WO2018103626A1 - 一类水溶性别孕烯醇酮衍生物及其用途 - Google Patents

一类水溶性别孕烯醇酮衍生物及其用途 Download PDF

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WO2018103626A1
WO2018103626A1 PCT/CN2017/114590 CN2017114590W WO2018103626A1 WO 2018103626 A1 WO2018103626 A1 WO 2018103626A1 CN 2017114590 W CN2017114590 W CN 2017114590W WO 2018103626 A1 WO2018103626 A1 WO 2018103626A1
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compound
pharmaceutically acceptable
acid
polymorph
solvate
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PCT/CN2017/114590
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English (en)
French (fr)
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李勤耕
王涛
陈刚
任亮
刘新
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江苏恩华络康药物研发有限公司
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Priority to KR1020197018713A priority Critical patent/KR20190092466A/ko
Priority to US16/466,819 priority patent/US20190322698A1/en
Priority to CA3045955A priority patent/CA3045955A1/en
Priority to EP17878651.3A priority patent/EP3549945A4/en
Priority to CN201780075016.0A priority patent/CN110049992B/zh
Priority to AU2017372251A priority patent/AU2017372251A1/en
Priority to EA201991374A priority patent/EA201991374A1/ru
Priority to JP2019549628A priority patent/JP2019536821A/ja
Publication of WO2018103626A1 publication Critical patent/WO2018103626A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not 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
    • A61K31/58—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/62—Quaternary ammonium compounds
    • C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/62—Quaternary ammonium compounds
    • C07C211/64—Quaternary ammonium compounds having quaternised nitrogen atoms bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms

Definitions

  • the invention relates to the field of medicine, in particular to a kind of water-soluble pregnenolone derivatives, pharmaceutical compositions containing the same, and the same for preventing or treating central nervous system diseases, for sedating and hypnosis, for treating Alzheimer's disease.
  • central nervous system diseases for sedating and hypnosis
  • Alzheimer's disease for treating Alzheimer's disease.
  • epilepsy for the treatment of epilepsy or for the treatment of depression, especially postpartum depression.
  • Allopregnanolone is a GABA ( ⁇ -aminobutyric acid) receptor agonist in human body, which can bind to GABA and exert physiological effects (J Physiol.2001;537(Pt 2) ): 453–465).
  • GABA ⁇ -aminobutyric acid
  • a method of formulating a composition of a pregnenolone with a cyclodextrin and introducing it intravenously for the treatment of epilepsy or persistent epilepsy is disclosed in Chinese Patent Application No. WO 104736158 A.
  • the proportion of the cyclodextrin is 1 to 30%
  • the blood concentration is 50 to 2300 nM
  • the treatment process is as long as 24 hours or more.
  • cyclodextrin is macromolecular Compound, has a certain risk of nephrotoxicity (safety study of cyclodextrin derivatives of medicinal supramolecular materials, China Materials Science and Technology, 2009, No. 5, pp. 1-3), thus posing a safety hazard.
  • the pregnane enolone is a steroidal compound, it has less solubility in water. It is therefore necessary to develop an epipregone ketone derivative having improved water solubility and improved safety.
  • the invention provides a class of water-soluble pregnenolone derivatives.
  • the water-soluble pregnenolone derivative has good physical/chemical stability and good water solubility, and can rapidly decompose and release the active drug (pregnenolone) in the body, thereby rapidly producing pharmacological effects.
  • the water-soluble pregnenolone derivative of the present invention is a compound of the formula (I) or a pharmaceutically acceptable salt, stereoisomer, polymorph or solvate thereof:
  • X is H or F
  • Y is H, F or a C 1-6 alkyl group optionally substituted by one or more F;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • W is W 1 or W 2 ;
  • W 1 is NR 1 R 2 ⁇ A or
  • R 1 and R 2 are each independently H, C 1-6 alkyl or C 3-6 cycloalkyl optionally substituted by phenyl;
  • n 0, 1, 2 or 3;
  • A is absent or is a pharmaceutically acceptable acid
  • W 2 is -COOH, -OPO 3 (H) 2 , -PO 3 (H) 2 , -COO(M) 1/t , -OPO 3 (M) 2/t or -PO 3 (M) 2/t ;
  • M is a metal ion, an ammonium ion or a basic amino acid cation
  • t is the number of charges carried by M.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, polymorph or solvate thereof, of the invention And one or more pharmaceutically acceptable carriers.
  • Another aspect of the present invention provides a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt, stereoisomer, polymorph or solvate thereof, or a pharmaceutical composition of the present invention, which is prepared for prevention Or use in the treatment of central nervous system disorders, for sedation and hypnosis, for the treatment of Alzheimer's disease, for the treatment of epilepsy or for the treatment of depression, in particular postpartum depression.
  • Another aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, polymorph or solvate thereof, or a pharmaceutical composition of the invention, for use in the prevention of the present invention Or treatment of central nervous system disorders, for sedation and hypnosis, for the treatment of Alzheimer's disease, for the treatment of epilepsy or for the treatment of depression, especially postpartum depression.
  • Another aspect of the invention provides a method of preventing or treating a central nervous system disorder, sedating hypnosis, treating Alzheimer's disease, treating epilepsy, or treating depression, particularly postpartum depression, comprising administering a prophylaxis to an individual in need thereof or A therapeutically effective amount of a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt, stereoisomer, polymorph or solvate thereof, or a pharmaceutical composition of the invention.
  • C 1-6 alkyl refers to a saturated straight or branched chain hydrocarbon radical having from 1 to 6, (eg, 1, 2, 3, 4, 5 or 6) carbon atoms, such as methyl, Ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc., preferably methyl, B Base, propyl, isopropyl, butyl or isobutyl, more preferably methyl, ethyl or propyl.
  • C 3-6 cycloalkyl refers to a saturated monocyclic hydrocarbon group having 3 to 6 (eg, 3, 4, 5 or 6) carbon atoms, such as cyclopropyl, cyclobutyl, or ring. Pentyl or cyclohexyl.
  • C 6-14 aryl refers to an aromatic group containing from 6 to 14 carbon atoms, such as phenyl or naphthyl.
  • Pharmaceutically acceptable salts of the compounds of the invention include those formed with pharmaceutically acceptable acids and salts formed with pharmaceutically acceptable bases.
  • pharmaceutically acceptable acid means a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, formic acid, acetic acid, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid.
  • pharmaceutically acceptable base refers to a pharmaceutically acceptable base such as an inorganic base (alkali metal hydroxide or alkaline earth metal hydroxide, etc.) or an organic base (eg an amine (primary, secondary or tertiary). Amine), etc.).
  • inorganic base alkali metal hydroxide or alkaline earth metal hydroxide, etc.
  • organic base eg an amine (primary, secondary or tertiary). Amine), etc.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, ammonia, primary, secondary and tertiary amines and cyclic amines (e.g., diethylamine salt, piperidine salt, morpholine salt, piperazine salt, choline) Salt, meglumine salt, tromethamine salt, etc.), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • basic amino acid refers to an amino acid having more hydroxide anions than hydrogen cations, such as arginine, lysine or histidine.
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • a compound having one or more (eg, one, two, three, or four) asymmetric centers which can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Separate diastereomers.
  • the compounds of the invention may exist in crystalline or polymorphic form, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • the compounds of the invention may exist in the form of their solvates, especially hydrates, wherein the compounds of the invention comprise a polar solvent as a structural element of the crystal lattice of the compound, such as water, ethanol, isopropanol, ethyl acetate or acetone.
  • a polar solvent as a structural element of the crystal lattice of the compound, such as water, ethanol, isopropanol, ethyl acetate or acetone.
  • the amount of polar solvent, particularly water may be present in stoichiometric or non-stoichiometric ratios.
  • the present invention provides a water-soluble pregnenolone derivative which is a compound of the formula (I) or a pharmaceutically acceptable salt, stereoisomer, polymorph, or solvent thereof Compound:
  • X is H or F
  • Y is H, F or a C 1-6 alkyl group optionally substituted by one or more F;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • W is W 1 or W 2 ;
  • W 1 is NR 1 R 2 ⁇ A or
  • R 1 and R 2 are each independently H, C 1-6 alkyl or C 3-6 cycloalkyl optionally substituted by phenyl;
  • n 0, 1, 2 or 3;
  • A is absent or is a pharmaceutically acceptable acid
  • W 2 is -COOH, -OPO 3 (H) 2 , -PO 3 (H) 2 , -COO(M) 1/t , -OPO 3 (M) 2/t or -PO 3 (M) 2/t ;
  • M is a metal ion, an ammonium ion or a basic amino acid cation
  • t is the number of charges carried by M.
  • Y is F, CF 3 , CH 2 F or CHF 2 .
  • W is W 1 .
  • R 1 and R 2 are each independently a C 1-6 alkyl group optionally substituted by phenyl, such as methyl, ethyl, propyl, isopropyl, butyl, iso Butyl or benzyl.
  • R 1 and R 2 are each independently C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 1 and R 2 are each independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl.
  • R 1 and R 2 are not simultaneously H.
  • W 1 is selected from
  • A is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, formic acid, acetic acid, propionic acid, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, Heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, isethionic acid, 1,5-naphthalene Disulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, sulfamic acid, lactic acid, benzenesulfonic acid, p-toluenesulfonic acid, malonic acid, succinic acid, glutaric acid, acetic acid,
  • W is W 2 .
  • M is an alkali metal ion (such as lithium ion, sodium ion or potassium ion), an alkaline earth metal ion (such as magnesium ion, zinc ion or calcium ion) or a trivalent metal ion (such as aluminum ion).
  • alkali metal ion such as lithium ion, sodium ion or potassium ion
  • alkaline earth metal ion such as magnesium ion, zinc ion or calcium ion
  • a trivalent metal ion such as aluminum ion
  • M by the general formula (NR 3 R 4 R 5 R 6) + , or An ammonium ion, wherein R 3 , R 4 , R 5 and R 6 are each independently H, alkyl, cycloalkyl or aryl optionally substituted by phenyl; and p is 0, 1, 2 or 3.
  • R 3 , R 4 , R 5 and R 6 are each independently H, C 1-6 alkyl optionally substituted by phenyl, C 3-6 cycloalkyl or C 6- 14 aryl.
  • R 3 , R 4 , R 5 and R 6 are each independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, benzyl , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 3 and R 4 are each independently H, methyl or ethyl.
  • M is selected from
  • M is arginine + H + , lysine + H + or histidine + H + .
  • X is different from Y, while the carbon atom attached to X and Y is a single R configuration, a single S configuration, or a mixture of R and S configurations.
  • the present invention encompasses compounds obtained by any combination of the various embodiments.
  • the R group is selected from the group consisting of:
  • Another embodiment of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of formula (I) of the invention, or a pharmaceutically acceptable salt, stereoisomer, polymorph or solvent thereof thereof And one or more pharmaceutically acceptable carriers.
  • “Pharmaceutically acceptable carrier” in the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil. , sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition can also be as needed A small amount of wetting agent, emulsifier (such as Tween-80, etc.) or pH buffer should be included.
  • compositions of the invention may be administered in a suitable route.
  • the pharmaceutical compositions of the invention are administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
  • the compounds of the invention are useful in the treatment of a variety of conditions that can be treated by the administration of an extraglycoside.
  • Another embodiment of the present invention provides a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt, stereoisomer, polymorph or solvate thereof, or a pharmaceutical composition of the present invention, which is used in the preparation of Use for the prevention or treatment of central nervous system disorders, for sedation and hypnosis, for the treatment of Alzheimer's disease, for the treatment of epilepsy or for the treatment of depression, in particular for postpartum depression.
  • Another embodiment of the present invention provides a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt, stereoisomer, polymorph or solvate thereof, or a pharmaceutical composition of the present invention, which is used for Prevention or treatment of central nervous system disorders, for sedation and hypnosis, for the treatment of Alzheimer's disease, for the treatment of epilepsy or for the treatment of depression, especially postpartum depression.
  • Another embodiment of the invention provides a method of preventing or treating a central nervous system disorder, sedating hypnosis, treating Alzheimer's disease, treating epilepsy, or treating depression, particularly postpartum depression, comprising administering to a subject in need thereof prevention Or a therapeutically effective amount of a compound of formula (I) of the invention, or a pharmaceutically acceptable salt, stereoisomer, polymorph or solvate thereof, or a pharmaceutical composition of the invention.
  • the central nervous system disorder is selected from the group consisting of traumatic brain injury, essential tremor, epilepsy (including refractory persistent epilepsy, rare genetic epilepsy (eg, Dravet syndrome and Rett synthesis) Signs), depression (including postpartum depression) and Alzheimer's disease.
  • terapéuticaally effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several sub-doses may be administered over time, or may be proportionally reduced or increased as indicated by the urgent need for treatment. dose. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or the progression of one or more symptoms of such a condition or condition, or preventing such A condition or condition or one or more symptoms of such condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • the compound of the present invention can obtain a water-soluble epignenolone derivative by structural modification of the hydroxyl group of the pregnenolone under the premise of retaining the pharmacological activity of the pregnenolone, which has good physical/chemical stability. After the injection of the aqueous solution containing the same, it can release the active drug in the body, thereby exerting pharmacological effects.
  • the water-soluble other pregnenolone derivative of the present invention is water-soluble, and thus can be prepared into a suitable liquid preparation, and is easily decomposed and released in vivo. drug. Therefore, the water-soluble epiconne ketone derivative of the present invention can improve the water solubility of the pregnenolone and reduce the side effects caused by the excipient.
  • step 1 In place of 4-(dimethylamino)-2-fluorobutyric acid, (R)-5-(diethylamino)-2-(trifluoromethyl)pentanoate (10 mmol) was replaced in step 1) In the same manner as in Example 1, except for the hydrochloride salt, (R)-5-(diethylamino)-2-(trifluoromethyl)pentanoic acid pregnenolone hydrochloride was obtained.
  • the pregnenolone (4.5 mmol) and 4-dimethylaminopyridine (8.2 mmol) were dissolved in 20 ml of anhydrous dichloromethane at room temperature, and dicyclohexylcarbodiimide (10 mmol) and (S) were added.
  • 3-(Benzyloxy)-2-fluoro-3-oxopropionic acid (8 mmol) was reacted at room temperature. The reaction was detected by HPLC. After the reaction was completed, the DCM layer was washed with aqueous hydrochloric The product obtained was dissolved in anhydrous tetrahydrofuran (30 ml) and hydrogenolyzed on palladium carbon (5-10%, w/w).
  • Example 1 The following compounds were prepared in a similar manner to Example 1 or Example 2:
  • Mass(ESI)[M+H] + 450.31
  • Mass(ESI)[M+H] + 487.30
  • Example 9 Stability test of compound in 5% dextrose aqueous solution
  • test compound 1 mg was weighed and placed in 5% glucose (2 ml) to prepare a solution having a concentration of about 0.5 mg/ml, which was allowed to stand at room temperature at various time points (0.5 h, 1 h, Samples were taken at 2h, 3h and 5h) and the samples were tested by HPLC.
  • concentration 0.5 mg/ml
  • the experimental results show that the compound of the present invention tested after being placed in a 5% dextrose solution (for example, after 5 h) has a decomposition rate of less than 1%, which indicates that it has good stability in a 5% dextrose solution and is suitable for administration by injection.
  • the compounds provided by the present invention have better solubility in water and change the solubility of the pregnane enone.
  • Example 11 Decomposition of compounds in rat whole blood
  • the experimental results show that the tested compound of the present invention can be decomposed and released in the rat plasma to release the active drug (pregnenolone), and the decomposition rate after 15 minutes is greater than 90%, indicating that the pregnane enolone derivative provided by the present invention is derived.
  • the substance can rapidly decompose the pregnenolone in the whole blood of the rat to exert a therapeutic effect.

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Abstract

本发明涉及医药领域，具体涉及一类水溶性别孕烯醇酮衍生物、包含其的药物组合物及其用于预防或治疗中枢神经系统病症、用于镇静催眠、用于治疗阿尔茨海默症、用于治疗癫痫或者用于治疗抑郁症特别是治疗产后抑郁症的用途。

Description

一类水溶性别孕烯醇酮衍生物及其用途
相关申请的交叉引用
本申请要求2016年12月5日提交的中国专利申请201611101726.X的优先权，所述申请的公开内容以其整体援引加入本文。
发明领域
本发明涉及医药领域，具体涉及一类水溶性别孕烯醇酮衍生物、包含其的药物组合物及其用于预防或治疗中枢神经系统病症、用于镇静催眠、用于治疗阿尔茨海默症、用于治疗癫痫或者用于治疗抑郁症特别是产后抑郁症的用途。
发明背景
神经甾体(Neurosteroid)在人体中发挥着重要的生理作用，其在体内合成受损会导致不同的神经(CN 104736158 A)或精神疾病(Expert Opin Ther Targets.2014；18(6):679-90)。神经甾体种类繁多，其中别孕烯醇酮(Allopregnanolone)是人体内GABA(γ-氨基丁酸)受体激动剂，其可以与GABA结合，发挥生理作用(J Physiol.2001；537(Pt 2):453–465)。科学家们已对别孕烯醇酮的治疗用途(如治疗阿尔茨海默症(1.Alzheimer's Assoc Int Conf(AAIC),2013,Abst P4-012；和2.12th IntConf Alzheimer Parkinson Dis(AD/PD),2015,Abst 155)、癫痫(1.Epilepsia 2013,54:81；2.68th Annu Meet Am Acad Neurol(AAN),2016,Abst P4.210；和3.68th Annu Meet Am Acad Neurol(AAN),2016,Abst S14.003)和产后抑郁症(DailyDrugNews.com,2015年6月11日)等神经系统病症)进行了大量研究。
在中国专利申请CN 104736158 A中公开了将别孕烯醇酮与环糊精配制形成组合物，并将其静脉输注以治疗癫痫或持续性癫痫的方法。在该专利申请的别孕烯醇酮与环糊精的组合物中，环糊精所占比例为1～30％，其血药浓度为50～2300nM，治疗过程长达24小时以上。然而，环糊精为高分子化 合物，具有一定肾毒性风险(药用超分子材料环糊精衍生物的安全性研究，中国材料科技与设备，2009年第5期，第1-3页)，因而存在安全性隐患。
由于别孕烯醇酮是甾体类化合物，在水中溶解度较小。因此开发具有改善的水溶性以及提高的安全性的别孕烯醇酮衍生物很有必要。
发明概述
根据本发明的一个方面，本发明提供一类水溶性别孕烯醇酮衍生物。所述水溶性别孕烯醇酮衍生物具有良好的物理/化学稳定性和良好的水溶性，并且在体内可快速分解并释放出活性药物(别孕烯醇酮)，进而迅速产生药理作用。
本发明的水溶性别孕烯醇酮衍生物为通式(I)的化合物或者其药学可接受的盐、立体异构体、多晶型物、或溶剂合物：
Figure PCTCN2017114590-appb-000001
其中，
Figure PCTCN2017114590-appb-000002
X为H或F；
Y为H、F或者任选地被一个或多个F取代的C1-6烷基；
n为0、1、2、3、4、5或6；
W为W1或W2；
W1为NR1R2·A或
Figure PCTCN2017114590-appb-000003
R1和R2各自独立地为H、任选地被苯基取代的C1-6烷基或C3-6环烷基；
m为0、1、2或3；
A不存在或者为药学可接受的酸；
W2为-COOH、-OPO3(H)2、-PO3(H)2、-COO(M)1/t、-OPO3(M)2/t或 -PO3(M)2/t；
M为金属离子、铵离子或碱性氨基酸阳离子；并且
t为M所带的电荷数。
本发明的另一方面提供药物组合物，其包含预防或治疗有效量的本发明的通式(I)的化合物或其药学可接受的盐、立体异构体、多晶型物或溶剂合物以及一种或多种药学可接受的载体。
本发明的另一方面提供本发明的通式(I)的化合物或其药学可接受的盐、立体异构体、多晶型物或溶剂合物或者本发明的药物组合物在制备用于预防或治疗中枢神经系统病症、用于镇静催眠、用于治疗阿尔茨海默症、用于治疗癫痫或者用于治疗抑郁症特别是产后抑郁症的药物中的用途。
本发明的另一方面提供本发明的通式(I)的化合物或其药学可接受的盐、立体异构体、多晶型物或溶剂合物或者本发明的药物组合物，其用于预防或治疗中枢神经系统病症、用于镇静催眠、用于治疗阿尔茨海默症、用于治疗癫痫或者用于治疗抑郁症特别是产后抑郁症。
本发明的另一方面提供预防或治疗中枢神经系统病症、镇静催眠、治疗阿尔茨海默症、治疗癫痫或者治疗抑郁症特别是产后抑郁症的方法，其包括向有需要的个体给药预防或治疗有效量的本发明的通式(I)的化合物或其药学可接受的盐、立体异构体、多晶型物或溶剂合物或者本发明的药物组合物。
具体实施方式
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
本文所用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
本文所用的术语“C1-6烷基”是指具有1-6个(例如1、2、3、4、5或6个)碳原子的饱和的直链或支链烃基，例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基等，优选甲基、乙基、丙基、异丙基、丁基或异丁基，更优选甲基、乙基或丙基。
本文所用的术语“C3-6环烷基”是指具有3-6个(例如3、4、5或6个)碳原子的饱和的单环烃基，例如环丙基、环丁基、环戊基或环己基。
本文所用的术语“C6-14芳基”是指含有6至14个碳原子的芳族基团，诸如苯基或萘基。
本发明的化合物的药学可接受的盐包括其与药学可接受的酸形成的盐以及其与药学可接受的碱形成的盐。
本文所用的术语“药学可接受的酸”是指可药用的酸，例如盐酸、氢溴酸、硫酸、硝酸、磷酸、碳酸、甲酸、乙酸、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、甲磺酸、三氟甲磺酸、乙二磺酸、羟乙基磺酸、1,5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、乳酸、苯磺酸、对甲苯磺酸、丙二酸、丁二酸、戊二酸、己二酸、马来酸、富马酸、乳酸、酒石酸、枸橼酸、苹果酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、甲基硫酸、十二烷基硫酸、谷氨酸、天冬氨酸、葡糖酸、葡糖醛酸或其任意组合。
本文所用的术语“药学可接受的碱”是指可药用的碱，例如无机碱(碱金属氢氧化物或碱土金属氢氧化物等)或有机碱(例如胺(伯胺、仲胺或叔胺)等)。适合的盐的实例包括但不限于得自氨基酸、氨、伯胺、仲胺和叔胺以及环胺的有机盐(例如二乙胺盐、哌啶盐、吗啉盐、哌嗪盐、胆碱盐、葡甲胺盐、氨丁三醇盐等)，以及得自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
本文所用的术语“碱性氨基酸”是指水解生成的氢氧根负离子多于氢正离子的氨基酸，例如精氨酸、赖氨酸或组氨酸。
本文所用的术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和 单独的非对映异构体。
本发明的化合物可以结晶形式或多晶型物形式存在，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
本发明的化合物可以其溶剂合物特别是水合物的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，例如水、乙醇、异丙醇、乙酸乙酯或丙酮。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
化合物
根据本发明的一个实施方案中，本发明提供水溶性别孕烯醇酮衍生物，其为通式(I)的化合物或者其药学可接受的盐、立体异构体、多晶型物、或溶剂合物：
Figure PCTCN2017114590-appb-000004
其中，
Figure PCTCN2017114590-appb-000005
X为H或F；
Y为H、F或者任选地被一个或多个F取代的C1-6烷基；
n为0、1、2、3、4、5或6；
W为W1或W2；
W1为NR1R2·A或
Figure PCTCN2017114590-appb-000006
R1和R2各自独立地为H、任选地被苯基取代的C1-6烷基或C3-6环烷基；
m为0、1、2或3；
A不存在或者为药学可接受的酸；
W2为-COOH、-OPO3(H)2、-PO3(H)2、-COO(M)1/t、-OPO3(M)2/t或-PO3(M)2/t；
M为金属离子、铵离子或碱性氨基酸阳离子；并且
t为M所带的电荷数。
根据本发明的一个实施方案，Y为F、CF3、CH2F或CHF2。
根据本发明的一个实施方案，W为W1。
根据本发明的一个实施方案，R1和R2各自独立地为任选地被苯基取代的C1-6烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基或苄基。
根据本发明的一个实施方案，R1和R2各自独立地为C3-6环烷基，例如环丙基、环丁基、环戊基或环己基。
根据本发明的一个实施方案，R1和R2各自独立地为H、甲基、乙基、丙基、异丙基、丁基、异丁基、苄基、环丙基、环丁基、环戊基或环己基。
根据本发明的一个实施方案，R1和R2不同时为H。
根据本发明的一个实施方案，W1选自
Figure PCTCN2017114590-appb-000007
Figure PCTCN2017114590-appb-000008
根据本发明的一个实施方案，A为盐酸、氢溴酸、硫酸、硝酸、磷酸、碳酸、甲酸、乙酸、丙酸、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、甲磺酸、三氟甲磺酸、乙磺酸、乙二磺酸、羟乙基磺酸、1,5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、乳酸、苯磺酸、对甲苯磺酸、丙二酸、丁二酸、戊二酸、己二酸、马来酸、富马酸、酒石酸、枸橼酸、苹果酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、甲基硫酸、十二烷基硫酸、谷氨酸、天冬氨酸、葡糖酸、葡糖醛酸或其任意组合。
根据本发明的一个实施方案，W为W2。
根据本发明的一个实施方案，M为碱金属离子(例如锂离子、钠离子或钾离子)、碱土金属离子(例如镁离子、锌离子或钙离子)或者三价金属离子(例如铝离子)。
根据本发明的一个实施方案，M为由通式(NR3R4R5R6)+或
Figure PCTCN2017114590-appb-000009
表示的铵离子，其中R3、R4、R5和R6各自独立地为H、 任选地被苯基取代的烷基、环烷基或芳基；并且p为0、1、2或3。
在优选的实施方案中，R3、R4、R5和R6各自独立地为H、任选地被苯基取代的C1-6烷基、C3-6环烷基或C6-14芳基。在更优选的实施方案中，R3、R4、R5和R6各自独立地为H、甲基、乙基、丙基、异丙基、丁基、异丁基、苯基、苄基、环丙基、环丁基、环戊基或环己基。在最优选的实施方案中，R3和R4各自独立地为H、甲基或乙基。
在优选的实施方案中，M选自
Figure PCTCN2017114590-appb-000010
根据本发明的一个实施方案，M为精氨酸+H+、赖氨酸+H+或组氨酸+H+。
在优选的实施方案中，W2选自-COONa、-COOK、-P(＝O)(OLi)2、-P(＝O)(ONa)2、-P(＝O)(OK)2、-P(＝O)O2Mg、-OP(＝O)(ONa)2和-OP(＝O)O2Ca。
在一个实施方案中，X与Y不同，同时与X和Y连接的碳原子为单一的R构型、单一的S构型或R与S构型的混合物。
本发明涵盖对各个实施方案进行任意组合所得的化合物。
根据本发明的一个实施方案，在本发明的化合物中R基团选自：
Figure PCTCN2017114590-appb-000011
Figure PCTCN2017114590-appb-000012
药物组合物
本发明的另一实施方案提供药物组合物，其包含预防或治疗有效量的本发明的通式(I)的化合物或其药学可接受的盐、立体异构体、多晶型物或溶剂合物以及一种或多种药学可接受的载体。
本发明中的“药学可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需 要包含少量的湿润剂、乳化剂(例如吐温-80等)或pH缓冲剂。
本发明的药物组合物可以适合的途径给药。优选地，本发明的药物组合物通过口服、静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药。
对于这些给药途径，可以适合的剂型给予本发明的组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
治疗方法和用途
本发明的化合物可用于治疗可通过给药别孕烯醇酮来治疗的各种疾病。
本发明的另一实施方案提供本发明的通式(I)的化合物或其药学可接受的盐、立体异构体、多晶型物或溶剂合物或者本发明的药物组合物在制备用于预防或治疗中枢神经系统病症、用于镇静催眠、用于治疗阿尔茨海默症、用于治疗癫痫或者用于治疗抑郁症特别是产后抑郁症的药物中的用途。
本发明的另一实施方案提供本发明的通式(I)的化合物或其药学可接受的盐、立体异构体、多晶型物或溶剂合物或者本发明的药物组合物，其用于预防或治疗中枢神经系统病症、用于镇静催眠、用于治疗阿尔茨海默症、用于治疗癫痫或者用于治疗抑郁症特别是产后抑郁症。
本发明的另一实施方案提供预防或治疗中枢神经系统病症、镇静催眠、治疗阿尔茨海默症、治疗癫痫或者治疗抑郁症特别是产后抑郁症的方法，其包括向有需要的个体给药预防或治疗有效量的本发明的通式(I)的化合物或其药学可接受的盐、立体异构体、多晶型物或溶剂合物或者本发明的药物组合物。
在本发明的另一实施方案中，所述中枢神经系统病症选自外伤性脑损伤、特发性震颤、癫痫(包括难治性持续性癫痫、罕见基因性癫痫(例如Dravet综合征和Rett综合征))、抑郁症(包括产后抑郁症)和阿尔茨海默症。
如本文中所使用的术语“治疗有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加 剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg、25mg等。
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
本发明的化合物的有益效果
本发明的化合物在保留别孕烯醇酮的药理活性的前提下，通过将别孕烯醇酮的羟基进行结构修饰得到水溶性别孕烯醇酮衍生物，其具有良好的物理/化学稳定性，将包含其的水溶液注射后其在体内可释放出活性药物，从而发挥药理作用。令人惊讶地是，本发明的水溶性别孕烯醇酮衍生物水溶性好，因此可以被制成合适的液体制剂，且其在体内容易分解释放活性 药物。因此，本发明的水溶性别孕烯醇酮衍生物可以改善别孕烯醇酮的水溶性，减少由辅料造成的副作用。
实施例
为了使本发明的目的和技术方案更加清楚，下面对本发明的优选实施例进行详细的描述。要说明的是：以下实施例只用于对本发明进行进一步的说明，而不能理解为对本发明保护范围的限制。本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。
实施例1：化合物1
步骤1)4-(二甲氨基)-2-氟代丁酰氯盐酸盐(中间体1)的制备
将4-(二甲氨基)-2-氟代丁酸盐酸盐(10mmol)置于10ml二氯亚砜中，缓慢升温至40℃，反应4小时。通过减压蒸发除去二氯亚砜，加入无水二氯甲烷(DCM)(15ml)，搅拌后通过减压蒸发除去溶剂。在残余物中加入无水二氯甲烷(20ml)，所得的溶液供下一步骤中使用。
步骤2)化合物1的制备
于-78℃下，将别孕烯醇酮(4.5mmol)和4-二甲氨基吡啶(DMAP)(8.2mmol)溶于20ml无水二氯甲烷中，缓慢滴加步骤1)制备的中间体1的二氯甲烷溶液。经HPLC检测反应，待反应完全后，用pH为约1.0的盐酸水溶液洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去溶剂，将残余物通过制备色谱法纯化，得到化合物1，Mass(ESI)[M+H]+＝450.31。
实施例2：化合物2
在室温下，将别孕烯醇酮(10mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(80mmol)、(R)-4-(二甲氨基)-2-氟代丁酸盐酸盐(70mmol)和DMAP(1mmol)加入干燥的二氯甲烷中，在氮气保护下加热回流。经HPLC监测完毕后，将反应液冷却至室温，依次用pH＝3的盐酸水溶液(70ml*3次)和饱和食盐水(70ml*1次)洗涤，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去溶剂，将残余物用异丙醇重结晶，得到化合物2，Mass(ESI)[M+H]+＝450.30。
实施例3：化合物3
除在步骤1)中用(S)-4-(二甲氨基)-2-氟代丁酸盐酸盐(10mmol)代替 4-(二甲氨基)-2-氟代丁酸盐酸盐外，按照与实施例1中类似的操作制备得到化合物3，Mass(ESI)[M+H]+＝450.31。
实施例4：化合物6
除在步骤1)中用(R)-5-(二乙氨基)-2-(三氟甲基)戊酸盐酸盐(10mmol)代替4-(二甲氨基)-2-氟代丁酸盐酸盐外，按照与实施例1中类似的操作制备得到(R)-5-(二乙氨基)-2-(三氟甲基)戊酸别孕烯醇酮酯盐酸盐。将该盐酸盐溶于二氯甲烷中，用含有甲磺酸钠(用甲磺酸调节pH＝3)的水溶液洗涤，将有机层干燥，过滤，蒸去溶剂，得到化合物6，Mass(ESI)[M+H]+＝514.32。
实施例5：化合物7
在室温下，将别孕烯醇酮(4.5mmol)和4-二甲氨基吡啶(8.2mmol)溶于20ml无水二氯甲烷中，加入二环己基碳二亚胺(10mmol)和3-(二甲氨基)-2-氟代丙酸盐酸盐(8mmol)，在室温反应。HPLC检测反应，待反应完全后，用pH为约1.0的盐酸水溶液洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去溶剂，将残余物用制备色谱法纯化得到化合物7，Mass(ESI)[M+H]+＝436.30。
实施例6：化合物11
于-40℃下，将别孕烯醇酮(4.5mmol)和4-二甲氨基吡啶(8.2mmol)溶于20ml无水二氯甲烷中，缓慢滴加(R)-4-氯-3-氟代-4-氧代丁酸苄酯(以(R)-4-(苄氧基)-2-氟代-4-氧代丁酸为原料，按实施例1步骤1)制得)在二氯甲烷中的溶液。经HPLC检测反应，待反应完全后，用pH为约1.0的盐酸水溶液洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去溶剂。将所得产物溶于无水四氢呋喃(45ml)中，将其在钯炭(5-10％，w/w)催化下氢解。在氢解完全后滤去钯炭，蒸发除去溶剂，将残余物用制备色谱法纯化得到相应的产物。在冰浴下，向含有所得产物的无水四氢呋喃溶液中缓缓加入等当量的叔丁醇钠的叔丁醇溶液。有固体析出，过滤，将滤饼用少量四氢呋喃洗涤并干燥后得到化合物11，Mass(ESI)[M-H]-＝435.23。
实施例7：化合物16
于-40℃下，将别孕烯醇酮(4.5mmol)和4-二甲氨基吡啶(8.2mmol)溶于20ml无水二氯甲烷中，缓慢滴加(R)-二苄基(4-氯-3-氟-4-氧代丁基)磷酸酯(以(R)-4-((双(苄氧基)磷酰基)氧基)-2-氟丁酸为原料，按实施例1步骤1)制 得)在二氯甲烷中的溶液。经HPLC检测反应，待反应完全后，用pH为约1.0的盐酸水溶液洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去溶剂，将所得产物溶于无水四氢呋喃(45ml)中，在钯炭(5-10％，w/w)催化下氢解。在氢解完全后滤去钯炭，蒸发除去溶剂，将残余物通过制备色谱法纯化得到相应的酸。在冰浴下，向所述酸的无水四氢呋喃溶液中缓缓加入含与所述酸等当量的叔丁醇钠的叔丁醇溶液。有固体析出，过滤，将滤饼用少量四氢呋喃洗涤并干燥后，得到化合物16，Mass(ESI)[M+H]-＝501.22。
实施例8：化合物22
在室温下，将别孕烯醇酮(4.5mmol)和4-二甲氨基吡啶(8.2mmol)溶于20ml无水二氯甲烷中，加入二环己基碳二亚胺(10mmol)和(S)-3-(苄氧基)-2-氟代-3-氧代丙酸(8mmol)，在室温下反应。通过HPLC检测反应，待反应完全后，用pH为约1.0的盐酸水溶液洗涤DCM层，用无水硫酸钠干燥有机层，过滤，通过旋转蒸发除去溶剂。将所得产物溶于无水四氢呋喃(30ml)，在钯碳(5-10％，w/w)催化下氢解。在氢解完全后滤去钯炭，蒸发除去溶剂，将残余物通过制备色谱法制备相应的酸。在冰浴下，向所述酸中加入与之等当量的精氨酸，有固体析出，过滤，将滤饼用冰冷的四氢呋喃洗涤，得到化合物22，Mass(ESI)[M-H]-＝421.22。
按照与实施例1或实施例2类似的方法制备以下化合物：
化合物 Mass
4 Mass(ESI)[M+H]+＝487.31
5 Mass(ESI)[M+H]+＝464.33
8 Mass(ESI)[M+H]+＝476.32
9 Mass(ESI)[M+H]+＝532.39
10 Mass(ESI)[M-H]-＝421.22
12 Mass(ESI)[M-H]-＝449.26
13 Mass(ESI)[M-2K+H]-＝471.19
14 Mass(ESI)[M-2K+H]-＝499.22
15 Mass(ESI)[M-2Li+H]-＝549.21
17 Mass(ESI)[M-Ca+H]-＝501.19
18 Mass(ESI)[M+H]+＝450.31
19 Mass(ESI)[M+H]+＝487.30
20 Mass(ESI)[M+H]+＝490.33
21 Mass(ESI)[M-H]-＝449.27
23 Mass(ESI)[M+H]-＝499.17
24 Mass(ESI)[M+H]-＝501.19
实施例9：化合物在5％葡萄糖水溶液中的稳定性试验
分别称取待测化合物1mg，将其置于5％葡萄糖(2ml)中，配制成浓度为约0.5mg/ml的溶液，将其在室温下放置，于多个时间点(0.5h、1h、2h、3h和5h)取样，并将样品通过HPLC检测，结果如下：
Figure PCTCN2017114590-appb-000013
实验结果表明，所测试的本发明的化合物在5％葡萄糖溶液中放置后(例如5h后)分解率小于1％，这说明其在5％葡萄糖溶液中稳定性良好，适合注射给药。
实施例10：化合物在水(25℃)中的溶解度表
化合物名称 溶解度(mg/ml)
化合物1 ＞0.5mg/ml
化合物2 ＞0.5mg/ml
化合物3 ＞0.5mg/ml
化合物10 ＞0.4mg/ml
化合物11 ＞0.4mg/ml
化合物16 ＞0.3mg/ml
说明本发明提供的化合物在水中具有较好的溶解度，改变了别孕烯醇酮的溶解度。
实施例11：化合物在大鼠全血中的分解实验
分别称取待测化合物1mg，将其置于水中(2ml)中以配制成浓度为约0.5mg/ml的溶液，作为储备液备用。取大鼠全血(0.45ml)置于2ml EP管中，放入37℃水浴中预热20s，然后快速加入化合物的储备液(50μL)，混匀后，将EP管置于37℃水浴中并开始计时。在预定的时间点(1min、5min、10min、15min)，立刻注入乙腈(1ml)，将溶液离心5min(15000转/分)，用0.22μm的滤膜过滤，并通过HPLC检测，结果如下：
Figure PCTCN2017114590-appb-000014
实验结果表明，所测试的本发明的化合物在大鼠血浆中可以分解释放出活性药物(别孕烯醇酮)，15min后的分解率大于90％，表明本发明提供的别孕烯醇酮衍生物，在大鼠全血中可以快速分解出别孕烯醇酮，发挥治疗作用。
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域 技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (12)

  1. 通式(I)的化合物或者其药学可接受的盐、立体异构体、多晶型物、或溶剂合物：
    Figure PCTCN2017114590-appb-100001
    其中，
    Figure PCTCN2017114590-appb-100002
    X为H或F；
    Y为H、F或者任选地被一个或多个F取代的C1-6烷基；
    n为0、1、2、3、4、5或6；
    W为W1或W2；
    W1为NR1R2·A或
    Figure PCTCN2017114590-appb-100003
    R1和R2各自独立地为H、任选地被苯基取代的C1-6烷基或C3-6环烷基；
    m为0、1、2或3；
    A不存在或者为药学可接受的酸；
    W2为-COOH、-OPO3(H)2、-PO3(H)2、-COO(M)1/t、-OPO3(M)2/t或-PO3(M)2/t；
    M为金属离子、铵离子或碱性氨基酸阳离子；并且
    t为M所带的电荷数。
  2. 如权利要求1所述的通式(I)的化合物或者其药学可接受的盐、立体异构体、多晶型物或溶剂合物，其特征在于：Y为F、CF3、CH2F或CHF2。
  3. 如权利要求1所述的通式(I)的化合物或者其药学可接受的盐、立体异构体、多晶型物或溶剂合物，其特征在于：当X与Y不同时，同时与X 和Y连接的碳原子为单一的R构型、单一的S构型或者R与S构型的混合物。
  4. 如权利要求1所述的通式(I)的化合物或者其药学可接受的盐、立体异构体、多晶型物或溶剂合物，其特征在于：R1和R2各自独立地为H、甲基、乙基、丙基、异丙基、丁基、异丁基、苄基、环丙基、环丁基、环戊基或环己基。
  5. 如权利要求1所述的通式(I)的化合物或者其药学可接受的盐、立体异构体、多晶型物或溶剂合物，其特征在于：所述金属离子为锂离子、钠离子、钾离子、镁离子、锌离子、钙离子或铝离子。
  6. 如权利要求1所述的通式(I)的化合物或者其药学可接受的盐、立体异构体、多晶型物或溶剂合物，其特征在于：所述铵离子为(NR3R4R5R6)+或
    Figure PCTCN2017114590-appb-100004
    R3、R4、R5和R6各自独立地为H、任选地被苯基取代的C1-6烷基、C3-6环烷基或C6-14芳基；并且
    p为0、1、2或3。
  7. 如权利要求6所述的通式(I)的化合物或者其药学可接受的盐、立体异构体、多晶型物或溶剂合物，其特征在于：R3、R4、R5和R6各自独立地为H、甲基、乙基、丙基、异丙基、丁基、异丁基、苯基、苄基、环丙基、环丁基、环戊基或环己基。
  8. 如权利要求1所述的通式(I)的化合物或者其药学可接受的盐、立体异构体、多晶型物或溶剂合物，其特征在于：所述碱性氨基酸阳离子为精氨酸+H+、赖氨酸+H+或组氨酸+H+。
  9. 如权利要求1所述的通式(I)的化合物或者其药学可接受的盐、立体 异构体、多晶型物或溶剂合物，其中R选自：
    Figure PCTCN2017114590-appb-100005
  10. 药物组合物，其包含预防或治疗有效量的权利要求1-9中任一项的通式(I)的化合物或其药学可接受的盐、立体异构体、多晶型物或溶剂合物以及一种或多种药学可接受的载体。
  11. 权利要求1-9中任一项的通式(I)的化合物或其药学可接受的盐、立体异构体、多晶型物或溶剂合物或者权利要求10的药物组合物在制备用于预防或治疗中枢神经系统病症、用于治疗阿尔茨海默症、用于治疗癫痫或者用于治疗抑郁症特别是产后抑郁症的药物中的用途。
  12. 权利要求11的用途，其中所述中枢神经系统病症选自外伤性脑损伤、特发性震颤、癫痫(包括难治性持续性癫痫、罕见基因性癫痫(例如Dravet综合征和Rett综合征))、抑郁症(包括产后抑郁症)和阿尔茨海默症。
PCT/CN2017/114590 2016-12-05 2017-12-05 一类水溶性别孕烯醇酮衍生物及其用途 WO2018103626A1 (zh)

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CZ309617B6 (cs) * 2019-04-05 2023-05-24 Ústav organické chemie a biochemie AV ČR, v. v. i 3α5ß-Neuroaktivní steroidy pro léčbu epilepsie a záchvatových onemocnění

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CN113368084A (zh) * 2020-03-10 2021-09-10 上海喀露蓝科技有限公司 含有大麻二酚，丙泊酚前药和别孕烯醇酮前药化合物的药物组合物及其在医药上的应用
CN114907436A (zh) * 2021-02-08 2022-08-16 南京诺瑞特医药科技有限公司 3-羟基-5-孕烷-20-酮衍生物的晶型及其制备方法和用途
WO2023040851A1 (zh) * 2021-09-14 2023-03-23 南京迈诺威医药科技有限公司 一种水溶性别孕烷醇酮衍生物及其制备方法和用途
CN117801047A (zh) * 2023-01-19 2024-04-02 北京华睿鼎信科技有限公司 神经甾体衍生物及其用途

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