormone-specific receptors.
  • a compound for the treatment of gout is described herein. Also described herein are methods of synthesizing such compounds, methods of using such compounds to treat diseases, including diseases in which the compound provides therapeutic benefits to patients suffering from the disease. Also described herein are combination products containing the compounds, including compositions, pharmaceutical preparations, and kits.
  • the compounds of formula I described herein also include those compounds of formula II.
  • the compounds described herein include the compound of formula I or its tautomers, mesoisomers, racemates, enantiomers, diastereomers, prodrugs or mixtures thereof; or I compound, its tautomer, meso, racemate, enantiomer, diastereomer, prodrug or pharmaceutically acceptable salt or solvate or hydrate of its mixture Or polymorphs:
  • R 1 is -H, (C 1 -C 4 )alkyl or -CH 2 -Ar (aryl);
  • R 2 is -H, (C 1 -C 4 )alkyl or -CH 2 -Ar (aryl);
  • X and Y are independently selected from H, -CH 3 or halogen
  • W is H, -CH 3 , or
  • M and N are independently selected from H, (C 1 -C 4 )alkyl, -Ar (aryl), heteroaryl or benzyl.
  • the dotted line between C-1 and C-2 indicates that it can be a double bond in addition to a single bond
  • the present invention relates to any of the aforementioned compounds, wherein: R 1 is -H or -CH 2 CH 3 ;
  • the present invention relates to any of the aforementioned compounds, wherein: R 2 is -H or -CH 2 CH 3 ;
  • the present invention relates to any of the aforementioned compounds, wherein: R 3 is -H, -OH, -Cl or -OAc, Or -CH 2 CH 3 ;
  • the present invention relates to any of the aforementioned compounds, wherein: R 4 is -H, -OH,
  • the present invention relates to any of the aforementioned compounds, wherein: X is -H, -F or -Cl.
  • the present invention relates to any of the above compounds wherein: Y is -H, -CH 3, -F or -Cl.
  • the present invention relates to any of the aforementioned compounds, wherein: W is -H, ⁇ -CH 3 , ⁇ -CH 3 , ⁇ -OH, ⁇ -OH,
  • the present invention relates to any of the aforementioned compounds, wherein: R 1 is -H or -CH 2 CH 3 ;
  • the present invention relates to any of the aforementioned compounds, wherein: R 2 is -H or -CH 2 CH 3 ;
  • the present invention relates to any of the aforementioned compounds, wherein: R 3 is -OH or -OAc;
  • the present invention relates to any of the aforementioned compounds, wherein: R 4 is -OH or -OAc;
  • the present invention relates to any of the aforementioned compounds, wherein: X is -H;
  • the present invention relates to any of the aforementioned compounds, wherein: Y is -H or -CH 3 ;
  • the present invention relates to any of the aforementioned compounds, wherein: W is -H.
  • the 20-position carbon (17-position side) in compound I The oxime groups of the chain) are all in the E configuration (trans).
  • W is When the group is a compound of formula II:
  • the present invention relates to the compound of formula II or its tautomer, meso, racemate, enantiomer, diastereomer, prodrug or mixture thereof Form; or a compound of formula II, its tautomer, meso, racemate, enantiomer, diastereomer, prodrug or a pharmaceutically acceptable salt of a mixture thereof or
  • M and N are independently selected from H, (C 1 -C 4 )alkyl, -Ar (aryl), heteroaryl or benzyl.
  • the present invention relates to the compounds numbered 1-17 below, or tautomers, mesoisomers, racemates, enantiomers, diastereomers thereof, Drugs or mixtures thereof; or the compounds, tautomers, mesoisomers, racemates, enantiomers, diastereomers, prodrugs or mixtures thereof are pharmaceutically acceptable Accepted salts or solvates or hydrates or polymorphs:
  • the compounds described herein can be used for the treatment of gout, and have significant therapeutic effects especially for acute gout.
  • the substituents in the compounds described herein can prolong the metabolic cycle of the compound in the body, and have a relatively long-lasting anti-gout effect.
  • the compounds described in this article also have strong anti-inflammatory effects, mainly for the effects of glucocorticoid receptor GRa, glucocorticoid receptor GRb, pro-inflammatory factor TNF- ⁇ , and inflammation protective factor IL-10 in the inflammatory response pathway.
  • Expression plays a regulatory role. Therefore the compounds described herein can also be used to treat inflammation.
  • the compounds described herein can also be used to treat cancer (or tumor), such as human lung adenocarcinoma, human acute lymphoblastic leukemia, human B-cell lymphoma, human breast cancer, human malignant glioblastoma, human liver cancer, Human cervical cancer, human non-small cell lung cancer, human osteosarcoma, human colon cancer, human osteosarcoma, human Burkitt ⁇ s lymphoma and other different tumors.
  • cancer or tumor
  • the compounds described in the following synthetic routes I-IV can be used to prepare the compounds of the present invention.
  • R is a linear saturated alkyl group, such as a linear saturated (C 1 -C 12 ) alkyl group, especially a linear saturated (C 1 -C 4 ) alkyl group. Specific examples include methyl, ethyl, n-propyl or N-butyl.
  • the o-dihydroxy groups at the R 4 and W positions in the substrate react with ketones (such as acetone) or aldehydes (such as butyraldehyde) to form ketals/acetals.
  • ketones such as acetone
  • aldehydes such as butyraldehyde
  • the operation in synthetic route III can be used.
  • the o-dihydroxy group at the R 4 and W positions in the substrate was first protected with a ketal, and then reacted with an acylating reagent (such as ROCl, specifically such as acid chloride), and then removed under acidic conditions. The ketal is removed and the product is obtained.
  • an acylating reagent such as ROCl, specifically such as acid chloride
  • R is a linear saturated alkyl group, such as a linear saturated (C 1 -C 12 ) alkyl group, especially a linear saturated (C 1 -C 4 ) alkyl group.
  • a linear saturated alkyl group such as a linear saturated (C 1 -C 12 ) alkyl group, especially a linear saturated (C 1 -C 4 ) alkyl group.
  • Specific examples include methyl, ethyl, n-propyl or N-butyl.
  • the oxime group in the substrate reacts with an alkylating reagent (such as ethyl iodide) to form an alkyl oxime.
  • an alkylating reagent such as ethyl iodide
  • synthetic route IV can be used.
  • R 1 , R 2 , R 3 , R 4 , X, Y, W, M, and N are as defined above.
  • the above preparation method may also include product separation and purification, and the separation and/or purification can be carried out by a suitable combination of methods commonly used in organic synthesis, such as filtration, extraction, washing, concentration, chromatography and the like.
  • the present invention also provides the above-mentioned compound or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, prodrug or mixture thereof; or the compound , Its tautomers, mesosomes, racemates, enantiomers, diastereomers, prodrugs or pharmaceutically acceptable salts or solvates or hydrates of their mixtures or Use of polymorphs in the preparation of drugs for the treatment or prevention of gout, or in the preparation of drugs for the treatment or prevention of inflammation; or in the preparation of drugs for the treatment or prevention of cancer (or tumor) use.
  • the drug further includes pharmaceutically acceptable excipients, such as diluents, excipients and/or binders.
  • pharmaceutically acceptable excipients such as diluents, excipients and/or binders.
  • the gout is preferably acute gout.
  • the inflammation is especially the inflammation associated with acute gout.
  • the inflammation is preferably any one or more of the expression of glucocorticoid receptor GRa, glucocorticoid receptor GRb, pro-inflammatory factor TNF- ⁇ , and inflammation protective factor IL-10 in the inflammatory response pathway.
  • glucocorticoid receptor GRa glucocorticoid receptor GRa
  • glucocorticoid receptor GRb pro-inflammatory factor TNF- ⁇
  • inflammation protective factor IL-10 in the inflammatory response pathway.
  • the cancer is selected from the group consisting of human lung adenocarcinoma, human acute lymphoblastic leukemia, human B-cell lymphoma, human breast cancer, human malignant glioblastoma, human liver cancer, human cervical cancer, human non-small cell lung cancer, human osteosarcoma , Human colon cancer, human osteosarcoma, human Burkitt ⁇ s lymphoma, any one or more of them.
  • the compounds, their tautomers, mesosomes, racemates, enantiomers, diastereomers, prodrugs or pharmaceutically acceptable salts or solvates or hydrates of their mixtures As the sole active ingredient or in combination with other biologically active substances.
  • the other biologically active substances include colchicine, non-steroidal anti-inflammatory drugs (including sodium salicylate, aspirin, ibuprofen, indomethacin, naproxen, rofecoxib), glucocorticoids (Including prednisone, methylprednisolone), anti-inflammatory factor drugs, methylprednisolone, etc.
  • non-steroidal anti-inflammatory drugs including sodium salicylate, aspirin, ibuprofen, indomethacin, naproxen, rofecoxib
  • glucocorticoids including prednisone, methylprednisolone
  • anti-inflammatory factor drugs methylprednisolone, etc.
  • the present invention also provides a combination product for treating or preventing gout or inflammation or cancer (or tumor), including the above-mentioned compound or its tautomers, mesosomes, racemates, and enantiomers , Diastereomers, prodrugs or mixtures thereof; or the compound, its tautomers, mesosomes, racemates, enantiomers, diastereomers, One or more of the pharmaceutically acceptable salts or solvates or hydrates or polymorphs of prodrugs or mixtures thereof.
  • the combination product further includes pharmaceutically acceptable excipients, such as diluents, excipients and/or binders.
  • pharmaceutically acceptable excipients such as diluents, excipients and/or binders.
  • the combination product is also referred to as a pharmaceutical composition.
  • the combination product is a kit.
  • the present invention also provides a method for treating or preventing gout or inflammation or cancer, which comprises administering an effective dose of the above-mentioned compound or its tautomer, meso, Racemates, enantiomers, diastereomers, prodrugs or mixtures thereof; or the compound, its tautomers, mesosomes, racemates, enantiomers A pharmaceutically acceptable salt or solvate or hydrate or polymorph of a conformer, diastereomer, prodrug or a mixture thereof, or a combination product of the above.
  • the gout is preferably acute gout.
  • the inflammation is related or not related to gout.
  • the inflammation is inflammation associated with acute gout.
  • the inflammation is preferably any one or more of the expression of glucocorticoid receptor GRa, glucocorticoid receptor GRb, pro-inflammatory factor TNF- ⁇ , and inflammation protective factor IL-10 in the inflammatory response pathway.
  • glucocorticoid receptor GRa glucocorticoid receptor GRa
  • glucocorticoid receptor GRb pro-inflammatory factor TNF- ⁇
  • inflammation protective factor IL-10 in the inflammatory response pathway.
  • the cancer is selected from the group consisting of human lung adenocarcinoma, human acute lymphoblastic leukemia, human B-cell lymphoma, human breast cancer, human malignant glioblastoma, human liver cancer, human cervical cancer, human non-small cell lung cancer, human osteosarcoma , Human colon cancer, human osteosarcoma, human Burkitt ⁇ s lymphoma, any one or more of them.
  • the oral or non-oral route can be delivered to the subject or patient by oral, injection, patch, spray and other known one or more.
  • the effective amount may include an amount effective to treat, reduce, alleviate, alleviate or eliminate one or more symptoms of a condition that seeks to be treated, or alternatively, that condition seeks to be avoided, or otherwise A clinically identifiable favorable change occurs in the condition or its effect.
  • the compounds provided herein are administered to a mammal.
  • the compounds provided herein are administered to humans.
  • the compounds provided herein are administered orally.
  • the compounds provided herein are used to formulate drugs for inhibiting and/or treating gout activity. In some other embodiments, the compounds provided herein are used to formulate drugs for inhibiting and/or treating acute gout activity.
  • Alkyl refers to a linear or branched saturated hydrocarbon group substituent containing 1-12 carbon atoms (ie, a substituent obtained by removing hydrogen from a hydrocarbon).
  • substituents include methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, Isoamyl, hexyl, etc.
  • Aryl refers to an aromatic substituent containing one ring or two or three condensed rings.
  • the aryl group may have 6-18 carbon atoms.
  • the aryl group may have 6-14 carbon atoms.
  • the term "aryl” may refer to substituents such as phenyl, naphthyl, and anthracenyl.
  • Halogen refers to fluorine (which can be represented as F), chlorine (which can be represented as Cl), bromine (which can be represented as Br), or iodine (which can be represented as I).
  • the halogen is chlorine.
  • the halogen is fluorine.
  • the halogen is bromo
  • compositions of the present invention may be referred to as "compounds of the present invention". Such terms are also defined to include all forms of the compounds of Formula I and Formula II, including their hydrates, solvates, isomers, crystalline and amorphous forms, isomorphs, polymorphs, and metabolites.
  • the compounds of Formula I and Formula II and their pharmaceutically acceptable salts can exist in unsolvated and solvated forms.
  • the solvent or water When the solvent or water is tightly bound, the compound will have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly combined, as in channel solvates and hygroscopic compounds, the water/solvent content will depend on humidity and drying conditions. Under such circumstances, non-stoichiometry will become the norm.
  • the compounds of the present invention may have asymmetric carbon atoms.
  • the carbon-carbon bonds of the compounds of the present invention can be shown herein using solid lines, solid wedge shapes, or imaginary wedge shapes.
  • the use of a solid line to show the bond to an asymmetric carbon atom is intended to mean that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) of the carbon atom are included.
  • the use of a solid or imaginary wedge to show a bond to an asymmetric carbon atom is intended to mean that only the stereoisomers shown are intended to be included. It is possible that the compounds of the invention may contain more than one asymmetric carbon atom.
  • the use of a solid line to show the bond to an asymmetric carbon atom is intended to mean that all possible stereoisomers are intended to be included.
  • the compounds of the present invention are intended to exist as enantiomers and diastereomers or as racemates and mixtures thereof.
  • the use of a solid line to show the bond to one or more asymmetric carbon atoms in the compound of the present invention and the use of a solid or imaginary wedge to show the bond to other asymmetric carbon atoms in the same compound is intended to indicate the presence of diastereomers mixture.
  • Stereoisomers of the compounds of the present invention include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, Rotamers, conformational isomers, and tautomers include compounds that exhibit more than one type of isomerism; and mixtures thereof (such as racemates and diastereomers). It also includes acid addition salts or base addition salts, where the counterion has optical activity, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-fine Acid.
  • the first type is the racemic compound (true racemate) mentioned above, in which a homogeneous form of crystal containing two enantiomers in equimolar amounts is produced.
  • the second type is racemic mixtures or aggregates, in which two forms of crystals are produced in equimolar amounts, each of which contains a single enantiomer.
  • the oxime groups at the 20-position carbon (17-position side chain) in compound I are all in the E configuration (trans ).
  • the compounds of the invention are administered in an amount effective to treat the conditions described herein.
  • the compound of the present invention is administered by any suitable route in the form of a pharmaceutical composition suitable for such route and in a dose effective for the intended treatment.
  • the therapeutically effective dose of the compound required to treat the progression of a medical condition can be easily determined by a person of ordinary skill in the art using preclinical and clinical methods familiar in the medical field.
  • the term "therapeutically effective amount” as used herein refers to the amount of the compound administered that alleviates one or more symptoms of the condition being treated to a certain extent.
  • the raw materials can be obtained from public commercial channels unless otherwise specified.
  • compound 2 is prepared with appropriate starting materials, and (3Z)-2 and (3E)-2 are isolated.
  • compound 3 is prepared with appropriate starting materials, and (3Z)-3 and (3E)-3 are isolated.
  • compound 4 is prepared with appropriate starting materials, and (3Z)-4 and (3E)-4 are isolated.
  • compound 5 was prepared with appropriate starting materials, and (3Z)-5 and (3E)-5 were isolated.
  • compound 6 was prepared with appropriate starting materials, and (3Z)-6 and (3E)-6 were isolated.
  • compound 7 was prepared with appropriate starting materials, and (3Z)-7 and (3E)-7 were isolated.
  • compound 8 is prepared with appropriate starting materials, and (3Z)-8 and (3E)-8 are isolated.
  • compound 9 was prepared with suitable starting materials, and (3Z)-9 and (3E)-9 were isolated.
  • compound 10 was prepared with suitable starting materials, and (3Z)-10 and (3E)-10 were isolated.
  • compound 11 was prepared with appropriate starting materials, and (3Z)-11 and (3E)-11 were isolated.
  • compound 12 was prepared with suitable starting materials, and (3Z)-12 and (3E)-12 were isolated.
  • compound 13 was prepared with appropriate starting materials, and (3Z)-13 and (3E)-13 were isolated.
  • compound 14 was prepared with appropriate starting materials, and (3Z)-14 and (3E)-14 were isolated.
  • compound 15 was prepared with appropriate starting materials, and (3Z)-15 and (3E)-15 were isolated.
  • compound 16 was prepared with appropriate starting materials, and (3Z)-16 and (3E)-16 were isolated.
  • compound 17 was prepared with appropriate starting materials, and (3Z)-17 and (3E)-17 were isolated.
  • the compounds prepared in Examples 1-17 have strong anti-gout efficacy.
  • the specific experiment is as follows. Among them, the example compounds used in the following experiments are the mixtures of the cis and trans configurations of the 3-oxime group of the compounds prepared in the examples in an equal ratio (1:1).
  • Gout is a disease unique to humans, and gouty arthritis is an inflammatory reaction caused by the deposition of sodium urate (MSU) in local joint tissues.
  • MSU sodium urate
  • MSU sodium urate
  • the purine metabolism pathways in some mammals, such as mice and rabbits, are different from those of humans, it is impossible to construct a model of gouty arthritis by interfering with purine metabolism disorders. Therefore, the most direct way to cause gouty arthritis is in model animals.
  • MSU is injected directly into the joint cavity of the joint. This model is only used to simulate the local joint inflammation of gout. It is suitable for the observation of local arthritis symptoms. It is a common method for screening the anti-inflammatory effects of gout drugs. It has the advantages of stability and ease of operation. (Reference: Li Na, Hua Long, Yuan Hui. Research progress in animal models of gout[J]. Medical Theory and Practice, 2016(24).)
  • the anti-gout effect of the compounds prepared in the above examples was tested using a rat plantar swelling model induced by sodium urate (MSU), and the control sample was methylprednisolone.
  • MSU was used as an inflammatory agent and injected into the subcutaneous of the hind limbs of the rats to cause the swelling of the feet, and then the volume of the feet was measured, and the swelling rate and the swelling inhibition rate of the plantars of the administration group and the control group were compared.
  • This method is one of the commonly used methods to screen the anti-inflammatory effects of gout drugs.
  • the model is stable and easy to operate.
  • the rats were given different doses of compounds continuously one week before the subcutaneous injection of MSU into the plantars of SD rats.
  • the test results showed that the swelling inhibition rate (%) of the compounds in the above examples was in the range of 64.65%-99.74%, and it was safe.
  • the compound has a stronger anti-gout effect.
  • the compound of the above examples and methylprednisolone can relieve gout symptoms and the swelling inhibition rate is significantly higher than that of methylprednisolone (53.83%), and replace the bisoxime group to prolong its metabolic cycle in the body, and has a relatively long-lasting effect on relieving gout.
  • the compounds prepared in Examples 1-17 have strong anti-inflammatory effects.
  • a mouse foot swelling model induced by carrageenan was used to test the anti-inflammatory effects of the compounds prepared in the above examples.
  • the control sample was methylprednisolone:
  • the carrageenan-induced mouse foot swelling model is a classic acute inflammation model often used to evaluate or screen the anti-inflammatory effects of drugs.
  • carrageenan When carrageenan is injected into the mouse foot plantar, it can cause local capillary dilatation, Increased vascular permeability, exudation, edema, and a series of reactions similar to acute inflammation in the human body, so this model is widely used in the evaluation of new drugs.
  • the experiment was designed according to the "Technical Guidelines for Acute Toxicity Testing of Chemical Drugs" issued by the State Food and Drug Administration in March 2005.
  • the dosages are: 4g/kg, 4.91g/kg, 6.14g/kg, 7.68g/kg, 9.6g/kg, 12g/kg, 15g/kg (the dosage can be adjusted according to the actual test results), each dosage group 12 ICR mice. If the administration volume is greater than 0.5ml, it is best to divide the administration into two or more times (Note: refer to the national standard GB 15193.3-2014. If multiple administrations are required, the interval between each administration is 4h-6h, and the day before the administration is forbidden Food).
  • the results of the acute toxicity test are shown in the following table:
  • the invention provides a compound for treating gout, and a preparation method and application thereof.
  • the compound is represented by formula I.
  • the invention discloses a preparation method of the compound and its use in preparing a medicine for treating or preventing gout.
  • the invention also discloses a combination product containing the compound.
  • the compound provided by the present invention can be used to treat inflammation and gout, and can also be used to treat cancer, and has good economic value and application prospects.

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Abstract

本发明涉及一种治疗痛风的化合物及其制备方法和用途。该化合物如式I所示。本发明公开了所述化合物的制备方法，以及在制备治疗或预防痛风的药物中的用途。本发明还公开了包含所述化合物的组合产品。本发明提供的化合物可用于治疗炎症和痛风，还可用于治疗癌症。

Description

一种治疗痛风的化合物及其制备方法和用途
交叉引用
本申请要求2020年4月7日提交的专利名称为“一种治疗痛风的化合物及其制备方法和用途”的第202010265895.7号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
技术领域
本发明涉及一种治疗痛风的化合物，该化合物可用于治疗痛风，尤其对于急性期痛风具有显著的治疗效果。本发明还提供该化合物的制备方法及用途。
背景技术
痛风是尿酸钠或尿酸钠结晶从超饱和的细胞外液沉积于组织或器官引起的一种临床综合征，血尿酸长期升高导致尿酸盐结晶沉淀在软组织是造成痛风的主要原因之一。目前市面上用于治疗痛风的西药通过不同机制可以治疗痛风，但存在较大的毒性不良反应和疗效差的问题。
目前针对急性期临床上已有很多种治疗痛风的西药，包括秋水仙碱、非甾体抗炎药、糖皮质激素以及抑炎因子药物等。秋水仙碱会引起腹泻、腹痛、肝脏损伤以及剂量依赖性等不良反应；非甾体抗炎药物包括水杨酸钠、阿司匹林、布洛芬、吲哚美辛、萘普生、罗非昔布等容易引发心血管疾病；细胞因子拮抗剂研发成本较高且用药具有局限性。
目前糖皮质激素类药物治疗痛风的有强的松和甲泼尼龙(中效糖皮质激素，其升糖、抗炎作用都不是最优，但是副作用也较小，对HPA轴的负反馈作用，对水电解质的影响都还在可接受的范围内)，适用于不能耐受非甾体抗炎药、秋水仙碱或肾功能不全者的痛风急性期。甲强龙在临床上起效时间很快，可以迅速抑制酶的活性，并使激素特异性受体达到饱和。
发明内容
本文中描述一种治疗痛风的化合物。本文中还描述合成这样的化合物的方法、使用这样的化合物治疗疾病的方法，所述疾病包括其中所述化合物向患有疾病的患者提供治疗益处的疾病。本文中还描述包含所述化合物的组合产品，包括组合物、药物制剂、试剂盒。
化合物
本文所述的化合物，除非另有说明，否则可使用本领域技术人员已知的常规质谱、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学方法。
本文中描述式I化合物，也包括式II的那些化合物。
本文中所述的化合物包括式I化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物：
Figure PCTCN2021081519-appb-000001
其中，
R 1为-H、(C 1-C 4)烷基或-CH 2-Ar(芳基)；
R 2为-H、(C 1-C 4)烷基或-CH 2-Ar(芳基)；
R 3为-H、-OH、卤素、-OC(＝O)-(CH 2)n-CH 3或-OC(＝O)-Ar；n为0-4的整数；
R 4为-H、-OH、-OC(＝O)-(CH 2)m-CH 3或-OC(＝O)-Ar；m为0-4的整数；
X和Y独立地选自H，-CH 3或卤素；
W为H，-CH 3，或
Figure PCTCN2021081519-appb-000002
M和N独立地选自H，(C 1-C 4)烷基，-Ar(芳基)，杂芳基或苄基。
在某些实施方案中，C-1与C-2位之间的虚线表示其除了单键外还可以为双键；
在某些实施方案中，本发明涉及任意上述化合物，其中：R 1为-H或-CH 2CH 3；
在某些实施方案中，本发明涉及任意上述化合物，其中：R 2为-H或-CH 2CH 3；
在某些实施方案中，本发明涉及任意上述化合物，其中：R 3为-H、-OH、-Cl或-OAc、
Figure PCTCN2021081519-appb-000003
或-CH 2CH 3；
在某些实施方案中，本发明涉及任意上述化合物，其中：R 4为-H、-OH、
Figure PCTCN2021081519-appb-000004
在某些实施方案中，本发明涉及任意上述化合物，其中：X为-H、-F或-Cl。
在某些实施方案中，本发明涉及任意上述化合物，其中：Y为-H、-CH 3、-F或-Cl。
在某些实施方案中，本发明涉及任意上述化合物，其中：W为-H、α-CH 3、β-CH 3、α-OH、β-OH、
Figure PCTCN2021081519-appb-000005
Figure PCTCN2021081519-appb-000006
在某些实施方案中，本发明涉及任意上述化合物，其中：R 1为-H或-CH 2CH 3；
在某些实施方案中，本发明涉及任意上述化合物，其中：R 2为-H或-CH 2CH 3；
在某些实施方案中，本发明涉及任意上述化合物，其中：R 3为-OH或-OAc；
在某些实施方案中，本发明涉及任意上述化合物，其中：R 4为-OH或-OAc；
在某些实施方案中，本发明涉及任意上述化合物，其中：X为-H；
在某些实施方案中，本发明涉及任意上述化合物，其中：Y为-H或-CH 3；
在某些实施方案中，本发明涉及任意上述化合物，其中：W为-H。
在某些实施方案中，本发明涉及任意上述化合物，其中，-C＝N-O-R 2包含Z/E两种构型并通过氢键和空间位阻可以确定，化合物Ⅰ中20位碳(17位侧链)的肟基团均为E构型(反式)。
在另一实施方案中，W为
Figure PCTCN2021081519-appb-000007
基团时，是式II化合物：
Figure PCTCN2021081519-appb-000008
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物，其中，R 1、R 2、R 3、X、Y、M、N的定义如上文中所述。
在某些实施方案中，本发明涉及的式II化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或式II化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物中，M和N独立地选自H，(C 1-C 4)烷基，-Ar(芳基)，杂芳基或苄基。
在某些实施方案中，本发明涉及下表编号1-17的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或所述化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物：
Figure PCTCN2021081519-appb-000009
Figure PCTCN2021081519-appb-000010
Figure PCTCN2021081519-appb-000011
Figure PCTCN2021081519-appb-000012
许多病症可以使用本文中所述的化合物进行治疗。例如，本文中所述的化合物可用于治疗痛风，尤其对于急性期痛风具有显著的治疗效果。另一方面，本文中所述的化合物中取代基可延长该化合物在体内的代谢周期，具有相对更为中长效的抗痛风效果。
本文中所述的化合物还具有较强的抗炎药效，主要对炎症反应通路中糖皮质激素受体GRa、糖皮质激素受体GRb、促炎因子TNF-α、炎症保护因子IL-10的表达起到调节作用。因此本文中所述的化合物还可用于治疗炎症。
本文中所述的化合物还可用于治疗癌症(或肿瘤)，例如人肺腺癌、人急性淋巴母细胞白血病、人B细胞淋巴瘤、人乳腺癌、人恶性胶质母细胞瘤、人肝癌、人宫颈癌、人非小细胞肺癌、人骨肉瘤、人结肠癌、人成骨肉瘤、人Burkitt`s淋巴瘤等不同肿瘤。
制备方法
一般的合成方法
在一些实施方案中，可以使用下面合成路线I-IV中所描述制备本发明中的化合物。
合成路线I中，在碱性条件下，底物中的羰基与盐酸羟胺反应，可以很容易制备出通式中R 1和/或R 2位的肟基团。
Figure PCTCN2021081519-appb-000013
合成路线I
在合成路线II中，在碱性条件下，底物中的羟基与酰化试剂(例如ROCl，具体如酰氯)，发生反应，可以很容易制备出通式中R 3位和/或R 4位对应的酰基化产物。在本发明实施例2、5、11、14、15、16、17化合物的制备中，可使用合成路线II。其中R为直链饱和烷基，例如直链饱和(C 1-C 12)烷基，尤其直链饱和(C 1-C 4)烷基，具体例子包括甲基、乙基、正丙基或正丁基。
Figure PCTCN2021081519-appb-000014
合成路线II
在合成路线III中，在酸性条件下，底物中的R 4和W位的邻二羟基与酮(如丙酮)，或醛(如丁醛)，发生反应，生成缩酮/缩醛。在本发明实施例7、8、13化合物的制备中，可使用合成路线III中的操作。在实施例14化合物的制备中，先用缩酮对底物中R 4和W位的邻二羟基进行保护，再与酰基化试剂(例如ROCl，具体如酰氯)反应，然后在酸性条件下脱除缩酮，获得产物。其中R为直链饱和烷基，例如直链饱和(C 1-C 12)烷基，尤其直链饱和(C 1-C 4)烷基，具体例子包括甲基、乙基、正丙基或正丁基。
Figure PCTCN2021081519-appb-000015
合成路线III
在合成路线IV中，在碱性条件下，底物中的肟基与烷基化试剂(如碘乙烷)反应，生成烷基肟。在本发明实施例9、11化合物的制备中，可使用合成路线IV。
Figure PCTCN2021081519-appb-000016
合成路线IV
上述制备方法中，R 1、R 2、R 3、R 4、X、Y、W、M、N的定义如前。
上述制备方法还可以包括产物分离、精制，所述分离和/或精制可以采用通常有机合成中采用的方法，例如过滤、萃取、洗涤、浓缩、层析等适当组合进行。
用途
本发明还提供上述所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或所述化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物在制备用于治疗或预防痛风的药物中的用途，或在制备用于治疗或预防炎症的药物中的用途；或在制备用于治疗或预防癌症(或肿瘤)的药物中的用途。
优选地，所述药物还包括药学上可接受的辅料，例如稀释剂、赋形剂和/或粘合剂。
其中，所述痛风优选为急性期痛风。
所述炎症尤其是与急性期痛风相关的炎症。
所述炎症优选为与炎症反应通路中糖皮质激素受体GRa、糖皮质激素受体GRb、促炎因子TNF-α、炎症保护因子IL-10的表达起到调节作用中任一种或几种相关的炎症。
所述癌症选自人肺腺癌、人急性淋巴母细胞白血病、人B细胞淋巴瘤、人乳腺癌、人恶性胶质母细胞瘤、人肝癌、人宫颈癌、人非小细胞肺癌、人骨肉瘤、人结肠癌、人成骨肉瘤、人Burkitt`s淋巴瘤中任一种或几种。
进一步地，所述用途中所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或所述化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物作为唯一活性成分或联合其它具有生物活性的物质。
所述其它具有生物活性的物质包括秋水仙碱、非甾体抗炎药(包括水杨酸钠、阿司匹林、布洛芬、吲哚美辛、萘普生、罗非昔布)、糖皮质激素(包括强的松、甲泼尼龙)、抑炎因子药物、甲强龙等。
组合产品
本发明还提供一种用于治疗或预防痛风或炎症或癌症(或肿瘤)的组合产品，包括上述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或所述化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物中的一种或几种。
优选地，所述组合产品还包括药学上可接受的辅料，例如稀释剂、赋形剂和/或粘合剂。
在一些实施例中，所述组合产品也称为药物组合物。
优选地，所述组合产品为试剂盒。
治疗方法
本发明还提供治疗或预防痛风或炎症或癌症的方法，包括对有需要的受试者或患者通过口服或非口服途径给予有效剂量的上述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或所述化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物，或上述组合产品。
其中，所述痛风优选为急性期痛风。
所述炎症与痛风相关或不相关。
优选所述炎症是与急性期痛风相关的炎症。
所述炎症优选为与炎症反应通路中糖皮质激素受体GRa、糖皮质激素受体GRb、促炎因子TNF-α、炎症保护因子IL-10的表达起到调节作用中任一种或几种相关的炎症。
所述癌症选自人肺腺癌、人急性淋巴母细胞白血病、人B细胞淋巴瘤、人乳腺癌、人恶性胶质母细胞瘤、人肝癌、人宫颈癌、人非小细胞肺癌、人骨肉瘤、人结肠癌、人成骨肉瘤、人Burkitt`s淋巴瘤中任一种或几种。
所述口服或非口服途径可以为通过口服、注射、贴片、喷雾和其他已知的一种或多种递送给所述受试者或患者。所述有效量可以包括对治疗、降低、缓和、减轻或消除等状况的一种或多种症状有效的量，所述状况寻求被治疗，或可选地，所述状况寻求被避免，或另外在所述状况或其效果中产生临床上可确认的有利变化。
在一些实施方案中，本文中所提供的化合物被向哺乳动物给药。
在一些实施方案中，本文中所提供的化合物被向人给药。
在一些实施方案中，本文中所提供的化合物被口服给药。
在其它实施方案中，本文中所提供的化合物用于配制用以抑制和/或治疗痛风活性的药物。在一些其它实施方案中，本文中所提供的化合物用于配制用以抑制抑制和/或治疗急性期痛风活性的药物。
术语定义
烷基，是指包含1-12个碳原子的线性或支化链的饱和烃基取代基(即，通过从烃移除氢获得的取代基)。这样的取代基的实例包括甲基、乙基、丙基(包括正丙基和异丙基)、丁基(包括正丁基、异丁基、仲丁基和叔丁基)、戊基、异戊基、己基等。
芳基(-Ar)，是指包含一个环或者两个或三个稠合环的芳族取代基。所述芳基可具有6-18个碳原子。作为实例，所述芳基可具有6-14个碳原子。术语“芳基”可以是指例如苯基、萘基和蒽基的取代基。
卤素，是指氟(其可以表示为F)、氯(其可以表示为Cl)、溴(其可以表示为Br)或碘(其可以表示为I)。在一个实施方案中，所述卤素是氯。在另一实施方案中，所述卤素是氟。在另一实施方案中，所述卤素是溴
本文中使用的术语“式I和式II”可以称为“本发明的化合物”。这样的术语也定义为包括所有形式的式I和式II的化合物，包括其水合物、溶剂合物、异构体、结晶和非结晶形式、同晶型体、多晶型体和代谢物。例如，式I和式II的化合物及其药学上可接受的盐可以未溶剂化和溶剂化的形式存在。当溶剂或水紧密结合时，复合物会具有定义明确的与湿度无关的化学计量。然而，当溶剂或水微弱结合时，如在通道溶剂合物(channel solvate)和吸湿化合物中，水/溶剂含量会取决于湿度和干燥条件。在这样的情况下，非化学计量会成为常态。
本发明的化合物可具有不对称碳原子。本发明的化合物的碳碳键在本文中可使用实线、实楔形或虚楔形示出。使用实线示出与不对称碳原子的键意欲表示所述碳原子的所有可能的立体异构体(例如特定的对映异构体、外消旋混合物等)都包括在内。使用实楔形或虚楔形示出与不对称碳原子的键意欲表示仅示出的立体异构体意欲包括在内。可能的是，本发明的化合物可包含一个以上不对称碳原子。在这些化合物中，使用实线示出与不对称碳原子的键意欲表示所有可能的立体异构体都意欲包括在内。例如，除非另有说明，否则本发明的化合物意欲可作为对映异构体和非对映异构体或者作为外消旋物和其混合物存在。使用实线示出本发明的化合物中与一个或多个不对称碳原子的键并且使用实楔形或虚楔形示出同一化合物中与其它不对称碳原子的键意欲表示存在非对映异构体的混合物。
本发明的化合物的立体异构体包括本发明的化合物的顺式和反式异构体、光学异构体例如R和S对映异构体、非对映异构体、几何异构体、旋转异构体、构象异构体和互变异构体，包括表现出一种以上类型的异构现象的化合物；以及其混合物(例如外消旋物和非对映异构体)。还包括酸加成盐或碱加成盐，其中平衡离子具有光学活性，例如，D-乳酸盐或L-赖氨酸，或者为外消旋的，例如，DL-酒石酸盐或DL-精氨酸。
当任何外消旋物结晶时，可能存在两种不同类型的晶体。第一种类型是上文提到的外消旋化合物(真外消旋物)，其中产生一种包含等摩尔量的两种对映异构体的均质形式的晶体。第二种类型是外消旋混合物或聚集物，其中产生等摩尔量的两种形式的晶体，每一种晶体各自包含单一对映异构体。
其中，-C＝N-O-R 2包含Z/E两种构型并通过氢键和空间位阻可以确定，化合物Ⅰ中20位碳(17位侧链)的肟基团均为E构型(反式)。
通常，本发明的化合物以有效治疗本文中所述的病症的量给药。本发明的化合物通过任何合适的途径以适合这样的途径的药物组合物的形式并且以对于意图的治疗有效的剂量给药。治疗医学病症的进展所需的化合物的治疗有效剂量由本领域的普通技术人员容易地使用医学领域熟悉的临床前和临床方法确定。本文中使用的术语“治疗有效量”是指将所治疗病症的一种或多种症状一定程度缓解的所给药的化合物的量。
除非另外指出，否则本发明的实践使用常规有机化学、药理学、分子生物学(包括重组体技术)、细胞生物学、生物化学和免疫学技术。这样的技术在现有文献中有说明，其各自以其整体援引加入本文。
具体实施方式
以下结合具体实施例对本发明作进一步详细说明，但不用来限制本发明的范围。
所述原材料如无特别说明，均能从公开商业途径获得。
实施例1
(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-二羟基-17-((E)-2-羟基-1-(羟基亚氨基)乙基)-6,10,13-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊烷[a]菲-3-酮肟
Figure PCTCN2021081519-appb-000017
在室温下，向溶有甲强龙a(500mg，1.0eq)的甲醇溶液中加入乙酸钠(370mg,2.5eq)分批加入盐酸羟胺(203mg,2.2eq)，室温反应6h,，TLC监测反应完毕后真空旋干溶剂。使用Biotage Isolera自动柱色谱仪，在EA和PE梯度中纯化，并接着在减压下干燥。得到米白色固体Z/E-1(510mg,95％)。而后进一步用RPHPLC，在MeOH和H 2O梯度中纯化，并减压干燥得到纯化合物3(Z)-1(200mg)和化合物3(E)-1(248mg)。
化合物3(Z)-1: 1H-NMR(600MHz,d 6-DMSO)δ H 0.629(m,1H),0.870-0.835(m,4H),1.051-1.035(d,3H),1.254-1.119(m,1H),1.323(s,3H),1.436-1.354(m,1H),1.604-1.590(m,2H),1.758-1.714(m,2H),1.995-1.969(m,2H),2.636-2.536(m,1H),2.734(m,1H),4.164-4.132(m,1H),4.274-4.225(m,2H),4.406-4.397(m,1H),4.589-4.560(m,1H),4.807(s,1H),6.116-6.087(m,1H),6.354-6.329(d,1H),6.446(s,1H),10.576(s,1H),10.796(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.24,18.62,23.45,23.60,31.71,32.73,32.83,39.96,43.51,43.67,47.07,50.90,55.74,56.94,67.76,85.67,104.83,121.59,141.73,148.76,159.72,161.47；LRMS(ES+)[C 22H 32N 2O 5+H]的计算值405.3实验值405.2。
化合物3(E)-1： 1H-NMR(600MHz,d 6-DMSO)δ H 0.632-0.612(m,1H),0.875-0.832(m,4H),1.032-1.021(d,3H),1.254-1.119(m,1H),1.324(s,3H),1.368-1.354(m,1H),1.607-1.595(m,2H),1.760-1.709(m,2H),2.004-1.943(m,2H),2.511(m,1H),2.731(m,1H),4.157-4.127(m,1H),4.266-4.233(m,2H),4.408-4.402(m,1H),4.592-4.572(m,1H),4.809(s,1H),5.708(s,1H),6.519-6.501(d,1H),6.779-6.759(m,1H),10.522(s,1H),10.793(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.23,18.57,23.31,23.48,31.74,32.64,32.83,39.95,43.42,43.62,47.03,50.92,55.76,56.69,67.70,85.71,112.20,113.75,145.96,149.06,156.86,159.72；LRMS(ES+)[C 22H 32N 2O 5+H]的计算值405.3实验值405.2。
实施例2
(2E)-2-((6S,8S,9S,10R,11S,13S,14S,17R)-11,17-二羟基-3-(羟基亚氨基)-6,10,13-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊烷[a]菲-17-基)-2-(羟基亚氨基)乙酸乙酯
Figure PCTCN2021081519-appb-000018
按照上文一般的合成方法中合成路线I、II中所示的方法，用合适的起始原料制备化合物2，并分离得到(3Z)-2和(3E)-2。
化合物3(Z)-2: 1H-NMR(600MHz,d 6-DMSO)δ H 0.630(m,1H),0.863-0.835(m,4H),1.044-1.032(d,3H),1.255-1.122(m,1H),1.325(s,3H),1.366-1.352(m,1H),1.603-1.590(m,2H),1.758-1.712(m,2H),1.998-1.953(m,2H),2.632(m,1H),2.688(s,3H),2.733(m,1H),4.166-4.142(m,1H),4.259-4.227(m,2H),4.405-4.386(m,1H),4.806(s,1H),6.113-6.078(m,1H),6.345-6.327(d,1H),6.452(s,1H),10.574(s,1H),10.793(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.22,18.56,22.93,23.39,23.60,31.72,32.69,32.81,39.94,43.52,43.66,47.07,50.92,55.75,56.92,67.74,85.65,104.81,121.60,141.71,148.78,159.73,161.47,168.91；LRMS(ES+)[C 24H 34N 2O 6+H]的计算值447.3实验值447.2。
化合物3(E)-2： 1H-NMR(600MHz,d 6-DMSO)δ H 0.628(m,1H),0.865-0.840(m,4H),1.038-1.025(d,3H),1.252-1.120(m,1H),1.327(s,3H),1.368-1.353(m,1H),1.605-1.596(m,2H),1.761-1.718(m,2H),2.002-1.956(m,2H),2.598(m,1H),2.730(m,4H),4.157-4.127(m,1H),4.263-4.237(m,2H),4.404-4.400(m,1H),4.807(s,1H),5.705(s,1H),6.518-6.502(d,1H),6.781-6.758(m,1H),10.524(s,1H),10.781(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.25,18.55,22.88,23.35,23.49,31.72,32.63,32.82,39.95,43.54,43.61,47.04,50.92,55.75,56.70,67.72,85.70,112.22,113.74,145.93,149.07,156.86,159.73,168.95；LRMS(ES+)[C 24H 34N 2O 6+H]的计算值447.3实验值447.2。
实施例3
(8S,9S,10R,11S,13S,14S,17R)-11,17-二羟基-17-((E)-2-羟基-1-(羟基亚氨基)乙基)-10,13-二甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊烷[a]菲-3-酮肟
Figure PCTCN2021081519-appb-000019
按照上文一般的合成方法中合成路线I中所示的方法，用合适的起始原料制备化合物3，并分离得到(3Z)-3和(3E)-3。
化合物3(Z)-3: 1H-NMR(600MHz,d 6-DMSO)δ H 0.630(m,1H),0.869-0.834(m,4H),1.253-1.120(m,1H), 1.325(s,3H),1.368-1.352(m,1H),1.601-1.592(m,2H),1.756-1.713(m,2H),1.998-1.971(m,2H),2.602-2.523(m,2H),2.735(m,1H),4.162-4.131(m,1H),4.273-4.224(m,2H),4.402-4.394(m,1H),4.591-4.557(m,1H),4.806(s,1H),6.114-6.085(m,1H),6.352-6.327(d,1H),6.448(s,1H),10.573(s,1H),10.798(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.23,23.47,23.58,31.73,32.49,32.84,39.93,43.58,43.67,47.06,50.92,55.75,56.94,67.77,85.65,104.82,121.60,141.72,148.76,159.73,161.49；LRMS(ES+)[C 21H 30N 2O 5+H]的计算值391.3实验值391.2。
化合物3(E)-3： 1H-NMR(600MHz,d 6-DMSO)δ H 0.627(m,1H),0.872-0.835(m,4H),1.250-1.122(m,1H),1.323(s,3H),1.364-1.357(m,1H),1.606-1.598(m,2H),1.768-1.709(m,2H),2.001-1.939(m,2H),2.589-2.478(m,2H),2.732(m,1H),4.153-4.125(m,1H),4.263-4.231(m,2H),4.409-4.404(m,1H),4.590-4.574(m,1H),4.810(s,1H),5.707(s,1H),6.518-6.502(d,1H),6.779-6.762(m,1H),10.524(s,1H),10.796(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.24,23.34,23.47,31.75,32.47,32.86,39.94,43.53,43.64,47.02,50.94,55.73,56.69,67.68,85.72,112.23,113.74,145.95,149.06,156.83,159.74；LRMS(ES+)[C 21H 30N 2O 5+H]的计算值391.3实验值391.2。
实施例4
(6S,8S,9S,10R,11S,13S,14S,17R)-11,17-二羟基-17-((E)-2-羟基-1-(羟基亚氨基)乙基)-6,10,13-三甲基-1,2,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-3H-环戊烷[a]菲-3-酮肟
Figure PCTCN2021081519-appb-000020
按照上文一般的合成方法中合成路线I中所示的方法，用合适的起始原料制备化合物4，并分离得到(3Z)-4和(3E)-4
化合物3(Z)-4: 1H-NMR(600MHz,d 6-DMSO)δ H 0.635(m,1H),0.868-0.837(m,4H),1.053-1.032(d,3H),1.085-1.089(m,1H),1.156-1.127(m,1H),1.284-1.277(m,1H),1.323(s,3H),1.371-1.352(m,1H),1.603-1.585(m,2H),1.759-1.713(m,2H),1.996-1.965(m,2H),2.636-2.534(m,1H),2.738(m,1H),2.979-2.965(m,2H),4.166-4.135(m,1H),4.273-4.226(m,2H),4.405-4.399(m,1H),4.588-4.561(m,1H),4.809(s,1H),6.407(s,1H),10.127(s,1H),10.791(s,1H)； 13C(600MHz,d 6-DMSO)δ C18.22,18.65,23.47,23.61,30.82,31.71,32.74,32.84,38.75,39.95,43.52,43.68,47.05,50.92,55.73,56.96,67.73,85.65,101.52,148.59,159.71,162.47；LRMS(ES+)[C 22H 32N 2O 5+H]的计算值407.3实验值407.2。
化合物3(E)-4： 1H-NMR(600MHz,d 6-DMSO)δ H 0.623(m,1H),0.873-0.834(m,4H),1.035-1.026(d,3H),1.089-1.082(m,1H),1.156-1.117(m,1H),1.282-1.274(m,1H),1.325(s,3H),1.367-1.358(m,1H),1.609-1.597(m,2H),1.759-1.708(m,2H),2.001-1.945(m,2H),2.514(m,1H),2.733(m,1H),3.124-3.037(m,2H),4.154-4.123(m, 1H),4.268-4.232(m,2H),4.406-4.401(m,1H),4.590-4.575(m,1H),4.811(s,1H),5.701(s,1H),10.124(s,1H),10.791(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.23,18.56,23.33,23.47,30.21,31.78,32.02,32.84,39.07,39.93,43.44,43.65,47.01,50.93,55.74,56.69,67.70,85.71,113.21,149.03,157.86,159.74；LRMS(ES+)[C 22H 32N 2O 5+H]的计算值407.3实验值407.2。
实施例5
(2E)-2-((8S,9S,10R,11S,13S,14S,17R)-11,17-二羟基-3-(羟基亚胺基)-10,13-二甲基-2,3,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-1H-环戊烷[a]菲-17-基)-2-(羟基亚胺基)乙酸乙酯
Figure PCTCN2021081519-appb-000021
按照上文一般的合成方法中合成路线I、II中所示的方法，用合适的起始原料制备化合物5，并分离得到(3Z)-5和(3E)-5
化合物3(Z)-5: 1H-NMR(600MHz,d 6-DMSO)δ H 0.631(m,1H),0.868-0.837(m,4H),1.085-1.089(m,1H),1.156-1.127(m,1H),1.284-1.277(m,1H),1.323(s,3H),1.371-1.352(m,1H),1.603-1.585(m,2H),1.759-1.713(m,2H),1.996-1.965(m,2H),2.602-2.523(m,2H),2.688(s,3H),2.738(m,1H),2.979-2.965(m,2H),4.166-4.135(m,1H),4.273-4.226(m,2H),4.405-4.399(m,1H),4.809(s,1H),6.407(s,1H),10.127(s,1H),10.791(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.22,22.93,23.47,23.61,30.82,31.71,32.48,32.84,38.75,39.95,43.52,43.68,47.05,50.92,55.73,56.96,67.73,85.65,101.52,148.59,159.71,162.47,168.91；LRMS(ES+)[C 23H 34N 2O 6+H]的计算值435.3实验值435.2。
化合物3(E)-5： 1H-NMR(600MHz,d 6-DMSO)δ H 0.624(m,1H),0.872-0.835(m,4H),1.091-1.078(m,1H),1.154-1.116(m,1H),1.283-1.275(m,1H),1.324(s,3H),1.366-1.359(m,1H),1.610-1.595(m,2H),1.754-1.706(m,2H),2.002-1.945(m,2H),2.603-2.522(m,2H),2.687(s,3H),2.735(m,1H),3.126-3.034(m,2H),4.155-4.124(m,1H),4.267-4.231(m,2H),4.408-4.403(m,1H),4.813(s,1H),5.704(s,1H),10.127(s,1H),10.793(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.23,22.88,23.33,23.47,30.21,31.78,32.02,32.44,39.06,39.94,43.45,43.66,47.02,50.94,55.73,56.68,67.71,85.72,113.23,149.07,157.88,159.75,168.95；LRMS(ES+)[C 23H 34N 2O 6+H]的计算值435.3实验值435.2。
实施例6
(8S,9S,10R,11S,13S,14S,16S,17R)-11,17-二羟基-17-((E)-2-羟基-1-(羟基亚氨基)乙基)-10,13,16-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊烷[a]菲-3-酮肟
Figure PCTCN2021081519-appb-000022
按照上文一般的合成方法中合成路线I、II中所示的方法，用合适的起始原料制备化合物6，并分离得到(3Z)-6和(3E)-6。
化合物3(Z)-6: 1H-NMR(600MHz,d 6-DMSO)δ H 0.630(m,1H),0.870-0.832(m,7H),1.252-1.123(m,1H),1.324(s,3H),1.602-1.593(m,2H),1.755-1.716(m,3H),2.001-1.974(m,2H),2.605-2.526(m,2H),4.162-4.135(m,1H),4.272-4.228(m,2H),4.403-4.397(m,1H),4.587-4.561(m,1H),4.806(s,1H),6.112-6.084(m,1H),6.353-6.328(d,1H),6.451(s,1H),10.569(s,1H),10.793(s,1H)； 13C(600MHz,d 6-DMSO)δ C 17.28,18.22,23.57,27.38,31.74,32.45,38.89,39.93,43.66,43.57,47.07,50.90,55.74,56.94,67.76,88.93,104.84,121.63,141.70,148.75,159.70,161.39；LRMS(ES+)[C 22H 32N 2O 5+H]的计算值405.43实验值405.3。
化合物3(E)-6： 1H-NMR(600MHz,d 6-DMSO)δ H 0.629(m,1H),0.872-0.8345(m,7H),1.251-1.123(m,1H),1.325(s,3H),1.604-1.596(m,2H),1.765-1.711(m,3H),2.001-1.969(m,2H),2.593-2.481(m,2H),4.152-4.137(m,1H),4.269-4.233(m,2H),4.405-4.402(m,1H),4.590-4.574(m,1H),4.810(s,1H),5.702(s,1H),6.513-6.501(d,1H),6.776-6.761(m,1H),10.523(s,1H),10.794(s,1H)； 13C(600MHz,d 6-DMSO)δ C 17.27,18.23,23.34,27.38,31.76,32.47,38.85,39.94,43.56,43.64,47.03,50.93,55.74,56.67,67.69,88.98,112.24,113.72,145.95,149.07,156.85,159.78；LRMS(ES+)[C 22H 32N 2O 5+H]的计算值405.43实验值405.3。
实施例7
(6aS,6bR,7S,8aS,8bR,11aR,12aS,12bS)-6b-氟-7-羟基-8b-((E)-2-羟基-1-(羟基亚氨基)乙基)-6a，8a，10,10-四甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-4H-萘并[2',1'：4,5]茚并[1,2-d][1,3]二氧杂环-4-酮肟
Figure PCTCN2021081519-appb-000023
按照上文一般的合成方法中合成路线I、III中所示的方法，用合适的起始原料制备化合物7，并分离得到(3Z)-7和(3E)-7。
化合物3(Z)-7: 1H-NMR(600MHz,d 6-DMSO)δ H 0.731(m,1H),0.877-0.852(m,4H),1.233(s,6H),1.287-1.198(m,1H),1.347(s,3H),1.611-1.597(m,1H),1.783-1.774(m,2H),1.998-1.972(m,2H),2.798(m,2H), 3.986(m,1H),4.174-4.163(m,1H),4.285-4.273(m,2H),4.411-4.402(m,1H),4.587-4.559(m,1H),6.118-6.097(m,1H),6.361-6.333(d,1H),6.442(s,1H),10.574(s,1H),10.799(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.34,23.62,26.57,33.86,33.92,34.37,39.94,43.51,43.69,47.08,50.92,55.76,70.83,83.49,96.91,100.24,104.82,121.62,123.13,141.72,148.75,159.73,161.49；LRMS(ES+)[C 23H 33F 2N 2O 6+H]的计算值465.3实验值465.2。
化合物3(E)-7： 1H-NMR(600MHz,d 6-DMSO)δ H 0.728(m,1H),0.874-0.833(m,4H),1.234(s,6H),1.256-1.121(m,1H),1.326(s,3H),1.609-1.593(m,1H),1.762-1.723(m,2H),2.003-1.965(m,2H),2.788(m,2H),3.979(m,1H),4.154-4.123(m,1H),4.269-4.253(m,2H),4.407-4.403(m,1H),4.591-4.570(m,1H),5.706(s,1H),6.513-6.504(d,1H),6.779-6.759(m,1H),10.522(s,1H),10.793(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.33,23.64,26.56,33.85,33.94,34.38,39.93,43.47,43.64,47.03,50.93,55.75,70.82,83.56,96.94,100.23,112.25,113.72,121.63,145.97,149.09,156.88,159.74；LRMS(ES+)[C 23H 33F 2N 2O 6+H]的计算值465.3实验值465.2。
实施例8
(2S,6aS,6bR,7S,8aS,8bR,11aR,12aS,12bS)-2,6b-二氟-7-羟基-8b-((E)-2-羟基-1-(羟基亚胺)乙基)-6a，8a，10,10-四甲基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-4H-萘并[2',1'：4,5]茚并[1,2-d][1,3]二氧杂醇-4-酮肟
Figure PCTCN2021081519-appb-000024
按照上文一般的合成方法中合成路线I、III中所示的方法，用合适的起始原料制备化合物8，并分离得到(3Z)-8和(3E)-8。
化合物3(Z)-8: 1H-NMR(600MHz,d 6-DMSO)δ H 0.702(m,1H),0.876-0.853(m,4H),1.235(s,6H),1.258-1.121(m,1H),1.331(s,3H),1.613-1.598(m,1H),1.782-1.775(m,2H),1.871-1.859(m,1H),1.998-1.972(m,1H),3.983(m,1H),4.093-4.087(m,1H),4.172-4.165(m,1H),4.289-4.276(m,2H),4.404(m,1H),4.583-4.563(m,1H),6.124-6.102(m,1H),6.364-6.341(d,1H),6.573(s,1H),10.576(s,1H),10.801(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.35,23.64,26.58,33.87,34.38,39.97,43.59,43.73,47.11,50.94,55.75,70.85,83.47,88.87,96.94,100.25,104.83,121.60,123.14,141.73,148.76,159.72,161.03；LRMS(ES+)[C 24H 32F 2N 2O 6+H]的计算值483.2实验值483.3。
化合物3(E)-8： 1H-NMR(600MHz,d 6-DMSO)δ H 0.703(m,1H),0.874-0.851(m,4H),1.234(s,6H),1.256-1.124(m,1H),1.328(s,3H),1.610-1.595(m,1H),1.771-1.765(m,2H),1.872-1.861(m,1H),2.002-1.974(m,1H),3.977(m,1H),4.091-4.085(m,1H),4.152-4.126(m,1H),4.271-4.254(m,2H),4.406(m,1H),4.587-4.569(m,1H),5.784(s,1H),6.521-6.510(d,1H),6.775-6.761(m,1H),10.523(s,1H),10.789(s,1H)； 13C(600MHz,d 6-DMSO)δ C 18.34,23.65,26.57,33.86,34.37,39.95,43.58,43.75,47.08,50.95,55.76,70.83,83.54,96.96, 100.24,112.24,113.75,121.62,145.96,149.11,156.87,159.72；LRMS(ES+)[C 24H 32F 2N 2O 6+H]的计算值483.2实验值483.3。
实施例9
(6S,8S,9S,10R,11S,13S,14S,17R,E)-17-((E)-1-(乙氧基亚胺基)-2-羟乙基)-11,17-二羟基-6,10,13-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊烷[a]菲-3-酮O-乙基肟
Figure PCTCN2021081519-appb-000025
按照上文一般的合成方法中合成路线I、IV中所示的方法，用合适的起始原料制备化合物9，并分离得到(3Z)-9和(3E)-9。
化合物3(Z)-9: 1H-NMR(600MHz,d 6-DMSO)δ H 0.629(m,1H),0.870-0.835(m,4H),0.987-0.975(m,6H),1.051-1.035(d,3H),1.254-1.119(m,1H),1.323(s,3H),1.396-1.354(m,1H),1.604-1.590(m,2H),1.758-1.714(m,2H),1.995-1.969(m,2H),2.636-2.536(m,1H),2.734(m,1H),3.882-3.754(m,4H),4.164-4.132(m,1H),4.274-4.225(m,2H),4.406-4.397(m,1H),4.589-4.560(m,1H),4.807(s,1H),6.116-6.087(m,1H),6.354-6.329(d,1H),6.446(s,1H),； 13C(600MHz,d 6-DMSO)δ C 13.9,18.26,18.64,23.47,23.62,31.73,32.75,32.84,39.93,43.52,43.66,47.09,50.95,55.79,56.97,66.93,67.02,67.75,85.69,104.84,121.61,141.76,148.73,159.74,161.48；LRMS(ES+)[C 26H 40N 2O 5+H]的计算值461.3实验值461.4。
化合物3(E)-9： 1H-NMR(600MHz,d 6-DMSO)δ H 0.631-0.624(m,1H),0.873-0.835(m,4H),0.985-0.974(m,6H),1.035-1.028(d,3H),1.253-1.121(m,1H),1.326(s,3H),1.365-1.351(m,1H),1.604-1.592(m,2H),1.760-1.713(m,2H),2.002-1.954(m,2H),2.516(m,1H),2.735(m,1H),3.796-3.728(m,4H),4.157-4.128(m,1H),4.269-4.235(m,2H),4.407-4.401(m,1H),4.590-4.571(m,1H),4.804(s,1H),5.702(s,1H),6.517-6.506(d,1H),6.801-6.762(m,1H)； 13C(600MHz,d 6-DMSO)δ C 14.01,18.24,18.58,23.33,23.49,31.75,32.66,32.83,39.96,43.41,43.64,47.02,50.93,55.85,56.70,67.72,85.73,112.21,113.76,145.94,149.07,156.83,159.74；LRMS(ES+)[C 26H 40N 2O 5+H]的计算值461.3实验值461.4。
实施例10
(8S,9S,10R,11S,13S,14S,16R,17S)-11-羟基-17-(2-羟基乙酰基)-10,13,16-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊烷[a]菲-3-酮
Figure PCTCN2021081519-appb-000026
按照上文一般的合成方法中合成路线I中所示的方法，用合适的起始原料制备化合物10，并分离得到(3Z)-10和(3E)-10。
化合物3(Z)-10: 1H-NMR(600MHz,d 6-DMSO)δ H 0.630(m,1H),0.870-0.832(m,4H),0.989-0.975(s,3H),1.254-1.126(m,1H),1.327(s,3H),1.602-1.593(m,2H),1.755-1.716(m,3H),1.896-1.874(m,1H),2.003-1.977(m,2H),2.606-2.528(m,2H),4.163-4.142(m,1H),4.273-4.231(m,2H),4.405-4.396(m,1H),4.591-4.575(m,1H),6.113-6.087(m,1H),6.354-6.329(m,1H),6.453(s,1H),10.567(s,1H),10.797(s,1H)； 13C(600MHz,d 6-DMSO)δ C 17.21,18.32,23.51,31.42,31.96,38.95,39.71,40.03,42.97,43.92,45.88,49.73,56.81,56.89,67.76,85.67,104.83,121.59,141.73,148.76,159.72,161.47；LRMS(ES+)[C 22H 32N 2O 4+H]的计算值389.3实验值389.2。
化合物3(E)-10： 1H-NMR(600MHz,d 6-DMSO)δ H 0.628(m,1H),0.873-0.834(m,4H),0.988-0.976(s,3H),1.253-1.121(m,1H),1.327(s,3H),1.606-1.594(m,2H),1.764-1.712(m,3H),1.894-1.873(m,1H),1.998-1.962(m,2H),2.597-2.485(m,2H),4.155-4.134(m,1H),4.267-4.231(m,2H),4.408-4.403(m,1H),4.588-4.572(m,1H),5.704(s,1H),6.511-6.503(d,1H),6.778-6.764(m,1H),10.522(s,1H),10.793(s,1H)； 13C(600MHz,d 6-DMSO)δ C 17.25,18.26,23.37,31.39,31.87,38.93,39.69,40.01,42.92,43.89,45.86,49.71,56.76,56.85,67.70,85.64,112.19,113.78,145.94,149.11,156.87,159.82；LRMS(ES+)[C 22H 32N 2O 4+H]的计算值389.3实验值389.2。
实施例11
(2E)-2-(乙氧基亚氨基)-2-((8S,9S,10R,11S,13S,14S,16R,17R)-3-(乙氧基亚氨基)-11,17-二羟基-10,13,16-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊[a]菲-17-基)乙酸乙酯
Figure PCTCN2021081519-appb-000027
按照上文一般的合成方法中合成路线I、IV中所示的方法，用合适的起始原料制备化合物11，并分离得到(3Z)-11和(3E)-11。
化合物3(Z)-10: 1H-NMR(600MHz,d 6-DMSO)δ H 0.641(m,1H),0.877-0.841(m,4H),0.992-0.975(s,9H), 1.254-1.126(m,1H),1.327(s,3H),1.602-1.593(m,2H),1.755-1.716(m,3H),2.003-1.977(m,2H),2.606-2.528(m,2H),2.688(s,3H),3.882-3.754(m,4H),4.163-4.142(m,1H),4.273-4.231(m,2H),4.405-4.396(m,1H),4.806(s,1H),6.113-6.087(m,1H),6.354-6.329(m,1H),6.453(s,1H)； 13C(600MHz,d 6-DMSO)δ C 13.56,17.21,18.33,23.53,30.35,31.63,32.58,36.83,39.98,42.36,43.62,46.11,50.83,56.89,56.93,67.74,69.81,69.84 88.87,104.85,121.54,141.76,148.74,159.71,161.45,169.88；LRMS(ES+)[C 28H 42N 2O 6+H]的计算值503.3实验值503.2。
化合物3(E)-10： 1H-NMR(600MHz,d 6-DMSO)δ H 0.633(m,1H),0.875-0.837(m,4H),0.987-0.979(s,9H),1.2543-1.120(m,1H),1.329(s,3H),1.604-1.592(m,2H),1.761-1.718(m,3H),1.997-1.965(m,2H),2.596-2.483(m,2H),2.687(s,3H),3.876-3.752(m,4H),4.154-4.132(m,1H),4.264-4.230(m,2H),4.404-4.398(m,1H),4.811(s,1H),5.706(s,1H),6.509-6.501(d,1H),6.776-6.763(m,1H)； 13C(600MHz,d 6-DMSO)δ C 13.55,17.23,18.34,23.51,30.39,31.67,32.56,36.76,39.96,42.37,43.69,46.13,50.79,56.86,56.96,67.72,69.79,69.83,88.84,112.21,113.76,145.92,149.15,156.86,159.76,169.87；LRMS(ES+)[C 28H 42N 2O 6+H]的计算值503.3实验值503.2。
实施例12
(2E)-2-((8S,9R,10S,11S,13S,14S,16S,17R)-9-氯-11,17-二羟基-3-(羟基亚氨基)-10,13,16-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊烷[a]菲-17-基)-2-(羟基亚氨基)丙酸乙酯
Figure PCTCN2021081519-appb-000028
按照上文一般的合成方法中合成路线I、II中所示的方法，用合适的起始原料制备化合物12，并分离得到(3Z)-12和(3E)-12。
化合物3(Z)-12: 1H-NMR(600MHz,d 6-DMSO)δ H 0.629(m,1H),0.872-0.833(m,7H),1.249-1.117(m,4H),1.326(s,3H),1.601-1.597(m,1H),1.754-1.718(m,3H),2.002-1.976(m,2H),2.601-2.522(m,4H),4.159-4.134(m,1H),4.274-4.229(m,2H),4.402-4.398(m,1H),4.811(s,1H),6.109-6.085(m,1H),6.353-6.321(d,1H),6.452(s,1H),10.574(s,1H),10.792(s,1H)； 13C(600MHz,d 6-DMSO)δ C 10.26,17.27,18.24,23.58,27.29,27.36,31.76,32.44,38.90,39.96,43.55,43.67,47.04,50.91,55.76,56.93,67.77,88.96,104.85,121.63,141.76,148.73,159.74,161.46,171.57；LRMS(ES+)[C 25H 35FN 2O 6+H]的计算值496.2实验值496.3。
化合物3(E)-12： 1H-NMR(600MHz,d 6-DMSO)δ H 0.631(m,1H),0.871-0.837(m,7H),1.252-1.121(m,4H),1.322(s,3H),1.603-1.597(m,1H),1.761-1.723(m,3H),1.998-1.967(m,2H),2.596-2.486(m,4H),4.154-4.133(m,1H),4.272-4.234(m,2H),4.406-4.397(m,1H),4.809(s,1H),5.698(s,1H),6.508-6.497(d,1H),6.772-6.760(m,1H),10.528(s,1H),10.791(s,1H)； 13C(600MHz,d 6-DMSO)δ C 10.24,17.25,18.23,23.39,27.31,27.40,31.75,32.48,38.89,39.93,43.54,43.67,47.04,50.93,55.77,56.71,67.68,88.92,112.21,113.78,145.96,149.11,156.82, 159.77,171.52；LRMS(ES+)[C 25H 35FN 2O 6+H]的计算值496.2实验值496.3。
实施例13
(6aR,6bS,7S,8aS,8bR,11aR,12aS,12bS)-7-羟基-8b-((E)-2-羟基-1-(羟基亚氨基)乙基)-6a,8a-二甲基-10-丙基-1,2,6a,6b,7,8,8a,8b,11a,12,12a,12b-十二氢-4H-萘并[2',1':4,5]吲哚[1,2-d][1,3]二氧杂环-4-酮肟
Figure PCTCN2021081519-appb-000029
按照上文一般的合成方法中合成路线I、III中所示的方法，用合适的起始原料制备化合物13，并分离得到(3Z)-13和(3E)-13。
化合物3(Z)-13: 1H-NMR(600MHz,d 6-DMSO)δ H 0.637(m,1H),0.873-0.858(m,4H),0.893-0.882(m,3H),1.233(s,2H),1.272-1.125(m,1H),1.347(s,3H),1.402(m,1H),1.613-1.602(m,3H),1.781-1.779(m,2H),1.994-1.961(m,2H),2.679-2.657(m,2H),3.986(m,1H),4.170-4.168(m,1H),4.283-4.269(m,2H),4.407-4.404(m,1H),4.583-4.563(m,1H),5.396(m,1H),6.118-6.097(m,1H),6.361-6.333(d,1H),6.442(s,1H),10.574(s,1H),10.799(s,1H)； 13C(600MHz,d 6-DMSO)δ C 13.22,14.57,18.36,23.55,33.88,33.91,34.36,36.69,42.85,43.54,43.61,46.97,52.38,55.76,56.98,70.21,89.97,96.91,103.62 104.83,120.31,141.75,148.73,159.76,161.46；LRMS(ES+)[C 25H 36N 2O 6+H]的计算值461.3实验值461.4。
化合物3(E)-13： 1H-NMR(600MHz,d 6-DMSO)δ H 0.635(m,1H),0.876-0.842(m,4H),0.891-0.884(m,3H),1.231(s,2H),1.269-1.123(m,1H),1.331(s,3H),1.398(m,1H),1.7-1.594(m,3H),1.767-1.728(m,2H),2.001-1.967(m,2H),2.749(m,2H),3.982(m,1H),4.163-4.139(m,1H),4.271-4.262(m,2H),4.409-4.405(m,1H),4.590-4.568(m,1H),5.704(s,1H),6.517-6.501(d,1H),6.778-6.757(m,1H),10.528(s,1H),10.796(s,1H)； 13C(600MHz,d 6-DMSO)δ C 13.26,14.55,18.34,23.57,33.87,33.89,34.35,36.72,42.83,43.49,43.63,46.94,52.37,55.74,56.97,70.24,89.95,96.93,103.65,112.29,113.74,120.33,145.94,149.03,156.86,159.73；LRMS(ES+)[C 25H 36N 2O 6+H]的计算值461.3实验值461.4。
实施例14
(2E)-2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-氟-11,16,17-三羟基-3-(羟基亚氨基)-10,13-二甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊烷[a]菲仑-17-基)-2-(羟基亚氨基)丙酸乙酯
Figure PCTCN2021081519-appb-000030
按照上文一般的合成方法中合成路线I、II中所示的方法，用合适的起始原料制备化合物14，并分离得到(3Z)-14和(3E)-14。
化合物3(Z)-14: 1H-NMR(600MHz,d 6-DMSO)δ H 0.728(m,1H),0.879-0.854(m,4H),1.211-1.199(m,3H),1.284-1.187(m,1H),1.347(s,3H),1.611-1.597(m,1H),1.783-1.774(m,2H),1.998-1.972(m,2H),2.399-2.367(m,2H),2.798(m,2H),3.873(m,1H),4.161-4.148(m,2H),4.376-4.363(m,1H),4.411-4.402(m,1H),5.223(s,1H),5.416(m,1H),6.114-6.093(m,1H),6.358-6.331(d,1H),6.438(s,1H),10.571(s,1H),10.795(s,1H)； 13C(600MHz,d 6-DMSO)δ C 10.32,18.21,23.32,23.57,27.46,33.89,33.94,34.29,39.91,43.50,43.71,47.08,50.81,56.69,70.81,82.34,92.73,100.21,104.84,121.60,141.71,148.77,159.72,161.45；LRMS(ES+)[C 24H 33F 1N 2O 7+H]的计算值481.2实验值481.3。
化合物3(E)-14： 1H-NMR(600MHz,d 6-DMSO)δ H 0.731(m,1H),0.872-0.835(m,4H),1.208-1.198(m,3H),1.253-1.119(m,1H),1.329(s,3H),1.607-1.592(m,1H),1.765-1.738(m,2H),2.001-1.969(m,2H),2.334-2.359(m,2H),2.787(m,2H),3.897(m,1H),4.154-4.123(m,2H),4.272-4.259(m,1H),4.406-4.401(m,1H),5.219(s,1H),5.408(m,1H),5.704(s,1H),6.511-6.502(d,1H),6.774-6.758(m,1H),10.523(s,1H),10.798(s,1H)； 13C(600MHz,d 6-DMSO)δ C 10.29,18.24,23.34,23.56,27.45,33.88,33.95,34.31,39.92,43.49,43.69,47.05,50.83,56.68,70.79,82.36,92.72,100.22,112.23,113.74,145.95,149.07,156.86,159.73；LRMS(ES+)[C 24H 33F 1N 2O 7+H]的计算值481.2实验值481.3。
实施例15
(8S,9R,10S,11S,13S,14S,16S,17R)-9-氟-11-羟基-17-((E)-2-羟基-1-(羟基亚氨基)乙基)-3-(羟基亚氨基)-10,13,16-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊酸菲-17-基丁酸盐
Figure PCTCN2021081519-appb-000031
按照上文一般的合成方法中合成路线I、II中所示的方法，用合适的起始原料制备化合物15，并分离得到(3Z)-15和(3E)-15。
化合物3(Z)-15: 1H-NMR(600MHz,d 6-DMSO)δ H 0.631(m,1H),0.872-0.833(m,7H),1.109-0.998(m,3H),1.249-1.119(m,1H),1.331(s,3H),1.601-1.597(m,1H),1.665-1.621(m,2H),1.754-1.718(m,2H),1.998 -1.975(m,2H),2.136-1.109(m,1H),2.322-2.317(m,2H),2.603-2.524(m,2H),4.145-4.122(m,1H),4.275-4.227(m,2H),4.403-4.396(m,1H),4.589-4.560(m,1H),6.113-6.086(m,1H),6.359-6.324(d,1H),6.448(s,1H),10.578(s,1H),10.799(s,1H)； 13C(600MHz,d 6-DMSO)δ C 14.11,17.21,18.25,18.46,23.52,23.66,31.62,32.49,32.79,36.32,40.11,43.46,43.62,47.87,51.12,55.72,67.77,88.91,100.01,104.83,121.67,141.72,148.75,159.71,161.48,172.13；LRMS(ES+)[C 26H 37FN 2O 6+H]的计算值493.3实验值493.2。
化合物3(E)-15： 1H-NMR(600MHz,d 6-DMSO)δ H 0.629(m,1H),0.873-0.834(m,7H),1.107-0.997(m,3H),1.246-1.117(m,1H),1.322(s,3H),1.602-1.599(m,1H),1.661-1.618(m,2H),1.755-1.721(m,2H),1.996-1.972(m,2H),2.133-1.107(m,1H),2.317-2.311(m,2H),2.597-2.493(m,2H),4.142-4.120(m,1H),4.272-4.225(m,2H),4.404-4.395(m,1H),4.588-4.571(m,1H),5.683(s,1H),6.507-6.494(d,1H),6.770-6.758(m,1H),10.526(s,1H),10.801(s,1H)； 13C(600MHz,d 6-DMSO)δ C 14.09,17.24,18.23,18.44,23.41,23.64,31.64,32.47,32.75,36.33,40.08,43.42,43.63,47.84,51.11,55.74,67.69,88.90,99.98,112.19,113.75,145.93,149.13,156.83,159.74,172.11；LRMS(ES+)[C 26H 37FN 2O 6+H]的计算值493.3实验值493.2。
实施例16
(8S,9S,10R,11S,13S,14S,17R)-11-羟基-3-(羟基亚氨基)-17-((E)-1-(羟基亚氨基)乙基)-10,13-二甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊烷[a]菲-17-基丙酸盐
Figure PCTCN2021081519-appb-000032
按照上文一般的合成方法中合成路线I、II中所示的方法，用合适的起始原料制备化合物16，并分离得到(3Z)-16和(3E)-16。
化合物3(Z)-16: 1H-NMR(600MHz,d 6-DMSO)δ H 0.628(m,1H),0.868-0.835(m,4H),1.226-1.213(m,3H),1.253-1.118(m,1H),1.325(s,3H),1.398-1.364(m,1H),1.606-1.590(m,2H),1.760-1.715(m,2H),1.998-1.972(m,2H),2.339-2.297(m,2H),2.606-2.527(m,2H),2.755(m,1H),3.037(s,3H),4.273-4.224(m,1H),4.402-4.394(m,1H),6.118-6.086(m,1H),6.355-6.329(d,1H),6.447(s,1H),10.575(s,1H),10.794(s,1H)； 13C(600MHz,d 6-DMSO)δ C 9.97,10.92,18.34,23.56,23.62,28.06,31.67,32.50,32.72,39.98,43.58,43.69,46.24,50.94,56.95,67.72,95.58,104.84,121.59,141.72,148.77,159.71,161.48,173.36；LRMS(ES+)[C 24H 34N 2O 5+H]的计算值431.2实验值431.3。
化合物3(E)-16： 1H-NMR(600MHz,d 6-DMSO)δ H 0.629(m,1H),0.870-0.834(m,4H),1.224-1.210(m,3H),1.250-1.121(m,1H),1.322(s,3H),1.375-1.363(m,1H),1.603-1.595(m,2H),1.755-1.709(m,2H),2.002-1.975(m,2H),2.331-2.295(m,2H),2.603-2.532(m,2H),2.745(m,1H),3.035(s,3H),4.271-4.228(m,2H),4.403-4.398(m,1H),5.704(s,1H),6.515-6.501(d,1H),6.776-6.758(m,1H),10.520(s,1H),10.791(s,1H)； 13C(600MHz,d 6-DMSO)δ C 9.98,10.89,18.33,23.46,23.61,28.04,31.63,32.46,32.84,39.97,43.54,43.66,46.20,50.92, 56.97,67.74,95.57,112.19,113.73,145.97,149.08,156.85,159.71,173.34；LRMS(ES+)[C 24H 34N 2O 5+H]的计算值431.2实验值431.3。
实施例17
(6S,8S,9S,10R,11S,13S,14S,17R,E)-11-羟基-17-((E)-2-羟基-1-(羟基亚氨基)乙基)-3-(羟基亚氨基)-6,10,13-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊烷[a]菲-17-基戊酸盐
Figure PCTCN2021081519-appb-000033
按照上文一般的合成方法中合成路线I、II中所示的方法，用合适的起始原料制备化合物17，并分离得到(3Z)-17和(3E)-17。
化合物3(Z)-17: 1H-NMR(600MHz,d 6-DMSO)δ H 0.628(m,1H),0.869-0.833(m,4H),0.942-0.921(m,3H),1.053-1.033(d,3H),1.253-1.117(m,1H),1.325(s,3H),1.387-1.334(m,2H),1.498-1.424(m,1H),1.604-1.588(m,2H),1.755-1.702(m,4H),1.996-1.971(m,2H),2.429-2.402(m,2H),2.634-2.532(m,1H),2.789(m,1H),4.160-4.129(m,1H),4.272-4.227(m,2H),4.403-4.396(m,1H),4.591-4.562(m,1H),6.115-6.089(m,1H),6.353-6.331(d,1H),6.446(s,1H),10.575(s,1H),10.794(s,1H)； 13C(600MHz,d 6-DMSO)δ C 13.92,18.34,18.61,22.37,23.57,23.61,27.59,31.65,32.57,32.74,33.98,40.13,43.52,43.69,45.02,50.99,56.32,56.95,67.63,89.34,104.83,121.60,141.72,148.75,159.73,161.48,173.24；LRMS(ES+)[C 27H 40N 2O 6+H]的计算值489.3实验值489.4。
化合物3(E)-17： 1H-NMR(600MHz,d 6-DMSO)δ H 0.623(m,1H),0.874-0.846(m,4H),0.940-0.918(m,3H),1.033-1.018(d,3H),1.252-1.120(m,1H),1.326(s,3H),1.385-1.327(m,2H),1.495-1.443(m,1H),1.603-1.592(m,2H),1.762-1.701(m,4H),2.002-1.958(m,2H),2.411-2.387(m,2H),2.514(m,1H),2.786(m,1H),4.156-4.125(m,1H),4.262-4.230(m,2H),4.410-4.405(m,1H),4.590-4.568(m,1H),5.704(s,1H),6.516-6.500(d,1H),6.781-6.758(m,1H),10.523(s,1H),10.795(s,1H)； 13C(600MHz,d 6-DMSO)δ C 13.91,18.29,18.60,22.35,23.37,23.52,27.61,31.69,32.58,32.75,33.96,40.14,43.51,43.67,45.03,50.98,56.33,56.96,67.71,89.28,112.21,113.76,145.94,149.08,156.85,159.73,173.22；LRMS(ES+)[C 27H 40N 2O 6+H]的计算值489.3实验值489.4。
实施例1-17所制备的化合物具有较强的抗痛风药效。具体实验如下。其中，以下实验所用实施例化合物均为各实施例制备的化合物的3位肟基团顺式、反式两种构型化合物等比例(1:1)混合物。
实验1
痛风是人类特有的疾病，痛风性关节炎是尿酸钠(MSU)沉积于局部关节组织引起的炎症反应。由于部分哺乳动物如鼠、兔等体内的嘌呤代谢途径与人类不同，所以无法从干扰嘌呤代谢紊乱的方法来构建痛风性关节炎的模型，故造成痛风性关节炎最直接的方法就是在模型动物的关节腔内直接注射MSU，该模型 仅用来模拟痛风的局部关节炎症，适用于局部关节炎症状的观察，是目前筛选痛风药物抗炎作用的常见方法，具有稳定、易操作等优点。(参考文献：李娜,华龙,袁慧.痛风动物模型的研究进展[J].医学理论与实践,2016(24).)
采用尿酸钠(MSU)诱导的大鼠足跖肿胀模型检测以上实施例所制备的化合物的抗痛风效果，对照样品为甲泼尼龙。
实验方法：用MSU为致炎剂，注入大鼠后肢足跖皮下，造成足跖肿胀，然后测量足跖的容积，比较给药组和对照组足跖部的肿胀率和肿胀抑制率。实验当日先测各大鼠右后足容积(ml)，致炎后测大鼠右后足容积，以致炎前后足容积之差为肿胀度，并计算足肿胀抑制率(肿胀抑制率％＝(C-T)/C*100％；C＝对照组的肿胀率％，T＝治疗组的肿胀率％)。该法为筛选痛风药物抗炎作用的常用方法之一，模型稳定，易于操作。
1)给药剂量与抗痛风效果呈现正相关，具体实验结果如下：
Figure PCTCN2021081519-appb-000034
2)在给大鼠足跖皮下注射MSU前一周给予大鼠不同剂量受试药物，灌胃给药，每天1次，连续7d。末次给药前标记并测定右后足周长，取两次测量的平均值为准。末次给药末次给药1h后，除空白对照组，其余各组动物给2％MSU 50μL，于致炎后1h测定足周长。在给予小鼠90mg/kg的甲泼尼龙，以上实施例化合物的结果如下：
Figure PCTCN2021081519-appb-000035
Figure PCTCN2021081519-appb-000036
本实验在给SD大鼠足跖皮下注射MSU前一周连续给予大鼠不同剂量的化合物，试验结果表明，以上实施例化合物的肿胀抑制率(％)在64.65％-99.74％范围内，且在安全剂量内，随着给药剂量的不断加大，化合物抗痛风的效果越强。以上实施例化合物与甲泼尼龙的缓解痛风症状肿胀抑制率显著高于甲泼尼龙(53.83％)，且取代双肟基延长其体内代谢周期，具有较为长效的缓解痛风效果。
实验2
实施例1-17所制备的化合物具有较强的抗炎药效。
采用角叉菜胶致小鼠足肿胀模型检测以上实施例所制备的化合物的抗炎效果，对照样品为甲泼尼龙：
角叉菜胶致小鼠足肿胀模型是一个常用于评价或筛选药物抗炎作用的经典的急性炎症模型，当给小鼠足跖内注射角叉菜胶时能使大鼠局部毛细血管扩张、血管通透性增高、渗出、水肿等一系列类似于人体急性炎症的反应，故该模型在新药评价中应用非常广泛。
实验方法参考文献：杨欢,程笑,王月华,杜冠华.秦皮甲素对角叉菜胶致小鼠足肿胀及炎症的作用[J].中国新药杂志,2016(25):2322。
实验当日先测各小鼠右后足周长(cm)，致炎后测小鼠右后足周长，以致炎前后足周长之差为肿胀度，并计算足肿胀抑制率(肿胀抑制率％＝(C-T)/C*100％；C＝对照组的肿胀率％，T＝治疗组的肿胀率％)。
1)给药剂量与抗炎效果呈现正相关，具体结果如下：
Figure PCTCN2021081519-appb-000037
Figure PCTCN2021081519-appb-000038
2)灌胃给药，每天1次，连续7d。末次给药前标记并测定右后足周长，取两次测量的平均值为准。末次给药30min后，于小鼠右后足踝部注射20μL/只0.5％的角叉菜胶致炎，于致炎后180min测定足周长。在给予小鼠130mg/kg的甲泼尼龙，以上实施例化合物的结果如下：
Figure PCTCN2021081519-appb-000039
本实验在给ICR小鼠足底注射0.5％角叉菜胶前一周连续给予小鼠不同剂量化合物，试验结果表明，以上实施例化合物的肿胀抑制率(％)在61.34％-96.44％范围内，且在安全剂量内，随着给药剂量的不断加大，化合物抗炎的效果越强；以上实施例所制备的化合物抑制足部肿胀效果优于甲泼尼龙(47.64％)，且取代双肟基延长其体内代谢周期，具有较为长效的抗炎效果。
从生化指标来看，在发生炎症反应时，糖皮质激素受体α(GRa)蛋白表达水平受到抑制，糖皮质激素受体β(GRb)蛋白表达水平受到促进，促炎因子TNF-α蛋白表达大量升高，炎症保护因子IL-10的表达受到抑制。试验表明，以上实施例化合物会促进GRa蛋白表达，GRb蛋白表达，抑制TNF-α的升高，增加IL-10的量，直至恢复到正常水平。
实验3急性毒性试验
根据国家食品药品监督管理局2005年3月颁发的《化学药物急性毒性试验技术指导原则》进行实验的设计。给药剂量为：4g/kg、4.91g/kg、6.14g/kg、7.68g/kg、9.6g/kg、12g/kg、15g/kg(可根据实际试验结果调整剂量)，每个剂量组12只ICR小鼠。如果给药体积大于0.5ml，最好就分两次或多次给药(注：参照国标GB 15193.3-2014，若需要多次给药时，每次时间间隔4h～6h，给药前一天禁食)。急性毒性试验结果见下表：
死亡率(死亡数/12) 4g/kg 4.91g/kg 6.14g/kg 7.68g/kg 9.6g/kg 12g/kg 15g/kg
甲泼尼龙(p.o.) 0/12 0/12 0/12 1/12 3/12 5/12 7/12
实施例1化合物(p.o.) 0/12 0/12 0/12 0/12 0/12 0/12 0/12
实施例2化合物(p.o.) 0/12 0/12 0/12 0/12 1/12 4/12 6/12
实施例3化合物(p.o.) 0/12 0/12 0/12 0/12 0/12 0/12 1/12
实施例5化合物(p.o.) 0/12 0/12 0/12 0/12 1/12 2/12 4/12
实施例8化合物(p.o.) 0/12 0/12 0/12 0/12 0/12 0/12 1/12
实施例9化合物(p.o.) 0/12 0/12 0/12 0/12 0/12 0/12 2/12
实施例10化合物(p.o.) 0/12 0/12 1/12 1/12 3/12 4/12 5/12
实施例11化合物(p.o.) 0/12 0/12 0/12 0/12 0/12 0/12 0/12
实施例14化合物(p.o.) 0/12 0/12 0/12 0/12 1/12 1/12 3/12
实施例17化合物(p.o.) 0/12 0/12 0/12 0/12 0/12 0/12 0/12
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
工业实用性
本发明提供一种治疗痛风的化合物及其制备方法和用途。该化合物如式I所示。本发明公开了所述化合物的制备方法，以及在制备治疗或预防痛风的药物中的用途。本发明还公开了包含所述化合物的组合产品。本发明提供的化合物可用于治疗炎症和痛风，还可用于治疗癌症，具有较好的经济价值和应用前景。
Figure PCTCN2021081519-appb-000040

Claims (10)

  1. 式I化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物：
    Figure PCTCN2021081519-appb-100001
    其中，
    R 1为-H、(C 1-C 4)烷基或-CH 2-Ar；
    R 2为-H、(C 1-C 4)烷基或-CH 2-Ar；
    R 3为-H、-OH、卤素、-OC(＝O)-(CH 2)n-CH 3或-OC(＝O)-Ar；n为0-4的整数；
    R 4为-H、-OH、-OC(＝O)-(CH 2)m-CH 3或-OC(＝O)-Ar；m为0-4的整数；
    X和Y独立地选自H，-CH 3或卤素；
    W为H，-CH 3，或
    Figure PCTCN2021081519-appb-100002
    M和N独立地选自H，(C 1-C 4)烷基，-Ar(芳基)，杂芳基或苄基。
  2. 根据权利要求1所述的式I化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物，其中，
    R 1为-H或-CH 2CH 3；和/或，
    R 2为-H或-CH 2CH 3；和/或，
    R 3为-H、-OH、-Cl或-OAc、
    Figure PCTCN2021081519-appb-100003
    或-CH 2CH 3；和/或，
    R 4为-H、-OH、
    Figure PCTCN2021081519-appb-100004
    和/或，
    X为-H、-F或-Cl；和/或，
    Y为-H、-CH 3、-F或-Cl；和/或，
    W为-H、α-CH 3、β-CH 3、α-OH、β-OH、
    Figure PCTCN2021081519-appb-100005
  3. 根据权利要求1所述的式I化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物，其中，
    R 1为-H或-CH 2CH 3；和/或，
    R 2为-H或-CH 2CH 3；和/或，
    R 3为-OH或-OAc；和/或，
    R 4为-OH或-OAc；和/或，
    X为-H；和/或，
    Y为-H或-CH 3；和/或，
    W为-H。
  4. 式II化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或式II化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物：
    Figure PCTCN2021081519-appb-100006
    其中，R 1、R 2、R 3、X、Y、M、N的定义与权利要求1-3任一项相同；
    优选地，M和N独立地选自H，(C1-C4)烷基，-Ar，杂芳基或苄基。
  5. 结构如下的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或所述化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物 或水合物或多晶型物：
    Figure PCTCN2021081519-appb-100007
    Figure PCTCN2021081519-appb-100008
    Figure PCTCN2021081519-appb-100009
  6. 权利要求1所述式I化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物的制备方法，包括以下合成路线：
    Figure PCTCN2021081519-appb-100010
    Figure PCTCN2021081519-appb-100011
    其中，R 1、R 2、R 3、R 4、X、Y、W、M、N的定义与权利要求1-3任一项相同；
    R为直链饱和烷基，优选为直链饱和(C 1-C 12)烷基，更优选为直链饱和(C 1-C 4)烷基，例如甲基、乙基、正丙基或正丁基。
  7. 权利要求4所述式II化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或式II化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物的制备方法，包括以下合成路线：
    Figure PCTCN2021081519-appb-100012
    其中，R 1、R 2、R 3、X、Y、M、N的定义与权利要求1-3任一项相同；
    优选地，M和N独立地选自H，(C1-C4)烷基，-Ar，杂芳基或苄基。
  8. 权利要求1-5任一项所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或所述化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的 盐或溶剂化物或水合物或多晶型物在制备用于治疗或预防痛风的药物中的用途，或在制备用于治疗或预防炎症的药物中的用途；或在制备用于治疗或预防癌症(或肿瘤)的药物中的用途；优选地，所述药物还包括药学上可接受的辅料；
    其中，所述痛风优选为急性期痛风；
    所述炎症优选是与急性期痛风相关的炎症，更优选为与炎症反应通路中糖皮质激素受体GRa、糖皮质激素受体GRb、促炎因子TNF-α、炎症保护因子IL-10的表达起到调节作用中任一种或几种相关的炎症；
    所述癌症优选自人肺腺癌、人急性淋巴母细胞白血病、人B细胞淋巴瘤、人乳腺癌、人恶性胶质母细胞瘤、人肝癌、人宫颈癌、人非小细胞肺癌、人骨肉瘤、人结肠癌、人成骨肉瘤、人Burkitt`s淋巴瘤中任一种或几种；
    进一步优选地，所述用途中所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或所述化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物作为唯一活性成分或联合其它具有生物活性的物质。
  9. 用于治疗或预防痛风或炎症或癌症(或肿瘤)的组合产品，包括权利要求1-5任一项所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或所述化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物中的一种或几种；优选还包括药学上可接受的辅料；和/或所述组合产品为试剂盒。
  10. 治疗或预防痛风或炎症或癌症的方法，包括：对有需要的受试者或患者通过口服或非口服途径给予有效剂量的权利要求1-5任一项所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物形式；或所述化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，前药或其混合物的药学上可以接受的盐或溶剂化物或水合物或多晶型物，或权利要求9所述的组合产品；
    其中，所述痛风优选为急性期痛风；
    所述炎症优选为与炎症反应通路中糖皮质激素受体GRa、糖皮质激素受体GRb、促炎因子TNF-α、炎症保护因子IL-10的表达起到调节作用中任一种或几种相关的炎症；
    所述癌症优选自人肺腺癌、人急性淋巴母细胞白血病、人B细胞淋巴瘤、人乳腺癌、人恶性胶质母细胞瘤、人肝癌、人宫颈癌、人非小细胞肺癌、人骨肉瘤、人结肠癌、人成骨肉瘤、人Burkitt`s淋巴瘤中任一种或几种。
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