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WO2025113519A1 - Composé cyclique lactame et son utilisation - Google Patents

Composé cyclique lactame et son utilisation Download PDF

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Publication number
WO2025113519A1
WO2025113519A1 PCT/CN2024/135048 CN2024135048W WO2025113519A1 WO 2025113519 A1 WO2025113519 A1 WO 2025113519A1 CN 2024135048 W CN2024135048 W CN 2024135048W WO 2025113519 A1 WO2025113519 A1 WO 2025113519A1
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compound
alkyl
aryl
pharmaceutically acceptable
prodrug
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Chinese (zh)
Inventor
崔巍
程旭
刘立鑫
王元强
姜凡
陈爽
于舟
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Chengdu Diao Pharmaceutical Group Co Ltd
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Chengdu Diao Pharmaceutical Group Co Ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present application generally belongs to the field of medicine. Specifically, the present application relates to compounds with rapid antidepressant effects and their use.
  • Depression is a common mental illness characterized by significant and persistent low mood. Clinically, it can be seen that the mood is low and disproportionate to the situation. The depression can range from melancholy to grief, inferiority and depression, and even pessimism and world-weariness. There may be suicidal attempts or behaviors; severe cases may have psychotic symptoms such as hallucinations and delusions. More than 350 million people suffer from depression worldwide, an increase of 18% in the past decade. As of 2017, there were more than 54 million depression patients in China alone. The recurrence rate of major depressive disorder is as high as 50%-85%, and the suicide rate is 4.0%-10.6%. It has become the most common mental illness.
  • the disorder of neurotransmitters such as norepinephrine, dopamine, and 5-HT (5-hydroxytryptamine) in the brain is considered to be the main biological factor leading to depression.
  • the main means of treating depression relies on the use of antidepressants, which are mainly divided into the following four categories according to their effects and mechanisms of action: 1) Monoamine oxidase inhibitors: such as iprohydrazine and isocarboxazid. Since these drugs contain ingredients with greater side effects, they are now basically discontinued; 2) Tricyclic antidepressants: This type of drug has a good effect on relieving depression, but has a greater adverse effect on patients with other diseases.
  • This drug includes clomipramine, imipramine hydrochloride, etc.; 3) Selective 5-HT reuptake inhibitors: This drug can make up for the symptoms of insufficient 5-hydroxytryptamine in depressed patients, mainly fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine; 4) 5-HT and norepinephrine reuptake inhibitors: This type of drug has a dual antidepressant mechanism and is relatively safe, such as venlafaxine, duloxetine, etc. Among them, categories 3 and 4 are the main drugs, and categories 1 and 2 are basically discontinued.
  • SSRi serotonin reuptake inhibitors
  • the top 10 are escitalopram, sertraline, venlafaxine, paroxetine, duloxetine, flupentixol + melitracen, mirtazapine, fluoxetine, citalopram and fluvoxamine, with a combined market share of over 90%.
  • One or more embodiments of the present application provide a compound represented by formula (I), or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer or racemate thereof:
  • C * Chiral carbon atom is preferably in S configuration
  • the lactam ring Cy is a 4-16 membered monocyclic, bicyclic or tricyclic ring system optionally containing one or more substitutions; wherein the monocyclic, bicyclic or tricyclic ring each independently contains 0-3 heteroatoms selected from oxygen, sulfur and nitrogen as one or more ring members;
  • R 1 is selected from R 5 C(O)-, R 5 OC(O)-, R 5 SO 2 -, (R 5 ) 2 NC(O)- or (R 5 )(R 6 )NC(O)-;
  • R5 , R6 , R8 are -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, -C3-12 monocyclic or bicyclic saturated or partially unsaturated cycloalkyl, -C3-12 monocyclic or bicyclic saturated or partially unsaturated heterocyclyl, -C6-10 monocyclic or bicyclic aryl, -C5-10 monocyclic or bicyclic heteroaryl, wherein the -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, -C3-12 monocyclic or bicyclic saturated or partially unsaturated cycloalkyl, -C3-12 monocyclic or bicyclic saturated or partially unsaturated heterocyclyl, -C6-10 monocyclic or bicyclic aryl, -C5-10 monocyclic or bicyclic heteroaryl are each optionally substituted by 0-3 deuterium, tritium, halogen
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a 3- to 8-membered monocyclic or polycyclic ring, the ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur as one or more ring members, the ring being optionally substituted by a substituent R7; wherein R 7 is independently selected from hydrogen, deuterium, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, -C 3-8 heterocyclyl, -C 6-10 aryl, and -C 5-10 heteroaryl;
  • R2 is independently selected from hydrogen, a substituted C1-8 alkyl, a substituted C2-8 alkenyl, a substituted C3-8 cycloalkyl, a substituted C6-14 aryl or a substituted C5-14 heteroaryl, wherein the substituted C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, C6-14 aryl and C5-14 heteroaryl are optionally substituted by one or more substituents selected from the following: halogen, hydroxyl, carboxyl, amino, nitro, cyano, -C1-6 acylamino, -C1-6 acyloxy, -C1-6 alkoxy, -C6-14 aryloxy, -C1-6 alkylthio, -C1-6 alkyl, -C1-6 acyl, -C6-10 aryl, -C3-8 cycloalkyl , -C2-6 alkenyl , C2-6 alkynyl,
  • R 3 is selected from -COOR 8 , -CONR 8 , -COR 8 , -OR 8 , -NR 8 , -C 3-15 cycloalkyl, -C 3-15 heterocycloalkyl, -C 6-15 aryl, -C 5-15 heteroaryl; wherein the -C 3-15 cycloalkyl, -C 3-15 heterocycloalkyl, -C 6-15 aryl, -C 5-15 heteroaryl are each optionally substituted by 0-8 R 9 ;
  • R 9 is optionally selected from hydrogen, deuterium, tritium, halogen, cyano, nitro, -OR 10 , -NR 10 R 11 , -SR 10 , -COR 10 , -SOR 10 , -SO 2 R 10 , -NR 10 COR 11 , -CONR 10 R 11 , -OCOR 10 , -COOR 10 , -OCOOR 10 , -OCONR 10 R 11 , -NR 10 CONR 11 R 12 , -NR 10 COOR 11 , -NR 10 SO 2 R 11 , -SO 2 NR 10 R 11 , -OSO 2 R 10 , -SO 3 R 10 , linear alkyl, hetero-linear alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein each linear alkyl, hetero-linear alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted
  • R10 , R11 , R12 are independently selected from hydrogen, deuterium, tritium, linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted by 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonate, sulfonamide, alkyl or haloalkyl;
  • R 13 is selected from hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each linear alkyl, heterolinear alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is independently substituted by 0-8 halogen, cyano, hydroxyl, thiol, ether, nitro, alkoxy, amino, carboxyl, sulfonic acid, ester, amide, sulfonic ester, sulfonamide, alkyl or haloalkyl.
  • the C * chiral carbon atom is in the S configuration.
  • Cy in the general formula (I) is selected from the group shown in (a):
  • X is independently selected from carbon, nitrogen, oxygen, and sulfur atoms
  • Y is independently selected from carbon and nitrogen atoms; wherein each ring is optionally substituted with one or more R 4 ;
  • R4 is independently at each occurrence deuterium, tritium, halogen, hydroxyl, amino, nitro, cyano, C1-6 alkyl, ORa , SRa , C(O)Ra, C ( O ) NRaRb , C(O) ORa , NRaRb , NRaC (O) Rb , SO2Ra , NRaSO2Rb , SO2NRaRb, -C6-10 aryl , -C3-8 cycloalkyl, -C5-10 heteroaryl, -C3-8 heterocycloalkyl or heterocycloalkenyl, wherein -C1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of amino , cyano , halogen, hydroxyl, -C1-6 alkoxy, -C3-8 heterocycloalkyl, -C3-8 cycloalkyl , -C5-10 heteroaryl, -
  • Ra and Rb are independently selected from hydrogen, -C1-6 alkyl, -C1-6 haloalkyl, -C3-8 cycloalkyl, -C6-10 aryl, -C5-10 heteroaryl, and -C3-8 heterocycloalkyl.
  • One or more embodiments of the present application provide a compound of formula (II), or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof:
  • Ring A is a 3-15 membered heterocyclyl or a 3-15 membered heteroaryl
  • R 1 is -C(O)OR 3 , -C(O)N(H)R 3 , -C(O)R 3 , -OR 3 , -N(H)R 3 , -C 3-15 cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 aryl, or 5-15 membered heteroaryl; optionally, the -C 3-15 cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 aryl, or 5-15 membered heteroaryl is substituted with one or more substituents selected from C 1-4 alkyl and halogenated C 1-4 alkyl;
  • R 2 is R 4 C(O)-, R 4 OC(O)-, R 4 S(O) 2 -, (R 4 ) 2 NC(O)-, -C 3-15 cycloalkyl, 3-15 membered heterocycloalkyl, -C 6-15 aryl, or 5-15 membered heteroaryl;
  • R3 and R4 are independently -C1-8 alkyl, -C1-8 deuterated alkyl, -C2-8 alkenyl, -C2-8 alkynyl, -C3-12 cycloalkyl, -C3-12 heterocycloalkyl , -C6-10 aryl, or 5-15 membered heteroaryl.
  • the C * carbon atom is in the S configuration.
  • the A ring is
  • the A ring is a 4-13 membered heterocyclyl or a 5-10 membered heteroaryl, and has 1-4 heteroatoms selected from N, O, and S.
  • the A ring is wherein n is 1, 2, 3 or 4, m is 1 or 2, p is 1 or 2, X 1 , X 2 and X 3 are independently O, S, N or NH, or C, wherein Indicates a single bond or a double bond.
  • the A ring is
  • R 1 is -C(O)OR 3 , -C(O)N(H)R 3 , -C 6-15 aryl, or 5-15 membered heteroaryl;
  • R 3 is -C 1-4 alkyl or -C 1-4 deuterated alkyl; the 5-15 membered heteroaryl has 1 or 2 heteroatoms selected from N, O, and S.
  • R 1 is
  • R 2 is R 4 C(O)- or 5-6 membered heteroaryl
  • R 4 is -C 1-4 alkyl, -C 1-4 deuterated alkyl or -C 3-5 cycloalkyl
  • the 5-6 membered heteroaryl has 1 N heteroatom.
  • R2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is selected from:
  • One or more embodiments of the present application provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • One or more embodiments of the pharmaceutical preparation of the present application include the compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.
  • One or more embodiments of the present application provide the use of the compound of the present application or its pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite in the preparation of a medicament for treating and/or preventing depression.
  • One or more embodiments of the present application provide use of the pharmaceutical composition of the present application in preparing a medicament for treating and/or preventing depression.
  • One or more embodiments of the present application provide use of the pharmaceutical preparation of the present application in preparing a drug for treating and/or preventing depression.
  • One or more embodiments of the present application provide the use of the compound of the present application or its pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite in the preparation of a fast-acting drug for treating and/or preventing depression.
  • One or more embodiments of the present application provide use of the pharmaceutical composition of the present application in preparing a fast-acting drug for treating and/or preventing depression.
  • One or more embodiments of the present application provide use of the pharmaceutical preparation of the present application in preparing a fast-acting drug for treating and/or preventing depression.
  • One or more embodiments of the present application provide the use of a compound of the present application or a pharmaceutically acceptable salt, prodrug, deuterated substance, hydrate, solvate, enantiomer, diastereomer, racemate, polymorph, cocrystal or metabolite thereof in the preparation of a medicament for preventing and/or treating dysphoria, depression, anxiety, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, appetite disorders, bulimia, obesity, drug abuse, alcoholism, tobacco addiction, obsessive-compulsive disorder, panic disorder, premenstrual syndrome, migraine, bipolar disorder, neuropathic pain, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease and vasomotor symptoms and hot flashes.
  • ADHD attention deficit hyperactivity disorder
  • the neuropathic pain is chronic pain.
  • the chronic pain is fibromyalgia.
  • One or more embodiments of the present application provide a compound of the present application for use as a medicament.
  • One or more embodiments of the present application provide the pharmaceutical composition of the present application, which is used as a medicament.
  • One or more embodiments of the present application provide the pharmaceutical preparation of the present application, which is used as a medicament.
  • One or more embodiments of the present application provide the compound, pharmaceutical composition or pharmaceutical preparation of the present application, which is used for preventing and/or treating depression.
  • One or more embodiments of the present application provide the compound, pharmaceutical composition or pharmaceutical preparation of the present application, which is used for preventing and/or rapidly treating depression.
  • One or more embodiments of the present application provide the compound, pharmaceutical composition or pharmaceutical preparation of the present application, which is used as a fast-acting drug for treating and/or preventing depression.
  • One or more embodiments of the present application provide a method for preventing and/or treating depression, which comprises administering the compound, pharmaceutical composition or pharmaceutical preparation of the present application to a subject in need thereof.
  • One or more embodiments of the present application provide a method for preventing and/or rapidly treating depression, which comprises administering the compound, pharmaceutical composition or pharmaceutical preparation of the present application to a subject in need thereof.
  • neuropathic pain e.g., chronic pain, such as fibromyalgia
  • ADHD attention deficit hyperactivity disorder
  • Alzheimer's disease and vasomotor symptoms or hot flashes
  • One or more embodiments of the present application also provide a pharmaceutical composition or pharmaceutical preparation comprising the compound of the present application.
  • the compound of the present application can be administered in pure form, in combination with other active ingredients, or in combination with a pharmaceutically acceptable non-toxic excipient or carrier.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • hydroxy refers to -OH.
  • Alkyl refers to a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; when the alkyl group is substituted, it may be optionally further substituted by one or more substituents.
  • Alkenyl refers to a straight-chain or branched aliphatic hydrocarbon group of 1 to 20 carbon atoms containing one or more double bonds, preferably an alkenyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkenyl group of 1 to 6 carbon atoms, and further preferably an alkenyl group of 1 to 4 carbon atoms.
  • Alkynyl refers to a straight-chain or branched aliphatic hydrocarbon group of 1 to 20 carbon atoms containing one or more triple bonds, preferably an alkynyl group of 1 to 8 (e.g., 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms, more preferably an alkynyl group of 1 to 6 carbon atoms, and further preferably an alkynyl group of 1 to 4 carbon atoms.
  • Heterocyclyl or “heterocycle” refers to a saturated or unsaturated non-aromatic heterocyclic ring, which can be a 3-10 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, a 4-12 membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (e.g., 1, 2, 3, 4) heteroatoms selected from N, O or S, for example, a 3-8 membered heterocyclyl.
  • 3-10 membered e.g., 3, 4, 5, 6, 7, 8, 9, 10 membered
  • monocyclic ring e.g., 4, 5, 6, 7, 8, 9, 10 membered
  • 4-12 membered e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 membered
  • bicyclic ring e.g
  • heterocyclyl e.g., 1, 2, 3, 4
  • N and S optionally substituted in the ring of "heterocyclyl” or “heterocycle” can be oxidized to various oxidation states;
  • heterocyclyl or “heterocycle” can be attached to a heteroatom or a carbon atom;
  • heterocyclyl or “heterocycle” can be a bridged ring or a spiro ring.
  • heterocyclyl or “heterocycle” include oxirane, oxirane, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, oxepinyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl, piperidinyl, homopiperidinyl, furanyl, pyridinyl, piperidinyl
  • pyridinyl pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, pyridinyl, py pyranyl, thiophene, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuranyl, dithiolanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyranyl, te
  • Heteroaryl refers to a substituted or unsubstituted aromatic ring, which can be a 3-8 membered (e.g., 3, 4, 5, 6, 7, 8 membered) monocyclic ring, a 5-12 membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring, or a 10-15 membered (e.g., 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, such as a 5-8 membered heteroaryl.
  • the 1 to 4 (e.g., 1, 2, 3, 4) N, S optionally substituted in the heteroaryl ring can be oxidized to various oxidation states.
  • Heteroaryl can be connected to a heteroatom or a carbon atom, and can be a bridged ring or a spiro ring, and non-limiting examples include cyclopyridyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl benzimidazolyl, benzopyridinyl, pyrrolopyridinyl.
  • Heteroaryl is optionally further substituted by one or more substituents.
  • Cycloalkyl refers to a cyclic saturated aliphatic hydrocarbon group of 1 to 15 carbon atoms, which can be a monocyclic ring of 3 to 10 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10), a bicyclic ring of 4 to 12 carbon atoms (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12), or a polycyclic ring system of 10 to 15 members (e.g., 10, 11, 12, 13, 14, 15), and the ring carbon atoms are preferably 3 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. When the cycloalkyl is substituted, it can be optionally further substituted by one or more substituents.
  • Heterocycloalkyl refers to a 3- to 15-membered cyclic saturated aliphatic hydrocarbon group, which can be a 3- to 10-membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) polycyclic ring system, which can contain one or more (e.g., 1, 2, 3 or 4) heteroatoms selected from N, O or S, and can be a monocyclic, fused, bridged or spirocyclic ring.
  • Aryl refers to a substituted or unsubstituted aromatic ring, which can be a monocyclic ring of 3 to 8 carbons (e.g., 3, 4, 5, 6, 7, 8 carbons), a bicyclic ring of 5 to 12 carbons (e.g., 5, 6, 7, 8, 9, 10, 11, 12 carbons), or a tricyclic ring system of 10 to 15 carbons (e.g., 10, 11, 12, 13, 14, 15 carbons), which can be a bridged ring or a spirocyclic ring, non-limiting examples include phenyl and naphthyl. The aryl group can be optionally further substituted by one or more substituents.
  • Alkoxy refers to a group formed by replacing at least one carbon atom in an alkyl group with an oxygen atom.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy.
  • the definition of alkyl is the same as that of "alkyl" described above.
  • the term "optionally substituted” refers to groups wherein hydrogen atoms are not substituted or one or more hydrogen atoms are substituted by one or more groups independently selected from the group consisting of alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanate, thiocyanate, isothiocyanate, nitro, sily
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds described herein, their pharmaceutically acceptable salts or prodrugs and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • Steps refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
  • heterocyclyl optionally substituted with alkyl means that the alkyl group may but need not be present, and the description includes instances where the heterocyclyl group is substituted with alkyl group and instances where the heterocyclyl group is not substituted with alkyl group.
  • the term "compound” includes all stereoisomers, geometric isomers, and tautomers.
  • the "compound” described herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, individual enantiomers and diastereomers or other stereoisomeric forms or mixtures thereof.
  • the compounds containing asymmetric carbon atoms herein can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.
  • the "compound” described herein also includes geometric isomeric forms, which refer to forms in which the substituents on the double bonds or rings of the compound have different cis-trans isomers without chirality.
  • the "compound” described herein also includes tautomeric forms. Tautomeric forms can be derived from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.
  • the compounds herein can also be isotopically labeled by replacing one or more atoms therein with atoms having different atomic masses or mass numbers.
  • Such isotopically labeled (i.e., radiolabeled) compounds are considered to be within the scope of this invention.
  • isotopes in the compounds herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, each having the same number of protons, but different mass numbers.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present invention, which are prepared from the compounds having specific substituents discovered in the present invention and pharmaceutically acceptable acids or bases.
  • pharmaceutically acceptable carrier refers to any formulation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient
  • representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc.
  • pharmaceutically acceptable excipients refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • “Pharmaceutically acceptable excipient” refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.
  • the compounds of the present application are more active than existing rapid antidepressant compounds.
  • existing compounds compound ZZL-7
  • the compounds of the present application have excellent rapid antidepressant activity in vivo, and their drugability (metabolic stability, AUC, bioavailability, etc.) is significantly better.
  • FIG. 1 is the result of the forced swimming test of in vivo efficacy test 1 of active example 3.
  • FIG. 2 is the tail suspension test result of in vivo efficacy test 1 of active example 3.
  • FIG. 3 is the tail suspension test result of in vivo efficacy test 2 of active example 3.
  • Acetylmethionine 1-1 (3.0 g, 15.7 mmol) was dissolved in N,N-dimethylformamide (30 mL), and L-valine methyl ester hydrochloride (3.16 g, 18.9 mmol), 1-hydroxybenzotriazole (3.18 g, 23.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.51 g, 23.6 mmol) and N,N-diisopropylethylamine (6.09 g, 47.1 mmol) were added thereto. The reaction solution was reacted at room temperature for 4 hours.
  • Acetylmethionyl-L-valine methyl ester 1-2 (2.8 g, 9.2 mmol) was dissolved in acetone (30 mL), and iodomethane (13.1 g, 92 mmol) was added thereto, and the mixture was reacted at room temperature for 4 hours. After the reaction was complete as monitored by TLC and LCMS, the solution was rotary evaporated to dryness, and then dissolved in acetonitrile (30 mL), and cesium carbonate (6.0 g, 18.4 mmol) was added thereto, and the mixture was reacted at 60°C for 6 hours.
  • compound 10-1 (550 mg, 2.18 mmol), dichloromethane (20 mL), methylamine hydrochloride (736 mg, 10.9 mmol), N,N-diisopropylethylamine (1.69 g, 13.08 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (2.49 g, 6.54 mmol) were added in sequence and reacted at 25 °C for 2 hours.
  • compound 12-1 500 mg, 1.80 mmol
  • dichloromethane (20 mL) methylamine hydrochloride
  • N, N-diisopropylethylamine (1.40 g, 10.80 mmol)
  • N, N, N', N'-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (2.74 g, 7.20 mmol) were added in sequence, and the mixture was reacted at 25°C for 2 hours.
  • compound 13-2 (375 mg, 2.45 mmol), anhydrous N, N-dimethylformamide (20 mL), sodium hydride (108 mg, 2.70 mmol) were added in sequence, nitrogen replacement protection was used, and the mixture was reacted at 25°C for 30 minutes.
  • Compound 2-2 (777 mg, 2.94 mmol) was added and reacted at 25°C for 2 hours. After the reaction was complete as monitored by LCMS and TLC, saturated sodium bicarbonate aqueous solution (150 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Table 1 shows the plasma stability data of some compounds. The results show that the compounds of the present application exhibit excellent plasma stability, which is significantly better than ZZL-7.
  • the pharmacokinetic test of the compound was carried out in 6-8 week old CD1 mice.
  • the compound to be tested was dissolved in a 10% hydroxypropyl- ⁇ -cyclodextrin aqueous solution containing 10% DMSO and administered by intravenous injection or oral gavage.
  • the compound concentration in the plasma sample will be analyzed by LC-MS/MS method.
  • Pharmacokinetic calculations were performed using WinNonlin (PhoenixTM, version 8.3) or other similar software. The following pharmacokinetic parameters were calculated based on the plasma concentration and time data:
  • Oral administration AUC last , bioavailability (F).
  • Table 2 shows the area under the concentration-time curve (AUC) and bioavailability (F) data of some compounds for oral administration. The results show that the compounds of the present application have good pharmacokinetic properties and are significantly better than ZZL-7.
  • mice 6-8 week old C57/B6 mice were selected to establish the 28-day animal chronic unpredictable mild stress model (CUMS).
  • OFT open field test
  • the experiment was divided into a blank control group, a model group, a solvent control group, a fluoxetine control group and a compound group.
  • the test compound was administered by a single intravenous injection (i.v.) at a dose of 100 mg/kg.
  • Tail suspension test (TST) and forced swimming test (FST) were performed 2 hours later to evaluate the depression of mice. The prolonged immobility time of mice in TST and FST indicated that the mice were in despair.
  • SPSS data statistical software was used for analysis, and Graph Pad software was used to draw images based on the SPSS analysis results.
  • test results show (see Figures 1 and 2) that compounds B1-1, B1-5 and B1-6 can quickly reverse the prolonged immobility time of chronic unpredictable stress model mice in forced swimming and tail suspension tests, proving that the embodiments of the present invention have a rapid antidepressant effect.
  • mice 6-8 week old C57/B6 mice were selected to establish the 28d animal chronic unpredictable mild stress model (CUMS).
  • the open field test (OFT) was used to evaluate the efficacy after the model was successfully evaluated.
  • the experiment was divided into a blank control group, a model group, a solvent control group, a fluoxetine control group, a ZZL-7 control group and a compound group.
  • the test compound was orally administered at a dose of 25 mg/kg.
  • TST tail suspension test
  • SPSS data statistical software was used for analysis, and Graph Pad software was used to draw images based on the SPSS analysis results.
  • test results show (see FIG. 3 ) that compound B1-6 can quickly reverse the prolonged immobility time of chronic unpredictable stress model mice in the tail suspension test, proving that the embodiments of the present invention have a rapid antidepressant effect.

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Abstract

La présente invention concerne un composé cyclique lactame et son utilisation. Le composé a un effet antidépresseur rapide.
PCT/CN2024/135048 2023-11-28 2024-11-27 Composé cyclique lactame et son utilisation Pending WO2025113519A1 (fr)

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CN1159196A (zh) * 1994-06-17 1997-09-10 沃泰克斯药物股份有限公司 白介素-1β转化酶抑制剂
CN1812972A (zh) * 2003-05-27 2006-08-02 沃泰克斯药物股份有限公司 天冬氨酸特异性半胱氨酸蛋白酶抑制剂及其用途
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