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WO2024208226A1 - Composé tétrahydronaphtalène, composition pharmaceutique et utilisation associées - Google Patents

Composé tétrahydronaphtalène, composition pharmaceutique et utilisation associées Download PDF

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Publication number
WO2024208226A1
WO2024208226A1 PCT/CN2024/085661 CN2024085661W WO2024208226A1 WO 2024208226 A1 WO2024208226 A1 WO 2024208226A1 CN 2024085661 W CN2024085661 W CN 2024085661W WO 2024208226 A1 WO2024208226 A1 WO 2024208226A1
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WO
WIPO (PCT)
Prior art keywords
compound
compound according
pharmaceutically acceptable
mmol
long
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/085661
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English (en)
Chinese (zh)
Inventor
李德耀
周溢谦
郭�旗
康宁
张礼军
张健存
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Henovcom Bioscience Co Ltd
Original Assignee
Guangzhou Henovcom Bioscience Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangzhou Henovcom Bioscience Co Ltd filed Critical Guangzhou Henovcom Bioscience Co Ltd
Priority to CN202480022508.3A priority Critical patent/CN121013844A/zh
Publication of WO2024208226A1 publication Critical patent/WO2024208226A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61P25/24—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • the present invention relates to the field of pharmaceutical chemistry, and more particularly to tetralin compounds, stereoisomers, solvates or pharmaceutically acceptable salts thereof, and compositions and uses thereof.
  • Rotigotine is a non-ergot dopamine receptor agonist that can treat Parkinson's disease by stimulating dopamine receptors.
  • rotigotine is also recommended by the European Federation of Neurological Societies, the European Academy of Neurology and the European Sleep Research Society as an effective treatment for RLS.
  • the rotigotine currently approved for the market is a once-a-day transdermal controlled-release patch. In May 2007, it was approved by the US FDA for the adjuvant treatment of early primary Parkinson's disease and late Parkinson's disease, and in February 2012, it was approved by the FDA to add the indication of restless legs syndrome (RLS).
  • patent WO2013067199 discloses a class of polymer conjugates, which connect water-soluble polymers as carriers in the structure of rotigotine to improve the bioavailability of rotigotine and achieve the purpose of long-term effect, but its polymer conjugate has obvious burst release phenomenon;
  • patent WO2016014242 improves the oral bioavailability of rotigotine by structural modification of rotigotine;
  • patent WO2018014277 achieves its long-term effect by connecting long-chain esters of different carbon atoms to rotigotine.
  • Patent applications CN108341798 and CN109415335 disclose a long-acting prodrug derivative of rotigotine, but the melting point of the compound does not exceed 53°C. The low melting point of the compound will bring great difficulties to the large-scale preparation of the preparation, and it is also easy to cause the drug to be stored for a long time.
  • Patent application CN114478476A is the previous research result of the applicant, which discloses a long-acting prodrug derivative of rotigotine.
  • the specific structures disclosed are relatively large, and the melting points of most compounds are above 53°C, and they have good long-acting effects.
  • there is still room for improvement in blood drug concentration and long-acting time which deserves further research and improvement.
  • the purpose of the present invention is to further enhance the long-acting effect of rotigotine prodrugs. Specifically, on the basis of the existing long-acting effect, the present invention maintains a stable effective blood concentration of rotigotine in the body and a longer duration of action. To achieve this purpose, the present invention provides a class of tetralin compounds, stereoisomers, solvates or pharmaceutically acceptable salts thereof.
  • the present application through further research, unexpectedly discovered a compound with a long-term effect of about 40 days or more, and under the premise of increasing the dosage, the release of the drug is still relatively stable, there is no obvious burst release phenomenon, and the blood concentration can be maintained within a safe and effective range for up to about 40 days or more, or even more than 42 days; indicating that when the compound described in the present application is used as a long-acting drug, even if the dosage is large at one time, there is no obvious burst release phenomenon, so the risk of side effects is significantly reduced, the safety is high, and the prodrug can be steadily, slowly, and long-term released and converted into rotigotine, thereby significantly reducing the frequency of administration while maintaining the therapeutic effect.
  • Another object of the present invention is to provide a composition
  • a composition comprising the tetralin compound, its stereoisomer, solvate or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient, carrier or diluent.
  • Another object of the present invention is to provide the tetralin compound, its stereoisomers, solvates or pharmaceutically acceptable salts, and uses of the composition comprising the aforementioned.
  • n is an integer from 14 to 20; and m is 3, 4 or 5.
  • n is an integer from 14 to 18; more preferably, n is 14, 16 or 18.
  • n is 14, 15, 16, 17, 18, 19 or 20; more preferably, n is 14, 16, 18 or 20.
  • n is 14, 15, 16, 17, 18, 19 or 20; more preferably, n is 14, 16, 18 or 20.
  • n is 14, 15, 16, 17, 18, 19 or 20; more preferably, n is 14, 16, 18 or 20.
  • the compound is selected from one of the following structures:
  • the present invention also protects a composition containing the above compound or its stereoisomer, solvate or pharmaceutically acceptable salt, and a pharmaceutically acceptable auxiliary material, carrier or diluent.
  • the present invention also protects the use of the above-mentioned compound or its stereoisomer, solvate or pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of drugs for preventing and/or treating central nervous system diseases.
  • the drug is a long-acting drug.
  • the central nervous system disease is Parkinson's disease, restless legs syndrome or depression.
  • the drug is an injection.
  • the inventors of the present application found in previous studies that the compounds of the general formula (I) generally have a higher melting point (melting point ⁇ 53°C) and can be well prepared into suspension injections. Compared with other rotigotine derivatives in the prior art, the long-acting effect is significantly improved. On this basis, the inventors of the present application conducted further screening studies and unexpectedly found that when m and n in the general formula (I) are specific values, the metabolism of the compound in the organism is further improved, and the long-acting time is also longer. Compared with previous studies, this discovery greatly improves the application prospects and market of the compounds of the present invention.
  • Stereoisomers refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.
  • “Pharmaceutically acceptable” refers to compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems and complications commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a specified substituent.
  • a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted by one or more substituents selected from a specified group, the substituents may be the same or different at each position.
  • rotigotine was prepared by an existing freely practicable method or purchased from a regular commercial channel.
  • EDCI 0.7 g, 3.6 mmol
  • rotigotine (0.84 g, 2.4 mmol)
  • (20-(butylamino)-20-oxoeicosanoyl)glycine 1.3 g, 2.9 mmol
  • HOBT 0.3 g, 2.4 mmol
  • DIPEA 1.3 mL, 7.2 mmol
  • acetonitrile 25 mL
  • reaction solution was cooled to ambient temperature, stirred with water (50 mL), filtered, and the solid was vacuum dried and eluted by silica gel column chromatography (DCM/EA 10:1 ⁇ 2:1 ⁇ DCM/THF 5:1) to obtain 0.72 g of the product with a yield of 40.0%.
  • EDCI 0.7 g, 3.6 mmol
  • rotigotine (0.85 g, 2.4 mmol)
  • (18-(hexylamino)-18-oxooctadecanoyl)glycine 1.2 g, 2.6 mmol
  • HOBT 0.3 g, 2.4 mmol
  • DIPEA 1.3 mL, 7.2 mmol
  • acetonitrile 25 mL
  • reaction solution was cooled to ambient temperature, stirred with water (50 mL), filtered, and the solid was vacuum dried and eluted by silica gel column chromatography (DCM/EA 10:1 ⁇ 1:1) to obtain 1.17 g of the product with a yield of 66.8%.
  • EDCI (0.82 g, 4.26 mmol) was added to a mixture of rotigotine (1.0 g, 2.84 mmol), (16-(hexylamino)-16-oxohexadecanoyl)glycine (1.5 g, 3.41 mmol), HOBT (0.4 g, 2.84 mmol), DIPEA (1.48 mL, 8.5 mmol) and acetonitrile (25 mL), and the reaction was carried out at an external temperature of 80 ° C for 4 h. The reaction was completed by TLC.
  • reaction solution was cooled to ambient temperature, water (50 mL) was added and stirred, filtered, and the solid was vacuum dried and eluted by silica gel column chromatography (DCM/EA 10:1 ⁇ 2:1 ⁇ DCM/THF 5:1) to obtain 1.03 g of the product with a yield of 50.0%.
  • EDCI (0.82 g, 4.26 mmol) was added to a mixture of rotigotine (1.0 g, 2.84 mmol), (18-(butylamino)-18-oxooctadecanoyl)glycine (1.5 g, 3.6 mmol), HOBT (0.4 g, 2.84 mmol), DIPEA (1.48 mL, 8.5 mmol) and acetonitrile (25 mL), and the reaction was carried out at an external temperature of 80 ° C for 4 h. The reaction was completed by TLC.
  • reaction solution was cooled to ambient temperature, water (50 mL) was added and stirred, filtered, and the solid was vacuum dried and eluted by silica gel column chromatography (DCM/EA 10:1 ⁇ 1:1) to obtain 1.06 g of the product with a yield of 49.5%.
  • EDCI (0.75 g, 3.9 mmol) was added to a mixture of rotigotine (0.9 g, 2.6 mmol), (20-(hexylamino)-20-oxoeicosanoyl)glycine (1.5 g, 3.1 mmol), HOBT (0.4 g, 2.6 mmol), DIPEA (1.4 mL, 7.8 mmol) and acetonitrile (20 mL), and the reaction was carried out at an external temperature of 80 ° C for 4 h. The reaction was completed by TLC.
  • reaction solution was cooled to ambient temperature, water (50 mL) was added and stirred, filtered, and the solid was vacuum dried and eluted by silica gel column chromatography (DCM/EA 10:1 ⁇ 2:1 ⁇ DCM/THF 5:1) to obtain 0.75 g of the product with a yield of 37.5%.
  • EDCI (0.82 g, 4.26 mmol) was added to a mixture of rotigotine (1.0 g, 2.84 mmol), (16-(butylamino)-16-oxohexadecanoyl)glycine (1.35 g, 3.41 mmol), HOBT (0.12 g, 0.85 mmol), DIPEA (1.48 g, 8.5 mmol) and acetonitrile (23 mL), and the reaction was carried out at an external temperature of 60 ° C for 1 h, then the temperature was raised to 80 ° C, and the reaction was carried out for 2.5 h. The reaction was detected by TLC.
  • reaction solution was cooled to ambient temperature, water (60 mL) was added and stirred, filtered, and the solid was vacuum dried and chromatographed on a silica gel column (DCM/EA 10:1 ⁇ 2:1) to obtain 1.53 g of the product as a white solid powder with a yield of 77.3%.
  • test compounds of the present invention all have a relatively high melting point ( ⁇ 100° C.), which can meet the requirements of preparing long-acting drugs by grinding method, that is, they can be well prepared into suspension injections.
  • the prepared suspension of the test sample was converted into a corresponding dose according to a dose of 36 mg/kg (in terms of rotigotine).
  • Three animals were given intramuscular injection to SD rats for each compound. Starting from the administration, the SD rats were given intramuscular injection at 1h, 4h, 8h, 24h (1d), 48h (2d), 72h (3d), 96h (4d), 120h (5d), 168h (7d), 216h (9d), 264h (11d), 31
  • Whole blood was collected at 2h(13d), 360h(15d), 432h(18d), 504h(21d), 576h(24d), 648h(27d), 720h(30d), 792h(33d), 864h(36d), 936h(39d), 1008h(42d), 1080h(45d), 1176h(49d), and 1272h(53d).
  • the blood volume was controlled at approximately 0.3mL/time point.
  • the dosage is 36 mg/kg, which is converted according to the weight of the experimental mice.
  • the test results are shown in Table 1.
  • the compound of the present invention has a short onset of action and can be continuously and slowly released in the body.
  • the blood drug concentration can be maintained at a level not lower than 0.5 ng/mL, and the drug effect lasts for a long time.

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

Abstract

La présente invention concerne un composé tétrahydronaphtalène, un stéréoisomère, un solvate ou un sel pharmaceutiquement acceptable de celui-ci, une composition et une utilisation associées. Sur la base d'une recherche à un stade précoce et au moyen d'un criblage et d'une recherche supplémentaires, il a été accidentellement découvert, selon la présente invention que lorsque m et n dans la formule générale (I) ont des valeurs spécifiques, le métabolisme du composé dans un organisme est également amélioré, et la durée d'action prolongée du composé est plus longue ; par comparaison avec la recherche à un stade précoce, la découverte améliore de manière considérable la perspective d'application et le marché du composé selon la présente invention.
PCT/CN2024/085661 2023-04-04 2024-04-02 Composé tétrahydronaphtalène, composition pharmaceutique et utilisation associées Pending WO2024208226A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202480022508.3A CN121013844A (zh) 2023-04-04 2024-04-02 四氢萘类化合物、其药物组合物及其用途

Applications Claiming Priority (2)

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CN202310350874 2023-04-04
CN202310350874.9 2023-04-04

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016014242A1 (fr) * 2014-07-21 2016-01-28 Spriaso Llc Compositions comprenant des dérivés bioréversibles d'hydroxy-2-aminotétralines n-substituées, formes posologiques et procédés associés
WO2018014277A1 (fr) * 2016-07-21 2018-01-25 山东绿叶制药有限公司 Béhénate de rotigotine, son procédé de fabrication et son application
CN108341798A (zh) * 2017-01-23 2018-07-31 沈阳药科大学 罗替戈汀衍生物及其制备和应用
CN114478476A (zh) * 2020-10-27 2022-05-13 广州市恒诺康医药科技有限公司 四氢萘类化合物、其药物组合物及其用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016014242A1 (fr) * 2014-07-21 2016-01-28 Spriaso Llc Compositions comprenant des dérivés bioréversibles d'hydroxy-2-aminotétralines n-substituées, formes posologiques et procédés associés
WO2018014277A1 (fr) * 2016-07-21 2018-01-25 山东绿叶制药有限公司 Béhénate de rotigotine, son procédé de fabrication et son application
CN108341798A (zh) * 2017-01-23 2018-07-31 沈阳药科大学 罗替戈汀衍生物及其制备和应用
CN114478476A (zh) * 2020-10-27 2022-05-13 广州市恒诺康医药科技有限公司 四氢萘类化合物、其药物组合物及其用途

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