WO2023088308A1 - 一种具有抗耐药性的抗菌化合物 - Google Patents

一种具有抗耐药性的抗菌化合物 Download PDF

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WO2023088308A1
WO2023088308A1 PCT/CN2022/132275 CN2022132275W WO2023088308A1 WO 2023088308 A1 WO2023088308 A1 WO 2023088308A1 CN 2022132275 W CN2022132275 W CN 2022132275W WO 2023088308 A1 WO2023088308 A1 WO 2023088308A1
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compound
formula
group
alkyl
pharmaceutical composition
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French (fr)
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王路
孟月垒
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石家庄迪斯凯威医药科技有限公司
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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
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to but not limited to the technical field of medicinal chemistry, and in particular relates to a novel steroid compound and its pharmaceutical composition and use.
  • NF- ⁇ B is related to various diseases of the human body.
  • Chinese patent CN1246328 discloses an ester-forming structure of this compound for treating acne, seborrheic dermatitis, alopecia, benign prostatic hyperplasia and cancer.
  • the invention discloses a steroid derivative.
  • the compound has antibacterial and antifungal effects, and has good resistance to drug resistance. Studies have shown that the inventive compound exhibits better proliferation-promoting activity on HHDPC cells, which indicates that it has a good effect of inhibiting androgenetic alopecia.
  • the compounds of the present invention have a specific distribution in skin tissue when administered dermally, while systemic exposure is low.
  • the present invention provides a compound represented by the following formula (I 0 ) or a hydrate, solvate, isotopic derivative, diastereomer or pharmaceutically acceptable salt thereof:
  • n 0, 1, 2, 3, 4 or 5;
  • X 1 , X 2 and X 3 are each independently O or S;
  • R is selected from the following groups substituted or unsubstituted by group A: C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 carbon Cyclic group, C2-C10 heterocyclic group, C6-C12 aryl group;
  • R is selected from the following groups: C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 carbocyclyl, C2-C10 hetero Cyclic group, C6-C12 aryl group;
  • the group A is selected from: hydroxyl
  • R 4 , R 5 and R 6 are independently selected from C1-C8 alkyl groups, or R 4 and R 5 are connected to form a ring;
  • B - is selected from organic anions and inorganic anions.
  • the present invention provides a compound represented by formula (II 0 ) or a hydrate, solvate, isotopic derivative, diastereomer or pharmaceutically acceptable salt thereof:
  • the present invention provides a compound represented by formula (III 0 ) or a hydrate, solvate, isotopic derivative, diastereomer or pharmaceutically acceptable salt thereof:
  • the present invention provides a compound represented by formula (IV 0 ) or a hydrate, solvate, isotopic derivative, diastereomer or pharmaceutically acceptable salt thereof:
  • the present invention provides a compound represented by formula (I) or a hydrate, solvate, isotopic derivative, diastereomer or pharmaceutically acceptable salt thereof:
  • n 0, 1, 2, 3, 4 or 5;
  • X 1 , X 2 and X 3 are each independently O or S;
  • R is selected from the following groups: C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 carbocyclyl, C2-C10 hetero Cyclic group, C6-C12 aryl group;
  • R is selected from the following groups: C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 carbocyclyl, C2-C10 hetero Cyclic group, C6-C12 aryl group;
  • the group A is selected from: hydroxyl group, monoalkylamine group and dialkylamine group.
  • n is 0; in some embodiments, n is 1 or 2; in some embodiments, n is 3, 4 or 5.
  • X 1 , X 2 and X 3 are all O, except when n is 0 and R 2 is hydrogen; in some embodiments, one of X 1 , X 2 and X 3 is S , and the rest are O; in some embodiments, two of X 1 , X 2 and X 3 are S, and the remaining one is O.
  • R 1 is not substituted by group A; in some specific embodiments, R 1 is selected from C1-C10 alkyl or C1-C10 alkoxy, preferably, R 1 is selected from C1 -C10 alkyl; In some specific embodiments, R is selected from the following groups: C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 carbocyclyl, C2-C10 heterocycle Base, C6-C12 aryl group;
  • R is substituted by group A; in some specific embodiments, R is selected from C1-C10 alkyl or C1-C10 alkoxy substituted by group A, preferably, R 1 is selected from C1-C10 alkyl substituted by group A; in some specific embodiments, R 1 is selected from the following groups substituted by group A: C2-C10 alkenyl, C2-C10 alkynyl , C3-C10 carbocyclic group, C2-C10 heterocyclic group, C6-C12 aryl group; wherein the group A is selected from: hydroxyl, R 4 , R 5 and R 6 are independently selected from C1-C8 alkyl groups, or R 4 and R 5 are connected to form a ring; B - is selected from organic anions and inorganic anions.
  • R2 can be substituted with group A; in some embodiments, R2 is unsubstituted with group A. In some embodiments, when R 2 is hydrogen and n is 0, at this time, X 1 , X 2 and X 3 are not O at the same time;
  • R is selected from the following groups substituted or unsubstituted by group A: C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkoxycarbonyloxy, C1-C10 Alkylcarbonyloxy, C1-C10 alkylaminocarbonyloxy;
  • R 2 is selected from C1-C10 alkyl substituted by hydroxy; In some embodiments, R 2 is selected from the following groups substituted by dialkylamino: C1-C10 alkyl, C1-C10 Alkoxy, C1-C10 alkoxycarbonyloxy, C1-C10 alkylcarbonyloxy, C1-C10 alkylaminocarbonyloxy;
  • R is selected from the following groups: C1-C10 alkyl, C1-C10 alkoxy, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 carbocyclyl , C2-C10 heterocyclic group, C6-C12 aryl group; preferably, R 3 is selected from C1-C10 alkyl; more preferably, R 3 is selected from the following groups: methyl, ethyl, propyl ,Isopropyl.
  • group A is hydroxyl; in some embodiments, group A is Wherein, R 4 , R 5 and R 6 are independently selected from C1-C8 alkyl groups, or R 4 and R 5 are connected to form a ring; B - is selected from organic anions and inorganic anions.
  • the alkyl group in the monoalkylamine group or dialkylamine group is an alkane group with 1 to 8 carbon atoms, and the alkyl group is inserted into -NH- or -NH2 at any reasonable position
  • Groups of groups including but not limited to methylamino, propylamino, isopropylamino, diethylamino, di-n-propylamino, diisopropylamino and the like.
  • amine group here is a quaternary ammonium salt.
  • the solvate refers to a complex formed by the interaction between the compound and a pharmaceutically acceptable solvent
  • the pharmaceutically acceptable solvent includes ethanol, isopropanol, and acetic acid.
  • the C1-C10 alkyl group refers to a linear or branched saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms in the molecule. Including but not limited to methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, heptyl, 3-methylheptyl, etc.
  • the C1-C10 alkoxy group refers to a group in which a saturated aliphatic hydrocarbon group containing 1 to 10 carbon atoms inserts an oxygen atom at any reasonable position in the molecule, including but not limited to Methoxy, ethoxy, propoxy, 2-ethylethoxy, ethoxybutyl, etc.
  • the C2-C10 alkenyl group refers to an aliphatic hydrocarbon group containing at least one unsaturated carbon-carbon double bond in a molecule composed of 2 to 10 carbon atoms and hydrogen atoms, including straight chain, Branched or cyclic olefins, including but not limited to propenyl, 2-methyl-2-butenyl, 1-hexenyl, dipentenyl, 5-methyl-2-heptene, 4-vinyl -1-cyclohexenyl, etc.
  • the C2-C10 alkynyl group refers to an aliphatic hydrocarbon group consisting of 2 to 10 carbon atoms and hydrogen atoms and containing at least one unsaturated carbon-carbon triple bond, including straight chain and branched chain or cyclic alkynes, including but not limited to propynyl, 2-pentynyl, 3-hexynyl, 2,4-hexadiynyl, 3-cyclohexylpropynyl, prop-1-ynyl ring Propanyl, 5-methyl-2-hexenyl, etc.
  • the C3-C10 carbocyclic group refers to a monocyclic or condensed polycyclic saturated or unsaturated cyclic hydrocarbon group containing 3 to 10 carbon atoms, including but not limited to cyclopropyl , cyclopentyl, bicyclo[3.2.0]heptyl, 1-methyl-1-cyclohexenyl, etc.
  • the C2-C10 heterocyclic group refers to a saturated or unsaturated cyclic group containing 2-10 carbon atoms and 1-4 heteroatoms in the molecule. Including but not limited to cycloethoxy, aziridinyl, tetrahydropyrrolyl, piperidinyl, hexahydropyridazinyl, dihydropyridyl, morpholinyl and the like.
  • the C6-C12 aryl group refers to an unsaturated aromatic group containing 6 to 12 carbon atoms in the molecule with a single ring or fused polycyclic rings, and the fused rings can be Saturated or unsaturated, including but not limited to phenyl, naphthyl, benzocycloheptyl and the like.
  • the C1-C10 alkoxycarbonyloxy, C1-C10 alkylcarbonyloxy, and C1-C10 alkylaminocarbonyloxy all refer to the alkyl group except the carbonyl group in the structure.
  • the base part has 1 to 10 carbon atoms, and the alkyl group of 1 to 10 carbon atoms is as described above.
  • the compounds provided by the invention are selected from the following compounds:
  • the steroid derivatives can be prepared from deoxycortisone or its living organisms and thio reagent The reaction is obtained, wherein R is a C1-C3 alkyl group, and R1 is as previously described.
  • said thio reagent It was obtained by referring to the synthesis method in the literature (J Org Chem, 1989, 54, 906-910).
  • Another aspect of the present invention is to provide a pharmaceutical composition containing a safe and effective amount of the above-mentioned compound or its hydrate, solvate, isotope derivative, diastereoisomer and a pharmaceutically acceptable carrier, which can be used clinically Administration to humans and other mammals.
  • the mass ratio of the compound of the present invention in the pharmaceutical composition is between 0.01% and 80%.
  • the administration route of the pharmaceutical composition of the present invention includes oral administration, injection, nasal cavity administration, pulmonary administration, gastrointestinal tract administration, external drops, transdermal absorption and the like.
  • the preferred dosage form is external ointment, external patch and external spray.
  • the pharmaceutical composition can be obtained through solutions, tablets, capsules, injections, powders, pills, powders, suspensions, pastes, ointments, cataplasms, aerosols, sprays, emulsions, Latex, gel, film transdermal administration.
  • the third aspect of the present invention is that the compounds described in the present invention or their pharmaceutical compositions have good antibacterial and fungal activity, and drug resistance will not occur substantially, and can effectively prevent and/or treat bacterial infections or Diseases associated with fungal infections.
  • the bacterial infection includes infection caused by Gram-positive bacteria or Gram-negative bacteria.
  • Gram-positive bacteria include but not limited to Staphylococcus (Staphylococcus), Streptococcus (Streptococcus), Bacillus anthracis (Bacillus anthracis), Tetanus (Bacillus tetanus);
  • Gram-negative bacteria include but not limited to Limited to Escherichia coli (Escherichia coli, P.aeruginosa);
  • the fungal infection is caused by fungi including but not limited to Candida albicans (Monilia albican).
  • the compound of the present invention is a kind of non-hormonal steroid regulator of NF- ⁇ B, which can be used for treating and preventing skin-related diseases or muscular atrophy diseases, including traumatic brain injury, spinal cord injury and other diseases.
  • Known HHDPC cell proliferation-promoting experiment can be used for preliminary evaluation compound to the inhibitory effect of androgenetic alopecia in vitro, and the compound of the present invention shows better pro-proliferative activity to HHDPC cell, it can be known that the compound of the present invention has better inhibition of androgenetic alopecia role.
  • the compounds of the present invention have the effect of treating acne and some other androgen-related diseases or cancers;
  • the androgen-related diseases include but not limited to seborrheic dermatitis, alopecia, alopecia, prostatic hyperplasia;
  • the cancers include but It is not limited to prostate cancer, bladder cancer, and the like.
  • the compound of the present invention has better exposure in the skin tissue when administered through the skin, relatively less in the distribution in the fat tissue, and is basically not detected in the blood, which shows that the compound of the present invention is in the skin tissue when administered through the skin There is a specific distribution, while the systemic exposure is very low.
  • Embodiment 1 the synthesis of AMX881 and AMX882
  • Embodiment 2 the synthesis of AMX883
  • Embodiment 3 the synthesis of AMX886
  • Embodiment 4 the synthesis of AMX8814
  • Embodiment 5 the synthesis of compound AMX8815 and AMX8817
  • Embodiment 6 the synthesis of compound AMX8819 and AMX8820
  • Embodiment 7 the synthesis of compound AMX8821, AMX8822 and AMX8823
  • Embodiment 8 Bacterial inhibition rate evaluation experiment
  • the substance to be tested was dissolved in DMSO, and diluted to 32 ⁇ g/ml with culture medium for later use.
  • CMCC (B) 26003 The frozen standard strain of Staphylococcus aureus (CMCC (B) 26003) was dissolved at room temperature, inoculated in LB solid medium, and cultured overnight at 37°C. On the next day, 2-3 single colonies that grew well were picked and cultured with shaking in MH broth medium to adjust the concentration of the bacterial suspension to 1.0 ⁇ 10 6 CFU/ml. Add the bacterial solution into the 96-well plate, add the same concentration and the same volume of the bacterial suspension and the same volume of the dilution of the test substance to each well, and set up a blank control group. Cultivate at 37°C for 24 hours, use a microplate reader to detect at a wavelength of 265nm, and calculate the bacterial inhibition rate, as shown in Table 1:
  • AMX886 95.1 AMX8815 96.7 AMX8824 96.2 AMX887 94.2 AMX8816 96.2 AMX8825 95.3 AMX888 94.5 AMX8817 95.8 AMX8826 94.7 AMX889 95.3 AMX8818 96.5 AMX8827 96.3
  • Embodiment 9 the mensuration of minimum inhibitory concentration (MIC)
  • Bacterial suspension preparation take frozen Escherichia coli (CMCC (B) 44102), Staphylococcus aureus (CMCC (B) 26003), Pseudomonas aeruginosa (CMCC10104) and beta-hemolytic streptococcus (CMCC (B) ) 32210) standard strains were dissolved at room temperature, inoculated in LB solid medium, and cultured overnight at 37°C. On the next day, pick 2 to 3 single colonies that grew well and place them in the MH broth medium for shaking culture to adjust the concentration of the bacterial suspension to 1.0 ⁇ 10 6 CFU/ml for later use.
  • CMCC Bacterial suspension preparation: take frozen Escherichia coli (CMCC (B) 44102), Staphylococcus aureus (CMCC (B) 26003), Pseudomonas aeruginosa (CMCC10104) and beta-hemolytic streptococcus (CMCC (B)
  • Preparation of fungal suspension Inoculate standard Candida albicans (JLC30364) in Sabao weak broth medium, shake and culture for 24-48 hours, microscopic examination proves that Candida has produced pseudohyphae, and then make spore liquid. Adjust the concentration of the fungal suspension to 1.0 ⁇ 10 6 CFU/ml of the bacterial solution for later use.
  • the experiment adopts the microdilution method to measure, observes the result, takes the minimum drug concentration that completely inhibits bacterial growth in the small hole as the minimum inhibitory concentration of the antibacterial drug to the bacterium, that is, the MIC value.
  • the results are shown in Table 2:
  • the compound of the present invention has an MIC of 0.25 ⁇ g/ml ⁇ 0.5 ⁇ g/ml for Escherichia coli (CMCC (B) 44102); and a MIC of 0.125 ⁇ g/ml ⁇ 0.25 for Staphylococcus aureus (CMCC (B) 26003).
  • MIC for Pseudomonas aeruginosa (CMCC10104) is 0.25 ⁇ g/ml ⁇ 0.5 ⁇ g/ml; MIC for beta-hemolytic streptococcus (CMCC(B)32210) is 0.125 ⁇ g/ml ⁇ 0.5 ⁇ g /ml; the MIC for Candida albicans (JLC30364) is between 1.0 ⁇ g/ml and 2.0 ⁇ g/ml, which indicates that the compound of the present invention has good antibacterial and fungal activities.
  • Embodiment 10 sub-inhibitory concentration (SMIC) drug-induced bacterial drug resistance test result
  • each bacterial strain corresponding to each drug determines the sub-inhibitory concentration (SMIC) value of each drug solution.
  • SMIC sub-inhibitory concentration
  • Two test strains were cultured in 4mL test tubes with MH broth medium, and the inoculated bacteria amount was about 5.0 ⁇ 10 5 CFU/ml.
  • the drugs were prepared so that each strain was co-cultured at 37° C. under the SMIC concentration of the drug. Co-cultured for 18-24 hours, recorded as the first generation. Then take an appropriate amount of bacterial solution from each well and dilute it to a concentration of 5.0 ⁇ 10 5 CFU/ml, inoculate it in the second test tube of the same group, and record it as the second passage, and repeat the passage in this way.
  • Bacteria were cultured 15 times (generations) for each medicinal solution, and then the MIC value of each medicinal solution under the action of the SMIC medicinal solution was detected every 5 generations. The results are shown in Table 3 and Table 4:
  • the results showed that the positive control drugs levofloxacin and fluconazole induced drug resistance to the experimental strains after MIC induction ⁇ MIC induction , combined with the CLSL standard, it was determined that drug resistance had been produced, and the compound of the present invention was treated In the 15 generations of induced drug resistance culture, the MIC value remained basically unchanged within the measured range, and no drug resistance was produced.
  • Embodiment 11 HHDPC cell proliferation-promoting experiment
  • HHDPC cells in the logarithmic growth phase were digested with trypsin, prepared into a cell suspension with a concentration of 1-10 ⁇ 104 cells/ml, inoculated in a 96-well plate with 3000-5000 cells per well, and added 100 ⁇ l to each well. Incubate overnight at 37°C and 5% CO2 to adhere to the wall, and fill the edge wells with sterile PBS. After observing the cell attachment, 10 ⁇ M of the test compound was added and incubated for 48 hours, and a blank control group was set at the same time. 20 ⁇ l of MTT solution (5 mg/ml, ie 0.5% MTT) was added to all the wells, and incubated in the incubator for 4 hours.
  • MTT solution 5 mg/ml, ie 0.5% MTT
  • the research results show that the compound of the present invention exhibits better proliferation-promoting activity on HHDPC cells. It is known that the HHDPC cell proliferation-promoting experiment can be used to preliminarily evaluate the inhibitory effect of the compound on androgenetic alopecia in vitro, so it can be seen that the compound of the present invention has better inhibitory effect on androgenetic alopecia.
  • Embodiment 12 skin administration pharmacokinetic test
  • Guangxi Bama miniature pigs (grade: common, age: 5-8 months, sex: all male, weight: 12-14kg, production unit: Beijing Shichuang Century Miniature Pig Breeding Center, production license number: SCXK (Beijing ) 2018-0008) 9 rats were randomly divided into two groups A/B/C according to body weight, fasted overnight (12-16 hours) before administration.
  • the miniature pigs of all groups selected a marked area of 20 ⁇ 20 cm 2 on the back, shaved off the hair, cleaned it, and marked 6 drug administration sites, each with a size of 5 ⁇ 8 cm 2 , for each sample The skin sampling locations corresponding to the time points.
  • each animal 0.2 mL of each administration site, a total of 1.0 mL of the test solution (1% dipropylene glycol solution) at 6 administration sites, wherein the 0h sampling point is not administered.
  • Group A was given dipropylene glycol solution of compound Clascoterone
  • group B was given dipropylene glycol solution of compound AMX8818
  • group C was given dipropylene glycol solution of compound AMX8826.
  • the animal was fixed for about 5 minutes. After the drug was basically absorbed on the skin, the gauze covered the administration area and fixed with medical adhesive tape.
  • Groups A, B and C were anesthetized by intramuscular injection of 5-10 mg ⁇ kg -1 Shutai 50 before administration and 10 minutes before the time point of 1, 2, 4, 8 and 24 hours after administration, respectively, and exfoliated layer.
  • Skin sample and fat sample collection Immediately use a skin biopsy device to collect skin samples with a diameter of 7 mm and a depth of 7-8 mm before administration and at the time points of 1, 2, 4, 8, and 24 hours after administration, and use them immediately Biological dressings fill wounds to stop bleeding. Skin samples were frozen at -20°C for 30 minutes, subcutaneous fat was separated and excess other tissues were removed, skin samples and fat samples were collected, washed 3 times with PBS, after washing, dried with filter paper, weighed and recorded, put into Store the samples in a collection tube at -90 to -60°C and transport them under dry ice.
  • Plasma samples 1 mL of whole blood was collected from the jugular vein before administration and at 0.5, 1, 2, 4, 8, 12, and 24 hours after administration, placed in EDTA-2K EP tubes for anticoagulation, and placed in wet ice Centrifuge (1500-1600g, 10min) within 30min to extract and separate plasma. Plasma samples are stored at -90 to -60°C for later analysis of biological samples. If the samples need to be rotated, they should be transported under dry ice.

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Abstract

一类甾体衍生物及其制备方法、药物组合物和用途，所述的甾体衍生物如式(I 0)所示，也包含该化合物的水合物、溶剂化物、同位素衍生物、非对映异构体或药学上可接受的盐；化合物表现出较好的抗菌活性，且对多种耐药菌有效。在皮肤给药时表现出很好的皮肤组织内的分布和很低的全身暴露量。

Description

一种具有抗耐药性的抗菌化合物 技术领域
本发明涉及但不限于药物化学技术领域，尤其涉及一种新型甾体化合物及其药物组合物和用途。
背景技术
NF-κB与人体多种疾病相关，中国专利CN1246328公开了一类该化合物成酯的结构，用于治疗痤疮、脂溢性皮炎、秃发症、前列腺增生和癌症。
尽管某些化合物在体外具有较好的活性，但由于化合物结构限制，在体内并不能表现出较好的治疗效果，或者不能满足某些给药途径的使用。对甾体类化合物进行结构修饰可在一定程度上调节甚至改变其作用；因此，开发新型结构的甾体类药物仍有必要。
我们对其结构优化的过程中，发现部分基团的改进使得该类化合物表现了以往未曾表现出的生物活性或作用。
发明内容
本发明公开了一种甾体衍生物，该化合物具有抗细菌和抗真菌等作用，且具有较好的抗耐药性。研究表明发明化合物对HHDPC细胞表现出较好的促增殖活性，这表明其具有很好的抑制雄激素脱发的作用。此外，本发明的化合物在皮肤给药时在皮肤组织中有特异性的分布，而全身暴露量却很低。
除本文另有特殊说明，本发明使用的专业术语均为本领域技术人员普遍了解的基本含义。
本发明提供一种如下(I 0)式所示的化合物或其水合物、溶剂化物、同位素衍生物、非对映异构体或药学上可接受的盐：
Figure PCTCN2022132275-appb-000001
式(I 0)中，n为0，1，2，3，4或5；
X 1、X 2和X 3各自独立的为O或S；
R 1选自基团A取代或未取代的下列基团：C1-C10的烷基、C1-C10的烷氧基、C2-C10的烯基、C2-C10的炔基、C3-C10的碳环基、C2-C10的杂环基、C6-C12的芳基；
R 2选自基团A取代或未取代的下列基团：氢、C1-C10的烷基、C1-C10的烷氧基、C1-C10的烷氧羰基氧基、C1-C10的烷基羰基氧基、C1-C10的烷氨基羰基氧基，或R 3-C(＝S)-O-，当n为0且R 2为氢时，X 1、X 2和X 3不同时为O；
R 3选自下列基团：C1-C10的烷基、C1-C10的烷氧基、C2-C10的烯基、C2-C10的炔基、C3-C10的碳环基、C2-C10的杂环基、C6-C12的芳基；
所述的基团A选自：羟基、
Figure PCTCN2022132275-appb-000002
其中，R 4、R 5和R 6各自独立地选自C1-C8的烷基，或R 4和R 5连接成环；B -选自有机阴离子、无机阴离子。
在一些实施方案中，本发明提供一种如式(II 0)所示的化合物或其水合物、溶剂化物、同位素衍生物、非对映异构体或药学上可接受的盐：
Figure PCTCN2022132275-appb-000003
式(II 0)中取代基的定义如式(I 0)所定义的。
在一些实施方案中，本发明提供一种如式(III 0)所示的化合物或其水合物、溶剂化物、同位素衍生物、非对映异构体或药学上可接受的盐：
Figure PCTCN2022132275-appb-000004
式(III 0)中取代基的定义如式(I 0)所定义的。
在一些实施方案中，本发明提供一种如式(IV 0)所示的化合物或其水合物、溶剂化物、同位素衍生物、非对映异构体或药学上可接受的盐：
Figure PCTCN2022132275-appb-000005
式(Ⅳ 0)中取代基的定义如式(I 0)所定义的。
在一些实施方案中，本发明提供一种如式(I)所示的化合物或其水合物、溶剂化物、同位素衍生物、非对映异构体或药学上可接受的盐：
Figure PCTCN2022132275-appb-000006
式(I)中，n为0，1，2，3，4或5；
X 1、X 2和X 3各自独立的为O或S；
R 1选自下列基团：C1-C10的烷基、C1-C10的烷氧基、C2-C10的烯基、C2-C10的炔基、C3-C10的碳环基、C2-C10的杂环基、C6-C12的芳基；
R 2选自基团A取代或未取代的下列基团：氢、C1-C10的烷基、C1-C10 的烷氧基、C1-C10的烷氧羰基氧基、C1-C10的烷基羰基氧基、C1-C10的烷氨基羰基氧基，或R 3-C(＝S)-O-，且当R 2为氢时，X 1、X 2和X 3不同时为O；
R 3选自下列基团：C1-C10的烷基、C1-C10的烷氧基、C2-C10的烯基、C2-C10的炔基、C3-C10的碳环基、C2-C10的杂环基、C6-C12的芳基；
所述的基团A选自：羟基、单烷基胺基、二烷基胺基。
在一些实施方案中，n为0；在一些实施方案中，n为1或2；在一些实施方案中，n为3、4或5。
在一些实施方案中，X 1、X 2和X 3均为O，但当n为0且R 2为氢时除外；在一些实施方案中，X 1、X 2和X 3中其中一个为S，其余为O；在一些实施方案中，X 1、X 2和X 3中其中两个为S，剩余一个为O。
在一些实施方案中，R 1未被基团A取代；在一些具体的实施方案中，R 1选自C1-C10的烷基或C1-C10的烷氧基，优选地，R 1选自C1-C10的烷基；在一些具体的实施方案中，R 1选自下列基团：C2-C10的烯基、C2-C10的炔基、C3-C10的碳环基、C2-C10的杂环基、C6-C12的芳基；
在一些实施方案中，R 1被基团A取代；在一些具体的实施方案中，R 1选自基团A取代的的C1-C10的烷基或C1-C10的烷氧基，优选地，R 1选自基团A取代的C1-C10的烷基；在一些具体的实施方案中，R 1选自基团A取代的下列基团：C2-C10的烯基、C2-C10的炔基、C3-C10的碳环基、C2-C10的杂环基、C6-C12的芳基；其中所述的基团A选自：羟基、
Figure PCTCN2022132275-appb-000007
Figure PCTCN2022132275-appb-000008
R 4、R 5和R 6各自独立地选自C1-C8的烷基，或R 4和R 5连接成环；B -选自有机阴离子、无机阴离子。
在一些实施方案中，R 2可被基团A取代；在一些实施方案中，R 2未被基团A取代。在一些实施方案中，R 2为氢且n为0时，此时，X 1、X 2和X 3不 同时为O；
在一些实施方案中，R 2选自基团A取代或未取代的下列基团：C1-C10的烷基、C1-C10的烷氧基、C1-C10的烷氧羰基氧基、C1-C10的烷基羰基氧基、C1-C10的烷氨基羰基氧基；
在一些实施方案中，R 2选自羟基取代的C1-C10的烷基；在一些实施方案中，R 2选自二烷基氨基取代的下列基团：C1-C10的烷基、C1-C10的烷氧基、C1-C10的烷氧羰基氧基、C1-C10的烷基羰基氧基、C1-C10的烷氨基羰基氧基；
在一些实施方案中，R 2选自基团A取代或未取代的R 3-C(＝S)-O-。
在一些实施方案中，R 3选自下列基团：C1-C10的烷基、C1-C10的烷氧基、C2-C10的烯基、C2-C10的炔基、C3-C10的碳环基、C2-C10的杂环基、C6-C12的芳基；优选地，R 3选自C1-C10的烷基；更优地，R 3选自下列基团：甲基、乙基、丙基、异丙基。
在一些实施方案中，基团A为羟基；在一些实施方案中，基团A为
Figure PCTCN2022132275-appb-000009
Figure PCTCN2022132275-appb-000010
其中，R 4、R 5和R 6各自独立地选自C1-C8的烷基，或R 4和R 5连接成环；B -选自有机阴离子、无机阴离子。
在本发明的实施方案中，
Figure PCTCN2022132275-appb-000011
表示单烷基胺基，
Figure PCTCN2022132275-appb-000012
表示双烷基胺基；所述单烷基胺基或双烷基胺基中的烷基为1～8个碳原子的烷烃基，烷基在任意合理的位置插入-NH-或者-NH 2基团的基团，包括但不限于甲氨基、丙氨基、异丙胺基、二乙胺基、二正丙氨基、二异丙氨基等。
在本发明的实施方案中，
Figure PCTCN2022132275-appb-000013
表示该处胺基成盐。
在本发明的实施方案中，
Figure PCTCN2022132275-appb-000014
表示该处胺基为季铵盐。
在本申请的实施方案中，所述的溶剂化物是指化合物与药学上可接受的溶剂相互作用形成的络合物，药学上可接受的溶剂包括乙醇，异丙醇、乙酸。
在本申请的实施方案中，所述的C1-C10的烷基是指分子中含有1～10个碳原子的组成的直链或支链的饱和脂肪族烃基。包括但不限于甲基、乙基、异丙基、丁基、异丁基、叔丁基、庚基、3-甲基庚基等。
在本申请的实施方案中，所述的C1-C10的烷氧基是指分子中含1～10个碳原子的饱和脂肪族烃基在任意合理的位置插入氧原子的基团，包括但不限于甲氧基、乙氧基、丙氧基、2-乙基乙氧基、乙氧基丁基等。
在本申请的实施方案中，所述的C2-C10的烯基是指由2～10个碳原子与氢原子组成的分子中至少含有一个不饱和碳碳双键的脂肪烃基，包括直链、支链或环状烯烃，包括但不限于丙烯基、2-甲基-2-丁烯基、1-己烯基、双戊烯基、5-甲基-2-庚烯、4-乙烯基-1-环己烯基等。
在本申请的实施方案中，所述的C2-C10的炔基是指由2～10个碳原子与氢原子组成的含有至少一个不饱和碳碳三键的脂肪烃基，包括直链、支链或环状炔烃，包括但不限于丙炔基、2-戊炔基、3-己炔基、2,4-己二炔基、3-环己基丙炔基、丙-1-炔基环丙烷基、5-甲基-2-己烯基等。
在本申请的实施方案中，所述的C3-C10碳环基是指含有3～10个碳原子的单环或者稠合多环的饱和或不饱和环状烃基，包括但不限于环丙基、环戊基、双环[3.2.0]庚基、1-甲基-1-环己烯基等。
在本申请的实施方案中，所述的C2-C10杂环基指分子中含有2～10个碳原子和1～4个杂原子的饱和或不饱和环状基团。包括但不限于环乙氧基、氮丙啶基、四氢吡咯基、哌啶基、六氢哒嗪基、二氢吡啶基、吗啉基等。
在本申请的实施方案中，所述的C6-C12的芳基是指分子中含有6～12个 碳原子具有单环或者稠合多环的不饱和芳香族基团，稠合的环可以是饱和的，也可以是不饱和的，包括但不限于苯基、萘基、苯并环庚基等。
在本申请的实施方案中，所述的C1-C10的烷氧羰基氧基、C1-C10的烷基羰基氧基、C1-C10的烷氨基羰基氧基，均指结构中除羰基外的烷基部分为1～10个碳原子，所述1～10个碳原子的烷基如前所述。
在一些实施方案中，本发明提供的化合物，选自下列化合物：
Figure PCTCN2022132275-appb-000015
Figure PCTCN2022132275-appb-000016
或其水合物、溶剂化物、同位素衍生物、非对映异构体。
在本发明的实施方案中，所述的甾体衍生物可以由脱氧可的松或其活生生物与硫代试剂
Figure PCTCN2022132275-appb-000017
反应得到，其中R为C1-C3的烷基，R 1如前所述。
在本发明的实施方案中，所述的硫代试剂
Figure PCTCN2022132275-appb-000018
参照文献(J Org Chem,1989,54,906-910)中合成方法得到。
本发明的另一方面是提供了含有安全有效量的上述化合物或其水合物、溶剂化物、同位素衍生物、非对映异构体与可药用载体制备的药组合物，可在临床上对人和其他哺乳动物给药。
在本申请的实施方案中，所述的药物组合物中本发明的化合物占药物组合物的质量比在0.01％～80％之间。
本发明的药物组合物的给药途径包括口服、注射、鼻腔给药、肺部给药、胃肠道给药、外用滴剂、透皮吸收等。优选地剂型为外用膏剂、外用贴剂、外用喷剂。
进一步地，所述的药物组合物可通过溶液剂、片剂、胶囊剂、注射剂、散剂、丸剂、粉剂、混悬剂、糊剂、软膏、巴布膏、气雾剂、喷剂、乳液、乳胶、凝胶剂、膜剂透皮给药。
本发明的第三方面是，本发明所述的化合物或其药物组合物具有很好的抗细菌和真菌的活性，且基本不会发生耐药性，可以有效地预防和/或治疗细菌感染或真菌感染的相关疾病。
进一步地，所述的细菌感染包括由革兰氏阳性菌或由革兰氏阴性菌引起的感染。所述的革兰氏阳性菌包括但不限于葡萄球菌(Staphylococcus)、链球菌(Streptococcus)、炭疽杆菌(Bacillus anthracis)、破伤风杆菌(Bacillus tetanus)；所述的革兰氏阴性菌包括但不限于大肠杆菌(Escherichia coli、铜绿假单胞菌(P.aeruginosa)；
所述的真菌感染由包括但不限于白色念珠菌(Monilia albican)等真菌引起的感染。
本发明的化合物是一类NF-κB的非激素甾体调节剂，可用于治疗和预防皮肤相关疾病或肌肉萎缩疾病，包括外伤性脑损伤、脊髓损伤等疾病。
已知HHDPC细胞促增殖实验可以用来初步评价化合物在体外对雄激素脱发的抑制作用，本发明化合物对HHDPC细胞表现出较好的促增殖活性，可 知本发明化合物具有更好的抑制雄激素脱发的作用。
本发明化合物具有治疗痤疮和一些其它雄激素相关疾病或癌症的作用；所述的雄激素相关的疾病包括但不限于脂溢性皮炎、脱发、秃发症、前列腺增生；所述的癌症包括但不限于前列腺癌、膀胱癌等。
本发明的化合物在皮肤给药时具有较好的皮肤组织内暴露量，在脂肪组织中分布相对较少，在血液中基本未检测到，这说明本发明的化合物在皮肤用药时在皮肤组织中有特异性分布，而全身暴露量却很低。
具体实施方式
下面结合具体实施例对本发明做进一步说明，但不以任何方式限制本发明，所有化合物的结构均经MS或 1H NMR确定。
实施例1：AMX881和AMX882的合成
Figure PCTCN2022132275-appb-000019
化合物2的合成：
在氩气气氛下，干燥的圆底烧瓶中加入150ml的四氢呋喃和13.66g二异丙胺，体系降温至-60℃。体系中滴入80ml正丁基锂溶液(1.6M的己烷溶液)，维持内温在-50℃下，滴入5g丙酸和12g六甲基磷酰三胺的四氢呋喃溶液。体系升温至35℃，反应30分钟。随后体系降温至-30℃，体系中滴入5.7g二硫化碳，维持该温度反应10分钟。体系降温至-50℃，滴入9.6g碘甲烷。体系缓慢升温至40℃继续反应1小时。体系降温，滴入1N盐酸淬灭反应。升温至室温，水相分出并用正己烷萃取，合并有机相，有机相用1N盐酸和水洗涤后，无水硫酸钠干燥。减压浓缩除去溶剂，粗品过硅胶柱得到2.5g化合物2，收率31％，[M+H] +＝120.77。
化合物AMX881和AMX882的合成：
氮气保护下,将1g脱氧可的松加入到15ml四氢呋喃中，冰水浴下缓慢加入0.25g氢化钠(60％),加毕，室温搅拌反应1小时。加入0.7g化合物2，体系加热至40℃反应12小时。冰水浴降温，加水淬灭反应，分出有机相，无水硫酸钠干燥，柱层析分离得0.34g化合物AMX881(收率24％，[M+H] +＝491.02)和0.46g化合物AMX882(收率38％，[M+H] +＝419.78)。
实施例2：AMX883的合成
Figure PCTCN2022132275-appb-000020
化合物3的合成：
氮气保护下向1.6g脱氧可的松(Cortexolone)中加入15mL干燥的二氯甲烷，加入0.46g二氢吡喃，冰水浴下加入80mg对甲苯磺酸，室温反应5.0h，依次用水和饱和食盐水洗涤，有机相无水硫酸钠干燥，浓缩得固体，柱层析分离得1.09g化合物3，收率：55％，[M+H] +＝430.33。
化合物4的合成：
氮气保护下,将0.9g化合物3加入到15ml四氢呋喃中，冰水浴下缓慢加入0.1g氢化钠(60％),加毕，室温搅拌反应1小时。加入0.3g化合物2，体系加热至40℃反应12小时。冰水浴降温，加水淬灭反应，分出有机相，无水硫酸钠干燥，柱层析分离得0.61g化合物4，收率24％，[M+H] +＝502.25。
化合物AMX883的合成：
向0.5g化合物4中加入50mL干燥DCM，冰水浴下加入10ml盐酸水溶液(0.01N),室温下反应12h，反应完毕后分出有机相，有机相依次用和饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析分离得0.32g化合物AMX883,收率：77％,[M+H] +＝419.78。
实施例3：AMX886的合成
Figure PCTCN2022132275-appb-000021
化合物5的合成：
氮气保护下,将1g脱氧可的松(Cortexolone)加入到15ml四氢呋喃中，冰水浴下缓慢加入0.14g氢化钠(60％),加毕，室温搅拌反应1小时。加入0.44g化合物溴乙醇，体系加热至40℃反应12小时。冰水浴降温，加水淬灭反应，分出有机相，无水硫酸钠干燥，柱层析分离得0.79g化合物5，收率70％，[M+H] +＝390.92。
化合物AMX886的合成：
氮气保护下,将0.5g化合物5加入到15ml四氢呋喃中，冰水浴下缓慢加入65mg氢化钠(60％),加毕，室温搅拌反应1小时。加入0.2g化合物2，体系加热至40℃反应12小时。冰水浴降温，加水淬灭反应，分出有机相，无水硫酸钠干燥，柱层析分离得0.26g化合物AMX886，收率44％，[M+H] +＝462.95。
实施例4：AMX8814的合成
Figure PCTCN2022132275-appb-000022
化合物7的合成
将1g氯甲酸氯甲酯(化合物6)溶于20mL无水乙腈中，冷却到0℃，加入0.63g盐酸二甲胺和2.5g二异丙基乙胺。室温反应6h薄层显示反应完全。蒸干反应液，加入乙酸乙酯150mL，依次用水、0.1N HCl和饱和食盐水各50mL洗涤，得产物为淡黄色油状液体2(10-44)0.68g，硅胶柱层析分离(PE:EA＝4:1～3:1)，得到纯品7的无色液体290mg，收率27％，[M+H] +＝137.63。化合物AMX8814的合成
氮气保护下,将0.3g化合物AMX883加入到15ml四氢呋喃中，冰水浴下缓慢加入35mg氢化钠(60％),加毕，室温搅拌反应1小时。加入0.12g化合物7的四氢呋喃溶液，体系加热至40℃反应12小时。冰水浴降温，加水淬灭反应，分出有机相，无水硫酸钠干燥，柱层析分离得0.25g化合物AMX8814，收率67％，[M+H] +＝519.35。
实施例5：化合物AMX8815和AMX8817的合成
Figure PCTCN2022132275-appb-000023
化合物8和化合物9的合成
室温下，向反应瓶中加入0.9g化合物Cortexolone和15ml的四氢呋喃，加入1.5g劳森试剂，室温下反应25小时。体系浓缩至干，二氯甲烷和水萃取，分出有机相浓缩至干，制备分离得到0.17g化合物8和0.38g化合物9；
化合物8，收率18％，[M+H] +＝362.67； 1H NMR(300MHz,CDCl3):δ＝0.69(s,3H),0.73-2.03(m,14H),1.17(s,3H),2.21-2.42(m,4H),2.60-2.69(m,1H),2.88(br s,2H),4.32-4.69(2H),5.73(s,1H,H-4)；
化合物9，收率42％，[M+H] +＝362.67； 1H NMR(300MHz,CDCl3):δ＝0.68(s,3H),0.76-2.05(m,14H),1.16(s,3H),2.19-2.46(m,4H),2.62-2.75(m,1H),2.76(brs,2H),4.26--4.58(2H),5.59(s,1H)。
化合物AMX8815和AMX8817的合成
完全参照化合物AMX883的合成方法，得到29mg化合物AMX8815(收 率18％，[M+H] +＝418.45)和54mg化合物AMX8817(收率42％，[M+H] +＝418.45)。
实施例6：化合物AMX8819和AMX8820的合成
Figure PCTCN2022132275-appb-000024
AMX8819的合成
氮气保护下向1g化合物AMX8815中加入20mL干燥DCM，冰浴下加入3-二乙基氨基丙酰氯(0.47g)与三乙胺(0.5g)，于室温下下反应2.0h，反应完毕后水洗(30mL×2)，饱和食盐水洗涤(30mL×1)，有机相无水硫酸钠干燥后浓缩得固体，柱层析分离得AMX8819精制品0.82g。收率：63％。纯度：98.2％。[M+H] +＝546.32。
AMX8820的合成
将AMX8819(0.6g)溶于10ml甲醇中，降温至0-5℃，然后缓慢加入5ml氢溴酸，搅拌反应2.0h；向体系缓慢加入30ml甲基叔丁基醚，析出固体，于0-5℃搅拌0.5h，过滤，甲基叔丁基醚淋洗，干燥，得产物0.54g，收率90％。[M-Br] +＝546.33。
实施例7：化合物AMX8821、AMX8822和AMX8823的合成
Figure PCTCN2022132275-appb-000025
化合物AMX8821的合成
参照化合物AMX8819的合成方法合成得到化合物AMX8821共1.4g，收率57％，[M+H] +＝558.36。
化合物AMX8822的合成
氮气保护下，向反应瓶中依次加入10ml的四氢呋喃和1g的AMX8821，在50℃下加热条件下，加入CH 3CH 2Cl(0.25g)的四氢呋喃溶液(3ml)，反应混合物继续加热0.5h。反应完毕，降温至10℃作用，析出固体，过滤，真空40℃干燥，得粗品经甲醇重结晶，得到0.61g化合物AMX8822，收率55％。[M-Cl] +＝586.37。
化合物AMX8823的合成
氮气保护下，向反应瓶中依次加入乙醇(10ml)、AMX8822(0.4g)，加热至50℃，加入醋酸银(0.12g)，反应混合物搅拌反应3h；热过滤除去固体，滤液冷却至10℃左右，加入13ml甲基叔丁基醚，析晶，得到0.39g化合物AMX8823，收率95％。[M-AcO] +＝586.37。
按照与上述实施例同样的方法，使用市售化合物或由市售化合物适当合成的中间体化合物，合成了下列实施例化合物：
Figure PCTCN2022132275-appb-000026
Figure PCTCN2022132275-appb-000027
Figure PCTCN2022132275-appb-000028
实施例8:细菌抑制率评估实验
将待测物用DMSO溶解，并用培养基稀释至32μg/ml，备用。
取冻存的金黄色葡萄球菌(CMCC(B)26003)标准菌株在室温条件下溶解，接种于LB固体培养基中，37℃条件下培养过夜。次日挑取生长良好的2～3个单菌落至M-H肉汤培养基中振荡培养调整细菌悬液浓度达到为1.0×10 6CFU/ml。将菌液加入96孔板中，每个孔中加入同等浓度等量的菌悬液及等体积的待测物稀释液，设置空白对照组。37℃条件下培养24小时，使用酶标仪在波长265nm处进行检测，并计算细菌抑制率，如表1所示：
表1：细菌抑制率评估(16μg/ml)
化合物 抑制率(％) 化合物 抑制率(％) 化合物 抑制率(％)
AMX881 94.5 AMX8810 93.9 AMX8819 95.4
AMX882 96.0 AMX8811 94.1 AMX8820 96.2
AMX883 93.8 AMX8812 93.2 AMX8821 96.6
AMX884 95.3 AMX8813 93.4 AMX8822 95.3
AMX885 95.7 AMX8814 94.6 AMX8823 95.5
AMX886 95.1 AMX8815 96.7 AMX8824 96.2
AMX887 94.2 AMX8816 96.2 AMX8825 95.3
AMX888 94.5 AMX8817 95.8 AMX8826 94.7
AMX889 95.3 AMX8818 96.5 AMX8827 96.3
由上表可知，在浓度为16μg/ml本发明化合物对于金黄色葡萄球菌(CMCC(B)26003)的抑制率均在93％以上，这说明本发明化合物具有良好的抗细菌活性。
实施例9:最低抑菌浓度(MIC)的测定
细菌悬液制备：取冻存的大肠杆菌(CMCC(B)44102)、金黄色葡萄球菌(CMCC(B)26003)、铜绿假单胞杆菌(CMCC10104)和乙型溶血性链球菌(CMCC(B)32210)标准菌株在室温条件下溶解，接种于LB固体培养基中，37℃条件下培养过夜。次日挑取生长良好的2～3个单菌落至M-H肉汤培养基中振荡培养调整细菌悬液浓度达到为1.0×10 6CFU/ml，备用。
真菌悬液制备：将标准白色念珠菌(JLC30364)接种于沙保弱肉汤培养基中，振荡培养24～48h，镜检证明念珠菌已产生假菌丝后制成孢子液。调整真菌悬液浓度为1.0×10 6CFU/ml的菌液，备用。
实验采用微量稀释法测定，观察结果，以小孔内完全抑制细菌生长的最低药物浓度为该抗菌药物对该细菌的最低抑菌浓度即MIC值。结果见表2：
表2：各待测物MIC结果(μg/ml)
Figure PCTCN2022132275-appb-000029
Figure PCTCN2022132275-appb-000030
结果表明：本发明化合物对于大肠杆菌(CMCC(B)44102)的MIC在0.25μg/ml～0.5μg/ml；对于金黄色葡萄球菌(CMCC(B)26003)的MIC在0.125μg/ml～0.25μg/ml；对于铜绿假单胞杆菌(CMCC10104)的MIC在0.25μg/ml～0.5μg/ml；对于乙型溶血性链球菌(CMCC(B)32210)的MIC在0.125μg/ml～0.5μg/ml；对于白色念珠菌(JLC30364)的MIC在1.0μg/ml～2.0μg/ml，这说明本发明化合物具有良好的抗细菌和真菌活性。
实施例10:亚抑菌浓度(SMIC)药物诱导细菌耐药实验结果
根据每个药物分别对应的各菌株MIC值，确定各药液的亚抑菌浓度(SMIC)值。用MH肉汤培养基在4mL试管中培养2种试验菌株，接种细菌量约为5.0×10 5CFU/ml。配置药物使各菌株在该药物SMIC浓度下置于37℃共同培养。共同培养18～24h，记为第1代。然后分别由各孔中取适量菌液稀释成5.0×10 5CFU/ml浓度，接种于同组的第2个试管中，记为第2代，如此重复传代。每种药液培养细菌15次(代)，然后每隔5代检测一次在SMIC药液作用下各药液的MIC值。结果如表3和表4所示：
表3：金黄色葡萄球菌诱导前后MIC值(μg/ml)
Figure PCTCN2022132275-appb-000031
表4：白色念珠菌诱导前后MIC值(μg/ml)
Figure PCTCN2022132275-appb-000032
Figure PCTCN2022132275-appb-000033
根据SMIC药物诱导进行耐药菌的传代培养，结果显示阳性对照药左氧氟沙星和氟康唑对实验菌株MIC 诱导后≥MIC 诱导前，结合CLSL的标准，判定为已经产生耐药，而本发明化合物经过15代的诱导耐药培养，MIC值保持在测定范围内基本没有变化，未产生耐药。
实施例11:HHDPC细胞促增殖实验
取对数生长期HHDPC细胞用胰蛋白酶消化，配制成浓度为1～10×10 4个/ml的细胞悬液，按每孔3000～5000个细胞接种于96孔板，每孔加100μl，在37℃、5％CO2环境中培养过夜贴壁，边缘孔用无菌PBS填充。察细胞贴壁后加入10μM供试品化合物孵育48h，同时设置空白对照组。所有孔中分别加入20μl MTT溶液(5mg/ml，即0.5％MTT)，培养箱中孵育4h。小心的吸除上清液，每孔加150μl的DMSO，低速(1 20～140rpm/min)震荡使结晶物充分溶解。使用酶标仪测定490nm光吸收值，并计算促增殖率，结果如表5所示：
表5：HHDPC细胞株促增殖活性结果：
化合物 增殖率(％) 化合物 增殖率(％)
AMX885 36.7 AMX8823 39.5
AMX8816 33.2 AMX8826 38.0
AMX8817 37.1 AMX8827 36.8
AMX8818 40.1 Clacoterone 27.8
研究结果表明，本发明化合物对HHDPC细胞表现出较好的促增殖活性。已知HHDPC细胞促增殖实验可以用来初步评价化合物在体外对雄激素脱发的抑制作用，由此可以看出，本发明化合物具有更好的抑制雄激素脱发的作用。
实施例12:皮肤给药药代动力学试验
广西巴马小型猪(级别：普通级，年龄：5-8月龄，性别：均为雄性，体重：12-14kg，生产单位：北京实创世纪小型猪养殖中心，生产许可证号：SCXK(京)2018-0008)9只，按照体重随机分为A/B/C两组，给药前日禁食不禁水过夜(12-16小时)。试验当天，所有组别的小型猪分别在背部选取标记面积为20×20cm 2的区域，剔除毛发、清洁，分别标记6个给药部位，每个给药 部位为5×8cm 2，为各采样时间点对应的皮肤取样位置。每只动物按照每个给药部位0.2mL，6个给药部位共计1.0mL的供试品溶液(1％的二丙二醇溶液)，其中0h取样点不给药。A组给予化合物Clascoterone的二丙二醇溶液，B组给予化合物AMX8818的二丙二醇溶液,C组给予化合物AMX8826的二丙二醇溶液。均匀涂抹给药后，固定动物5分钟左右，待皮肤上药物基本吸收后，纱布覆盖给药区域并使用医用胶布固定。A组、B组和C组分别于给药前及给药后药后1、2、4、8和24h时间点前10min，肌肉注射给予5～10mg×kg -1舒泰50麻醉，去除角质层。
皮肤样本和脂肪样本采集：分别于给药前及给药后1、2、4、8和24h时间点，立即使用皮肤活检器采集直径为7mm、深度为7～8mm的皮肤样本，并立即使用生物敷料填充伤口止血。皮肤样本在-20℃条件下冷冻30min，分离皮下脂肪和去除多余的其他组织，采集皮肤样本和脂肪样本，使用PBS清洗3次，洗涤后，用滤纸吸干水分，称重并记录，放入样品收集管中，保存于-90～-60℃环境中，放置在干冰下运输。
血样采集及处理：于给药前及给药后0.5、1、2、4、8、12和24h由颈静脉采集1mL全血，置于EDTA-2K EP管中抗凝后，放置在湿冰上，30min内离心(1500-1600g，10min)，提取分离血浆。血浆样品在-90～-60℃环境条件下保存，用于后期对生物样品进行分析，样品如需要转动，应在干冰下运输。
生物样本经处理后，LC/MS/MS分析检测化合物原形。结果如下表6和表7：
表6：皮肤给药后血药浓度(ng/mL)
time Clascoterone组 AMX8818组 AMX8826组
0h 13.3 6.76 BQL
0.5h 5.84 BQL BQL
1h BQL BQL BQL
2h 7.38 BQL BQL
4h 6.53 BQL BQL
8h 5.97 BQL BQL
12h BQL BQL BQL
24h BQL 3.35 BQL
备注：BQL为低于定量下限浓度值，BQL＝0.25ng/mL。
表7:脂肪组织和皮肤组织的浓度(ng/g)
Figure PCTCN2022132275-appb-000034
备注：BQL为低于定量下限浓度值，BQL＝100ng/g。
由上表6和表7可知，化合物Clascoterone及AMX8818和AMX8826皮肤给药后，很少量或几乎没有进入血液循环系统。在脂肪组织中，AMX8818和AMX8826的暴露量要远小于Clascoterone；在皮肤组织中，AMX8818和AMX8826的暴露量要远大于Clascoterone。这说明本发明化合物AMX8818和AMX8826在皮肤中具有更好的分布。
本申请描述了多个实施例，但是不以任何方式限制本发明，在本申请所描述的实施例包含的范围内可以有更多的实施例和实现方案。

Claims (12)

  1. 一种如式(I 0)所示的化合物或其水合物、溶剂化物、同位素衍生物、非对映异构体或药学上可接受的盐：
    Figure PCTCN2022132275-appb-100001
    式(I 0)中，n为0，1，2，3，4或5；
    X 1、X 2和X 3各自独立的为O或S；
    R 1选自基团A取代或未取代的下列基团：C1-C10的烷基、C1-C10的烷氧基、C2-C10的烯基、C2-C10的炔基、C3-C10的碳环基、C2-C10的杂环基、C6-C12的芳基；
    R 2选自基团A取代或未取代的下列基团：氢、C1-C10的烷基、C1-C10的烷氧基、C1-C10的烷氧羰基氧基、C1-C10的烷基羰基氧基、C1-C10的烷氨基羰基氧基，或R 3-C(＝S)-O-，当n为0且R 2为氢时，X 1、X 2和X 3不同时为O；
    R 3选自下列基团：C1-C10的烷基、C1-C10的烷氧基、C2-C10的烯基、C2-C10的炔基、C3-C10的碳环基、C2-C10的杂环基、C6-C12的芳基；
    所述的基团A选自：羟基、
    Figure PCTCN2022132275-appb-100002
    其中，R 4、R 5和R 6各自独立地选自C1-C8的烷基，或R 4和R 5连接成环；B -选自有机阴离子、无机阴离子。
  2. 如权利要求1所述的化合物，如式(II 0)所示：
    Figure PCTCN2022132275-appb-100003
    式(II 0)中取代基的定义如权利要求1式(I 0)所定义的。
  3. 如权利要求1所述的化合物，如式(III 0)所示：
    Figure PCTCN2022132275-appb-100004
    式(III 0)中取代基的定义如权利要求1式(I 0)所定义的。
  4. 如权利要求1所述的化合物，如式(Ⅳ 0)所示：
    Figure PCTCN2022132275-appb-100005
    式(Ⅳ 0)中取代基的定义如权利要求1式(I 0)所定义的。
  5. 根据权利要求1所述化合物或其水合物、溶剂化物、同位素衍生物、非对映异构体，其中，B -选自有机或无机负离子；进一步地，B -优选自卤离子、高卤酸根、硝酸根、硫酸根、硫氢酸根、亚硫酸根、磷酸根、磷酸氢根、C1-C12烷基酸根、C1-C12烷基磺酸根、C1-C12烷基硫酸根、C1-C12芳基磺酸根；更进一步的，B -优选自乙酸根、丙酸根、氯离子、溴离子。
  6. 如权利要求1～5所述的化合物，具有如下结构：
    Figure PCTCN2022132275-appb-100006
    Figure PCTCN2022132275-appb-100007
    或其水合物、溶剂化物、同位素衍生物、非对映异构体。
  7. 一种药物组合物，其包含可药用载体与权利要求1～6中任一项所述的化合物。
  8. 权利要求1～6中任一项所述的化合物或权利要求7所述的药物组合物，可用于制备抗细菌感染、抗真菌药物的作用。
  9. 如权利要求8所述的细菌感染由革兰氏阳性菌如葡萄球菌、链球菌、炭疽杆菌、破伤风杆菌引起或由革兰氏阴性菌如大肠杆菌、铜绿假单胞菌等引起。
  10. 权利要求1～6中任一项所述的化合物或权利要求7所述的药物组合物，可用于制备治疗和预防雄激素相关疾病的药物的作用，所述的雄激素相关疾病包括脂溢性皮炎、脱发、秃发症、前列腺增生、前列腺癌、膀胱癌等。
  11. 权利要求1～6中任一项所述的化合物或权利要求7所述的药物组合物，可用于制备治疗和预防肌肉萎缩疾病的药物的作用，包括外伤性脑损伤、脊髓损伤等疾病；
  12. 权利要求7所述的药物组合物可通过溶液剂、片剂、胶囊剂、注射剂、 散剂、丸剂、粉剂、混悬剂、糊剂、软膏、巴布膏、气雾剂、喷剂、乳液、乳胶、凝胶剂、膜剂透皮给药。
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