WO2021098872A1 - Dérivé d'alloprégnénolone phosphonamide, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Dérivé d'alloprégnénolone phosphonamide, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
WO2021098872A1
WO2021098872A1 PCT/CN2020/130719 CN2020130719W WO2021098872A1 WO 2021098872 A1 WO2021098872 A1 WO 2021098872A1 CN 2020130719 W CN2020130719 W CN 2020130719W WO 2021098872 A1 WO2021098872 A1 WO 2021098872A1
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disorder
pharmaceutically acceptable
compound
stereoisomer
tautomer
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PCT/CN2020/130719
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English (en)
Chinese (zh)
Inventor
林其先
宫爱申
刘建余
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上海喀露蓝科技有限公司
澳创药业有限公司
四川夏派森医药科技有限公司
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Publication of WO2021098872A1 publication Critical patent/WO2021098872A1/fr

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    • 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
    • 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
    • A61K31/664—Amides of phosphorus acids
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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 an allopregnenolone phosphonamide derivative, an intermediate and a preparation method thereof, and use in the preparation of medicines.
  • Allopregnenolone a metabolite of naturally occurring neurosteroids and progesterone, is an allosteric GABA-A receptor modulator.
  • allopregnenolone is administered by injection and cannot be administered orally.
  • the present invention transforms the hydroxyl group of allopregnenolone into precursors to improve its solubility and stability, so as to improve the physical and chemical properties of the drug, and improve the absorption, distribution, metabolism and excretion process of the drug in the body.
  • Improve the oral bioavailability increase the selectivity of the drug's action on the target site, reduce the toxic and side effects of the drug, and prolong the action time.
  • these drugs can release allopregnenolone at a certain rate of hydrolysis according to the design requirements, thereby treating central nervous system-related diseases, including tremor, depression, postpartum depression, insomnia, mood disorders, and convulsions.
  • Disorders memory disorders, attention disorders, anxiety, bipolar disorder, schizophrenia, bipolar disorder, schizoaffective mental disorder, mood disorder, anxiety disorder, personality disorder, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder, Autism spectrum disorder, depression, social anxiety disorder, obsessive-compulsive disorder, pain, sleep disorders, memory disorders, dementia, Alzheimer's disease, episodic disease, traumatic brain injury, stroke, addictive disorder, self Autism, Huntington’s disease, Parkinson’s disease, Rett syndrome, withdrawal syndrome or tinnitus; thereby helping to overcome the shortcomings of poor water solubility and stability of allopregnenolone.
  • the physicochemical properties of allopregnenolone are changed through the phosphoamide group, such as changing the original properties, stability, fat solubility, etc. of allopregnenolone, thereby changing the transmembrane absorption, distribution and metabolic behavior in the body.
  • the phosphoamide-modified drug enters the body, it is hydrolyzed to release allopregnenolone under the action of hydrolase in the body.
  • the present invention relates to a compound represented by general formula (I), its stereoisomer, its tautomer or its pharmaceutically acceptable salt,
  • R 1 is selected from C 1 -C 6 alkoxy or C 3 -C 8 cycloalkyloxy
  • R 2 is selected from a hydrogen atom or a C 1 -C 6 alkyl group
  • R 3 and R 4 are each independently selected from a hydrogen atom or a C 1 -C 6 alkyl group, wherein the alkyl group is optionally further substituted with one or more halogens;
  • R 3 and R 4 together with the carbon atoms to which they are attached may form a 3- to 6-membered ring, the ring contains 0 to 6 heteroatoms selected from N, O or S, and the ring may optionally further Is substituted by one or more substituents selected from hydroxyl, halogen or amino; and
  • R 5 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or benzyl.
  • a compound of general formula (I), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof are a compound of general formula (II) Compound, its stereoisomer, its tautomer or its pharmaceutically acceptable salt:
  • R 1 to R 5 are as described in the general formula (I).
  • R 1 is selected from a C 1 -C 6 alkoxy group
  • R 2 is selected from a hydrogen atom
  • one of R 3 and R 4 is a hydrogen atom and the other is a C 1 -C 6 alkyl group
  • R 5 is selected from a C 1 -C 6 alkyl.
  • Typical compounds of the present invention include, but are not limited to:
  • the present invention relates to a pharmaceutical composition containing a therapeutically effective dose of a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier And excipients.
  • the present invention relates to a compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its composition, used in the preparation of treatment and/or prevention of diseases related to the central nervous system Uses, wherein the central nervous system related diseases are selected from tremor, depression, insomnia, mood disorders, convulsive disorders, memory disorders, attention disorders, anxiety, bipolar disorder, schizophrenia, bipolar disorder, emotion Schizophrenic disorder, mood disorder, anxiety disorder, personality disorder, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder, autism spectrum disorder, psychiatric depression, social anxiety disorder, obsessive-compulsive disorder, pain, sleep disorder, memory disorder , Dementia, Alzheimer’s disease, paroxysmal disease, traumatic brain injury, stroke, addictive disorder, autism, Huntington’s disease, Parkinson’s disease, Rett syndrome, withdrawal syndrome or tinnitus; among them, preferred It is tremor or depression; the depression described therein is preferably postpartum depression.
  • the present invention relates to a compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition, which is used in the preparation of a compound for improving the oral bioavailability of a drug and prolonging the parent drug The pharmacodynamic half-life of the drug, reducing the dosage and frequency of administration, or extending the half-life of the drug.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H) and deuterium (D, also known as heavy hydrogen).
  • tritium T, also known as superheavy hydrogen
  • oxygen isotopes include 16 O, 17 O and 18 O
  • sulfur isotopes include 32 S, 33 S, 34 S and 36 S
  • nitrogen isotopes include 14 N and 15 N
  • the isotope of fluorine is 19 F
  • the isotope of chlorine includes 35 Cl and 37 Cl
  • the isotope of bromine includes 79 Br and 81 Br.
  • Alkyl when regarded as a group or a part of a group refers to a straight or branched aliphatic hydrocarbon group containing 1 to 20 carbon atoms. It is preferably 1 to 10 alkyl groups, more preferably 1 to 6 alkyl groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait.
  • Alkyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups: alkyl, alkoxy, halogen, hydroxyl, nitro, cyano, cycloalkyl, ring Alkyloxy or amino.
  • Cycloalkyl refers to a saturated or partially saturated monocyclic, fused ring, bridged ring, and spirocyclic carbocyclic ring, but none of the rings has a fully conjugated ⁇ -electron aromatic ring system. It is preferably a 3 to 12 membered cycloalkyl group, more preferably a 3 to 8 membered cycloalkyl group, and most preferably a 3 to 6 membered cycloalkyl group.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl.
  • Cycloalkyl groups can be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups: alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, cycloalkyloxy or amino.
  • Alkoxy refers to a (alkyl-O-) group. Among them, the alkyl group is defined in this article. C 1 -C 6 alkoxy groups are preferred. Examples thereof include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • Cycloalkyloxy refers to a (cycloalkyl-O-) group. Among them, cycloalkyl see the relevant definitions herein. C 3 -C 8 cycloalkoxy is preferred. Examples thereof include, but are not limited to: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • Amino refers to -NH 2 .
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • DMSO dimethyl sulfoxide
  • Optional or “optionally” means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur.
  • Alkyl optionally substituted by F means that an alkyl group may but need not be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • “Pharmaceutical composition” means a mixture of one or more of the compounds described in the text or their physiologically/pharmaceutically acceptable salts and other components, wherein the other components include physiologically/pharmaceutically acceptable carriers and excipients.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, ingredients Granules, lubricants, binders, disintegrants, etc.
  • Prodrug refers converted by solvolysis or biologically active drug under physiological conditions.
  • the prodrug of the present invention is prepared by modifying the functional groups in allopregnenolone, and the modification can be removed by conventional operations or in vivo to obtain allopregnenolone.
  • Stepoisomers refer to isomers arising from the different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • Effective dose refers to the amount of a compound that causes a physiological or medical response in a tissue, system, or subject. This amount is sought and includes one or more of the compounds that are sufficient to prevent the disease or condition being treated when administered to the subject. The amount of the compound that occurs or alleviates the symptoms to a certain degree.
  • pharmaceutically acceptable salts and pharmaceutically acceptable salts have the same definition.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • the mass spectrum is measured by an LC/MS instrument, and the ionization method can be ESI or APCI.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. ⁇ 0.5mm.
  • HPLC measurement uses Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18 100x4.6mm).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the compound was purified by silica gel column chromatography and thin layer chromatography, wherein the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: acetic acid Ethyl; D: petroleum ether: dichloromethane system; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents can also be added to adjust, such as acetic acid or triethylamine.
  • the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: acetic acid Ethyl; D: petroleum ether: dichloromethane system; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents
  • Ethyl diethoxyphosphonocarboxylate 1a (210.0 g, 1.0 mol) was dissolved in 800 mL of acetonitrile, and bromotrimethylsilane (460.0 g, 3.0 mol) was added dropwise, and reacted at 65°C for 2 hours. After the reaction, concentrate under reduced pressure to obtain the crude ethoxycarbonylphosphonic acid trimethylsilyl ester, dissolve it in 650mL dichloromethane, add oxalyl chloride (510.0g, 4.0mol), N , N-Dimethylformamide (10 drops), warm to room temperature and react for 2 hours.
  • Ethyl dichlorophosphonocarboxylate (10.0g, 52.4mol) was dissolved in 100mL of dichloromethane, and allopregnenolone (10.0g, 31.3mmol) was added at -20°C.
  • Synthesis of J.Med.Chem. 2009,52,6012-6023) and triethylamine (11.5g, 0.112mol) in dichloromethane (50mL) solution incubate the reaction for 30 minutes, drop in L-alanine isopropyl ester hydrochloride (8.8g , 52.4mmol) in dichloromethane (50mL) solution, triethylamine (11.5g, 0.112mol), stirred at room temperature for 2 hours.
  • Experimental animals 9 healthy adult SD rats, male, 180-250g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Drug preparation accurately weigh a certain amount of test compound, add DMSO and Solutol HS-15 to dissolve, then add physiological saline, vortex to mix evenly.
  • the final dosing solvent ratio was DMSO: Solutol HS-15: physiological saline (10:10:80, v/v/v), and all test compounds were prepared fresh before use.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Anesthesiology (AREA)
  • Addiction (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé représenté par la formule générale (I) ou un stéréoisomère, un tautomère ou un sel pharmaceutiquement acceptable de celui-ci, ainsi qu'une utilisation pharmaceutique associée. Le composé de formule générale (I) est représenté par la structure suivante, et les définitions des groupes de celle-ci sont compatibles avec les définitions dans la description.
PCT/CN2020/130719 2019-11-21 2020-11-23 Dérivé d'alloprégnénolone phosphonamide, son procédé de préparation et son utilisation pharmaceutique WO2021098872A1 (fr)

Applications Claiming Priority (2)

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CN201911150746.X 2019-11-21
CN201911150746.XA CN112824426B (zh) 2019-11-21 2019-11-21 一种别孕烯醇酮膦酰胺衍生物、其制备方法及其在医药上的用途

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009108804A2 (fr) * 2008-02-26 2009-09-03 Emory University Analogues stéroïdiens utilisés en neuroprotection
WO2015081170A2 (fr) * 2013-11-26 2015-06-04 Systamedic Inc. Dérivés de ganaxolone pour le traitement de troubles du système nerveux central
WO2018103626A1 (fr) * 2016-12-05 2018-06-14 江苏恩华络康药物研发有限公司 Dérivé d'alloprégnénolone soluble dans l'eau et son utilisation
CN108517001A (zh) * 2018-05-17 2018-09-11 江苏恩华络康药物研发有限公司 水溶性别孕烯醇酮衍生物及其用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003901813A0 (en) * 2003-04-15 2003-05-01 Vital Health Sciences Pty Ltd Pharmaceutical derivatives
CN107709288A (zh) * 2016-02-03 2018-02-16 四川海思科制药有限公司 一种磷酰胺衍生物及制备方法和用途
CN109400645A (zh) * 2017-08-18 2019-03-01 四川海思科制药有限公司 一种磷酸衍生物及制备方法和用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009108804A2 (fr) * 2008-02-26 2009-09-03 Emory University Analogues stéroïdiens utilisés en neuroprotection
WO2015081170A2 (fr) * 2013-11-26 2015-06-04 Systamedic Inc. Dérivés de ganaxolone pour le traitement de troubles du système nerveux central
WO2018103626A1 (fr) * 2016-12-05 2018-06-14 江苏恩华络康药物研发有限公司 Dérivé d'alloprégnénolone soluble dans l'eau et son utilisation
CN108517001A (zh) * 2018-05-17 2018-09-11 江苏恩华络康药物研发有限公司 水溶性别孕烯醇酮衍生物及其用途

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