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WO2025061176A1 - Dérivé d'amine à substitution de cycloalcane, son procédé de préparation et son utilisation - Google Patents

Dérivé d'amine à substitution de cycloalcane, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2025061176A1
WO2025061176A1 PCT/CN2024/120190 CN2024120190W WO2025061176A1 WO 2025061176 A1 WO2025061176 A1 WO 2025061176A1 CN 2024120190 W CN2024120190 W CN 2024120190W WO 2025061176 A1 WO2025061176 A1 WO 2025061176A1
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compound
formula
independently
alkyl
substituted
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Chinese (zh)
Inventor
程建军
汪胜
段文文
唐凌杰
王欢
余竞
曹冬梅
贺莉聪
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ShanghaiTech University
Center for Excellence in Molecular Cell Science of CAS
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ShanghaiTech University
Center for Excellence in Molecular Cell Science of CAS
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings

Definitions

  • the present invention relates to cycloalkane substituted amine derivatives, preparation methods and applications thereof.
  • Serotonin 5-HT 2A receptor is a 5-HT receptor, belonging to the 5-HT 2 receptor subfamily.
  • 5-HT 2A receptor belongs to G protein-coupled receptor (GPCR), widely distributed in the central nervous system and peripheral nervous system. Its endogenous ligand 5-hydroxytryptamine, as a monoamine neurotransmitter, is an endogenous agonist of 5-HT 2A receptor, and participates in a wide range of biological functions in the body, such as regulating the mood and consciousness of the central nervous system, as well as cardiovascular function and peripheral intestinal motility.
  • GPCR G protein-coupled receptor
  • Exogenous 5-HT 2A receptor agonists are mainly derived from natural extracts or semi-synthetic analogs, such as psilocybin, lysergic acid diethylamide (LSD), mescaline, etc., and are mainly used in medical applications (David E. Nichols; Pharmacol Rev, 2016, 68, 264-355). In early clinical trials, it was found that such compounds have antidepressant and sedative effects.
  • 5-HT 2A receptor agonists The chemical structure of current 5-HT 2A receptor agonists is still mainly concentrated in the three types of mother nuclei of natural extracts: tryptamines, ergoline and phenylethylamine. Based on these three types of mother nuclei, a large number of 5-HT 2A receptor agonists have been reported. However, due to toxic side effects and poor drug properties, the small molecules approved for marketing and clinical research are still concentrated in natural extracts discovered decades ago. No new chemical structure of 5-HT 2A receptor agonists has been further developed clinically.
  • Pimavanserin is Modifying it to improve its pharmaceutical properties, such as making it exhibit agonist activity, is of great significance for the treatment of neurological diseases.
  • the present invention provides cycloalkane substituted amine derivatives, preparation methods and applications thereof.
  • the cycloalkane substituted amine derivatives provided by the present invention have 5-HT 2A receptor agonist activity and have broad application prospects.
  • n are each independently 1, 2 or 3;
  • R 1 and R 2 are each independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by 1, 2 or 3 R 1-1 ;
  • R 1-1 is each independently a C 6 -C 10 aryl group or a C 6 -C 10 aryl group substituted by 1, 2 or 3 R 1-1a ;
  • R 1-1a is halogen, hydroxyl or C 1 -C 6 alkyl
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl substituted by 1, 2 or 3 R 3-1 ;
  • R 3-1 is each independently halogen, hydroxyl or C 6 -C 10 aryl substituted by 1, 2 or 3 R 3-1a ;
  • R 3-1a are each independently C 1 -C 4 alkoxy
  • X is NH or a single bond
  • Ar is a C 6 -C 10 aryl group, a C 5 -C 12 heteroaryl group, a C 6 -C 10 aryl group substituted by 1, 2 or 3 R 5 groups, or a C 5 -C 12 heteroaryl group substituted by 1, 2 or 3 R 6 groups, wherein the heteroatom in the C 5 -C 12 heteroaryl group is selected from one or more of N, O and S, and the number of the heteroatoms is 1, 2 or 3;
  • R5 and R6 are each independently halogen, hydroxy, C1 - C10 alkyl, C1 - C10 alkoxy, C1 - C10 alkylthio or
  • R N-1 and R N-2 are each independently H or C 1 -C 6 alkyl.
  • the C1 - C6 alkyl group and the C1 - C6 alkyl group substituted by 1, 2 or 3 R1-1 are each independently methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl or tert-butyl, such as methyl.
  • the C 6 -C 10 aryl group and the C 6 -C 10 aryl group substituted by 1, 2 or 3 R 1-1a are each independently phenyl or naphthyl, for example phenyl.
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the halogen is fluorine, chlorine or bromine.
  • the C 1 -C 6 alkyl group and the C 1 -C 6 alkyl group substituted by 1, 2 or 3 R 3-1 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as methyl, ethyl or isopropyl.
  • the C 3 -C 6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl, and for example cyclopropyl or cyclobutyl.
  • the halogen is fluorine, chlorine or bromine, for example fluorine.
  • the C 6 -C 10 aryl group substituted by 1, 2 or 3 R 3-1a is phenyl or naphthyl, for example phenyl.
  • the C 1 -C 4 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, for example, methoxy.
  • the C 6 -C 10 aryl group and the C 6 -C 10 aryl group substituted by 1, 2 or 3 R 5 groups are each independently phenyl or naphthyl, for example phenyl.
  • the C 5 -C 12 heteroaryl group and the C 5 -C 12 heteroaryl group substituted with 1, 2 or 3 R 6 are each independently C 5 -C 9 heteroaryl groups, wherein the heteroatom is preferably N, and the number of heteroatoms is preferably 1.
  • the C 5 -C 12 heteroaryl group is
  • the halogen is fluorine, chlorine or bromine, for example fluorine.
  • the C1 - C10 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.
  • the C1 - C10 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, n-heptyloxy, n-octyloxy, n-nonyloxy or n-decyloxy, for example, n-hexyloxy, isobutoxy, n-decyloxy, n-heptyloxy, n-octyloxy or methoxy.
  • the C1 - C10 alkylthio group is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, n-hexylthio, n-heptylthio, n-octylthio, n-nonylthio or n-decylthio.
  • the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • the compound represented by Formula I is a compound represented by Formula I-1a, I-2a, I-3a or I-4a:
  • R 1 , R 2 , R 3 , X, Ar, Y, m and n are each independently as described in any one of the present invention.
  • the compound represented by Formula I is a compound represented by Formula I-5a or I-6a:
  • n and n are each independently 1 or 2.
  • R1 and R2 are each independently hydrogen, C1- C6 alkyl or C1- C6 alkyl substituted by 1, 2 or 3 R1-1 ;
  • R1-1 is C6 - C10 aryl substituted by 1 , 2 or 3 R1-1a ;
  • R1-1a is hydroxyl; preferably, R1 and R2 are each independently hydrogen.
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 alkyl substituted by 1, 2 or 3 R 3-1 ;
  • R 3-1 is independently halogen or C 6 -C 10 aryl substituted by 1 R 3-1a ;
  • R 3-1a is independently C 1 -C 4 alkoxy; preferably, R 3 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted by 1, 2 or 3 (e.g., 1) R 3-1 (e.g., C 1 -C 6 alkyl substituted by 1, 2 or 3 R 3-1 is );
  • R 3-1 is each independently a C 6 -C 10 aryl group (e.g.
  • R 3-1a is each independently a C 1 -C 6 alkoxy group (e.g. methoxy group); further preferably, R 3 is hydrogen or C 1 -C 6 alkyl, such as hydrogen or a straight-chain C 1 -C 6 alkyl group, and further, R 3 is a straight-chain C 1 -C 6 alkyl group (e.g. methyl).
  • X and Y are not both single bonds.
  • R 5 and R 6 are each independently a C 1 -C 10 alkoxy group; preferably, when X is NH and Y is -CH 2 -, R 5 and R 6 are each independently a linear C 1 -C 10 alkoxy group.
  • R1 and R2 are each independently hydrogen, or methyl.
  • R3 is methyl, hydrogen, Isopropyl, Ethyl, or cyclopropane, for example methyl or H.
  • R3 is methyl, hydrogen, Isopropyl, Ethyl, Cyclopropyl or cyclobutane.
  • X is NH or a single bond.
  • Ar is N-phenyl
  • R 5 is
  • R 6 is
  • the compound as shown in formula I is any of the following compounds:
  • the pharmaceutically acceptable salt of the compound represented by formula I is the hydrochloride salt of the compound represented by formula I.
  • the present invention provides a method for preparing the compound represented by the above formula I, which is any of the following schemes:
  • W is an amino protecting group, such as tert-butyloxycarbonyl (BOC) or benzyloxycarbonyl (CBz), for example tert-butyloxycarbonyl;
  • R 1 , R 2 , R 3 , X, Ar, Y, m and n are each independently as described in any one of the present invention.
  • the present invention also provides a compound represented by the following formula Ia or Ib:
  • R 2 , R 3 , X, Ar, Y, m and n are as described in any one of the present invention.
  • the compound represented by formula Ia is any of the following compounds:
  • the compound represented by formula Ib is any of the following compounds:
  • the present invention provides a pharmaceutical composition comprising:
  • the present invention provides use of a compound as shown in formula I, a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in preparing a drug, wherein the drug is used for treating and/or preventing diseases associated with 5-HT 2A receptors.
  • the disease associated with the 5-HT 2A receptor is a disease associated with the ⁇ -arrestin2 recruitment signaling pathway downstream of the 5-HT 2A receptor and/or the Gq protein activation signaling pathway downstream of the 5-HT 2A receptor, for example, the disease associated with the 5-HT 2A receptor is depression.
  • the present invention provides a use of a compound as shown in formula I, a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a 5-HT 2A receptor agonist, wherein the 5-HT 2A receptor agonist is an agonist of a 5-HT 2A receptor downstream ⁇ -arrestin2 recruitment signaling pathway and/or an agonist of a 5-HT 2A receptor downstream Gq protein activation signaling pathway, for example, an agonist of a 5-HT 2A receptor downstream ⁇ -arrestin2 recruitment signaling pathway.
  • the key is a solid wedge. and dotted wedge key Indicates the absolute configuration of a stereocenter.
  • a compound when a compound has a double bond structure, such as a carbon-carbon double bond, and each atom on the double bond is connected to two different substituents, if a wavy line is used between the atom on the double bond and the substituent in the compound, , it represents the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.
  • the following formula (A) represents that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2) or in the form of formula (A-1) and formula (A-2) exists as a mixture of two isomers;
  • pharmaceutically acceptable means relatively non-toxic, safe, and suitable for use by patients.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • a group substituted with 1, 2 or 3 substituents means that 1, 2 or 3 hydrogen atoms in a group are independently replaced by the substituents. When multiple substituents are present at the same time, their definitions are independent of each other and do not affect each other unless otherwise specified. Therefore, if a group is substituted with 1, 2 or 3 R 1-1 groups, that is, the group may be substituted with up to 3 R 1-1s , the definition of R 1-1 at that position is independent of the definitions of the remaining R 1-1s . In addition, combinations of substituents and/or variables are allowed only if the combination results in stable compounds.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a linear or branched (e.g., linear), saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1 - C10 , C1 - C6 ).
  • Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl, etc.
  • alkoxy refers to the group -OR X , where RX is defined as the term “alkyl”. Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • alkylthio refers to the group -SR X , where RX is defined as the term “alkyl”.
  • Alkoxy includes, but is not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio and the like.
  • aryl refers to a ring having a specified number of carbon atoms (e.g., C 6 -C 10 ) and consisting only of carbon atoms, which is monocyclic or polycyclic, and each ring is aromatic (complying with Huckel's rule).
  • Aryl includes, but is not limited to, phenyl and naphthyl.
  • heteroaryl refers to a ring having a specified number of ring atoms (e.g., 5-12 members, and also 6-10 members), a specified heteroatom
  • a heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom; a heteroaryl group is attached to the rest of the molecule through a ring with a heteroatom or a ring without a heteroatom.
  • cycloalkyl refers to a saturated monocyclic, spirocyclic, bridged or paracyclic cyclic group having a specified number of ring carbon atoms (e.g., C 3-6 ), wherein the ring atoms consist only of carbon atoms.
  • Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive and progressive effect of the present invention is that the compound of formula I provided by the present invention has improved pharmaceutical properties, can exhibit agonistic activity, and has broad application prospects.
  • Benzaldehyde (0.2 mL, 2 mmol), tert-butyl (4-aminocyclohexyl)carbamate (428 mg, 2 mmol) were placed in Add methanol (10 mL) to the reaction flask and stir at room temperature to dissolve.
  • sodium cyanoborohydride (138 mg, 2.2 mmol) was added to the system in batches and continued to stir at room temperature.
  • TLC was used to monitor the reaction progress. After 4 hours, the reaction was completed and water was added to quench the reaction. Most of the solvent was removed by vacuum distillation, and the mixture was extracted three times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate.
  • Step 2 Preparation of tert-butyl (4-(benzyl(methyl)amino)cyclohexyl)carbamate (compound DW03113)
  • Step 3 Preparation of (tert-butyl (4-methylamino) cyclohexyl) carbamate (compound DW03115)
  • Step 4 Preparation of 4-n-hexyloxybenzyl cyanide (compound DW03067)
  • Step 5 Preparation of 4-n-hexyloxyphenethylamine (compound DW03073)
  • Step 6 Preparation of N-(4-(n-hexyloxy)benzyl)-1H-imidazole-1-carboxamide (compound DW03075)
  • Step 7 Preparation of tert-butyl (4-(3-(4-(n-hexyloxy)-1-methylureido)cyclohexyl)carbamate) (Compound DW03116)
  • Step 8 Preparation of (1-(4-aminocyclohexyl)-3-(4-n-hexyloxy)benzyl)-1-methylurea (Compound I-1)
  • the preparation method is similar to that of I-1, except that tert-butyl (4-aminocyclohexyl)carbamate is replaced with 1-N-Boc-trans-1,4-cyclohexanediamine to obtain white solid I-3 (yield 90%).
  • the preparation method is similar to that of I-3, except that n-hexanol is replaced with 2-tert-butanol to obtain white solid I-4 (yield 90%).
  • Step 1 Preparation of trans-tert-butyl 4-(1-benzyl-3-(4-(hexyloxy)benzyl)ureidocyclohexyl)carbamate) (compound DW04018-1)
  • Step 2 Preparation of 1-(4-amino-trans-cyclohexyl)-1-benzyl-3-(4-hexyloxy)benzylurea (Compound I-11) preparation:
  • the preparation method is the same as that of DW03112, except that tert-butyl (4-aminocyclohexyl)carbamate is replaced by I-3, and benzaldehyde is replaced by 2-hydroxybenzaldehyde to obtain a light yellow solid I-15 (yield: 45%).
  • Step 1 Preparation of 3-(4-hexyloxy)benzyl)-1-methyl-1-(4-oxocyclohexyl)urea (compound DW04108):
  • Step 1 Preparation of methyl 3-(4-(hexyloxy)phenyl)acrylate (compound DW04093):
  • Step 2 Preparation of 3-(4-(hexyloxy)phenyl)acrylic acid (compound DW04094):
  • Step 3 Preparation of tert-butyl 4-(3-(4-(hexyloxy)phenyl)-N-methylacrylamido)cyclohexyl)carbamate (compound DW04095):
  • Step 4 Preparation of N-(4-amino-trans-cyclohexyl)-3-(4-hexyloxy)phenyl-N-methylacrylamide (Compound I-17):
  • Step 1 Preparation of 3-(4-(hexyloxy)phenyl)propanoic acid (compound DW04096):
  • Step 2 Preparation of tert-butyl 4-(3-(4-(hexyloxy)phenyl)-N-methylpropionamido)cyclohexyl)-trans-carbamate (compound DW04097):
  • Step 3 Preparation of N-(4-amino-trans-cyclohexyl)-3-(4-hexyloxyphenyl)-N-methylpropionamide (Compound I-18):
  • Step 1 Preparation of methyl 2-(4-(hexyloxy)phenyl)acetate (compound DW04100):
  • Step 2 Preparation of 2-(4-(hexyloxy)phenyl)acetic acid (compound DW04101):
  • Step 3 Preparation of tert-butyl 4-(2-(4-(hexyloxy)phenyl)-N-methylacetylamino)cyclohexyl)-trans-carbamate (compound DW04102):
  • Step 1 In a round-bottom flask, tert-butyl (3-amino-trans-cyclobutyl)carbamate (500 mg, 2.69 mmol) and a tetrahydrofuran solution of acetaldehyde (0.65 mL, 5 M) were dissolved in methanol (10 mL), and glacial acetic acid (30 ⁇ L) was added and stirred at room temperature for 30 minutes. Subsequently, NaBH 3 CN (339 mg, 5.38 mmol) was added, and the reaction system was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was removed and WHH114 (0.5 g, 88%) was purified and separated by rapid silica gel column chromatography.
  • Step 3 Add WHH116 (0.19 g, 0.44 mmol) to a round-bottom flask, then add a solution of hydrogen chloride in 1,4-dioxane (6 mL, 1 M), and stir overnight at room temperature. After the reaction is completed, filter to obtain white solid compound I-41 (70 mg, 50%).
  • Step 1 Add 3-N-Boc-cyclobutanone (0.5 g, 2.7 mmol) and cyclopropylamine (0.23 g, 4 mmol) to a round-bottom flask. Dissolve with methanol (10 mL) and add glacial acetic acid (30 ⁇ L). Stir at room temperature for 30 minutes. min. NaBH 3 CN (2.28 g, 10.7 mmol) was then added. The reaction system was stirred at room temperature overnight. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate.
  • Step 3 Add compound WHH99 (210 mg, 0.45 mmol) to a round-bottom flask, add a solution of hydrogen chloride in 1,4-dioxane (2 mL, 2 M), and stir at room temperature for 4 hours. After the reaction is completed, remove the solvent, dissolve in MeOH, and then HPLC preparation and purification to obtain oily compound I-43 (50 mg, yield 59%).
  • HRMS (ESI) C 13 H 25 N 2 O 2 + [M+H] + calculated value: 241.1911; found value: 241.19112.
  • Step 3 Add compound WHH78 (57 mg, 0.124 mmol) to a round-bottom flask, add a solution of hydrogen chloride in 1,4-dioxane (5 mL, 2 M), and stir at room temperature for 4 hours. Filter to obtain white solid compound I-45 (24 mg, 54%).
  • Step 1 Dissolve tert-butyl (4-amino-trans-cyclohexyl)carbamate (0.5 g, 2.34 mmol) and acetaldehyde in tetrahydrofuran (0.56 mL, 5 M) in methanol (10 mL), add glacial acetic acid (30 ⁇ L), and stir at room temperature for 1 hour. Then add NaBH 3 CN (295 mg, 4.68 mmol), and continue to stir the reaction system at room temperature overnight. After the reaction, remove the solvent, separate and purify by rapid silica gel column chromatography to obtain oily compound WHI14 (0.47 g, 84%).
  • HRMS (ESI) [M+H + ] C 13 H 27 N 2 O 2 + calculated value: 243.2067; found value: 243.2068.
  • Step 2 Add WHI14 (0.47 g, 1.94 mmol), N-(4-(hexyloxy)benzyl)-1H-imidazole-1-carboxamide (876 mg, 2.91 mmol), K 2 CO 3 (745 mg, 5.82 mmol), and solvent DMF (8 mL) into a round-bottom flask, and stir the reaction system at room temperature overnight. After the reaction, remove the solvent, separate and purify by rapid silica gel column chromatography to obtain WHI16-1 (0.17 g, 18%).
  • Step 3 Add 1,4-dioxane solution of hydrogen chloride (2 mL, 3 M) to intermediate WHI16-1 (0.15 g, 0.32 mmol) and stir overnight at room temperature. After the reaction is completed, filter to obtain white solid compound I-46 hydrochloride (0.1 g, 83%).
  • 4-Amino-1-methylpiperidine (571 mg, 5 mmol) was dissolved in methanol (10 mL), and acetone (0.4 mL, 5 mmol) was added under stirring at room temperature, and stirring was continued at room temperature for 1 hour.
  • Sodium cyanoborohydride (471 mg, 7.5 mmol) was added to the reaction system, and stirred at room temperature overnight. TLC was used to monitor the reaction progress. After the reaction was completed, water (5 mL) was added to the reaction system to quench the reaction.
  • the first step is to prepare the cell membrane fraction containing 5-HT 2A receptors.
  • 293T cells ATCC CRL-112648 cultured in a 10 cm culture dish were transfected with 5-HT 2A receptors (10 ⁇ g) and PEI (Cat. No.: 24765-1, 1 g/L, 40 ⁇ L). After 48 hours, 5-HT 2A receptors were expressed on the cell membrane.
  • the cell culture medium was aspirated, 2 mL of lysis buffer (1 mM HEPES, 2 mM EDTA, pH 7.4) was added to the culture dish, and the cells were transferred to a 2 mL centrifuge tube and centrifuged at 4 °C. Centrifuge at 15000rpm for 5 minutes and discard the supernatant.
  • the above membrane fractions were used for ligand competition binding experiments.
  • the membrane fractions were broken and resuspended with standard binding buffer (50mM HEPES, 5mM MgCl 2 , 0.5mM EDTA, pH 7.4), and 30 ⁇ L of membrane protein suspension was added to each well of the 96-well plate.
  • the membrane bound to the isotope was collected by rapid vacuum filtration on GF/A filter paper (Perkin Elmer) soaked with 0.3% polyethyleneimine, and the unbound isotope was washed away with washing buffer (50 mM Tris, pH 7.4). Solid scintillator (Perkin Elmer) was dissolved on the dried filter paper, and the radioactivity was detected using a Wallac Trilux MicroBeta counter. The machine readout was the amount of [ 3 H]-LSD bound to the membrane, and the affinity K i values of different compounds for 5-HT 2A receptors were obtained after further data processing using the Graphpad Prism "One-site-Fit K i " formula.
  • the culture medium was removed from the 384-well plate, and 15 ⁇ L of dye Fluo-4 (concentration 4 ⁇ M, Invitrogen) was added, and incubated in a 37 degree 5% carbon dioxide incubator for 1 hour.
  • the drugs were prepared with drug buffer containing 2.5 mM probenecid (Sigma) to ensure that the final concentrations of the drugs added to the 384-well plate by the machine were 10 - 4.5 M, 10 -5 M, 10 -5.5 M, 10 -6 M, 10 -6.5 M, 10 -7 M, 10 -7.5 M, 10 -8 M, 10 -8.5 M, 10 -9 M, 10 -9.5 M, 10 -10 M, 10 -10.5 M, 10 -11 M, 10 -11.5 M, 0 M, three replicates for each treatment.
  • the FLIPR Penta high-throughput real-time fluorescence detector was used to add drugs (7.5 ⁇ L per well) and read the plate.
  • the 520 nm fluorescence reading reflects the amount of intracellular calcium signal release induced by cell Gq protein activation, and the increase in the reading represents receptor activation.
  • the EC 50 values of different compounds on 5-HT 2A receptor Gq protein activation were obtained by processing the data using the Graphpad Prism "log (agonist) vs. response--Variable slope (four parameters)" formula.
  • the downstream ⁇ -arrestin2 signaling pathway mediated by 5-HT 2A receptor was detected by BRET.
  • 293T cells cultured in 6 cm culture dishes (DMEM + 10% FBS (ExCell Bio)) were transfected with 500 ⁇ g of 5-HT 2A receptor containing algae luciferase at the C-terminus (5-HT 2A -Rluc), 500 ⁇ g of Gq protein-coupled receptor kinase 2 (GRK2), 3000 ⁇ g of ⁇ -arrestin2 containing green fluorescent protein at the N-terminus (GFP2-ARRB2) and 16 ⁇ L PEI.
  • DMEM + 10% FBS ExCell Bio
  • the cells were digested, and a 96-well all-white plate (Biyuntian) was laid on each 6 cm culture dish, with 100 ⁇ L of culture solution (DMEM + 2% dFBS) per well.
  • culture solution DMEM + 2% dFBS
  • drug addition was performed for detection.
  • the culture medium was removed from the 96-well plate, and 40 ⁇ L of substrate coelenterazine 400a (final concentration 5 ⁇ M, Goldbio) was added to each well, followed by 20 ⁇ L of drugs of different concentrations, prepared with drug buffer, to ensure that the final drug concentrations were 10-5 M, 10-6 M, 10-7 M, 10-8 M, 10-9 M, 10-10 M, 10-11 M, and 0 M from bottom to top.
  • the compounds of the present invention exhibited good 5-HT 2A receptor agonist activity.
  • the calcium signal was detected to detect the activity of the compound inhibiting the downstream Gq protein signaling pathway mediated by 5-HT 2A receptor.
  • the BRET detection compound inhibits the activity of the downstream ⁇ -arrestin2 signaling pathway mediated by the 5-HT 2A receptor.
  • the ⁇ -arrestin2 signaling pathway is tested as shown in Table 2 to determine whether the compound has agonist activity. After the machine detection is completed, for compounds that do not show agonist activity (see Table 3 below), 20 ⁇ L of serotonin is added immediately so that all concentration treatment wells of the compound contain a final concentration of 10 -7 M serotonin, and the plate is read again by the machine.
  • the data is processed using the Graphpad Prism "log (inhibitor) vs. response--Variable slope (four parameters)" formula to obtain the IC 50 values of different compounds for the inhibition of the 5-HT 2A receptor ⁇ -arrestin2 signaling pathway.
  • the comparative compounds exhibited inhibitory activity on 5-HT 2A receptor-related targets but failed to exhibit agonistic activity.

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Abstract

La présente invention concerne un dérivé d'amine à substitution de cycloalcane, son procédé de préparation et son utilisation. L'invention concerne spécifiquement un composé tel que représenté dans la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. Le dérivé d'amine à substitution de cycloalcane selon la présente invention présente une bonne activité agoniste du récepteur 5-HT2A et de larges perspectives d'application.
PCT/CN2024/120190 2023-09-20 2024-09-20 Dérivé d'amine à substitution de cycloalcane, son procédé de préparation et son utilisation Pending WO2025061176A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009039461A2 (fr) * 2007-09-21 2009-03-26 Acadia Pharmaceuticals, Inc. Dérivés de pipéridine n-substitués en tant qu'agents récepteurs de la sérotonine
WO2019040106A2 (fr) * 2017-08-21 2019-02-28 Acadia Pharmaceuticals Inc. Composés, sels associés et méthodes pour le traitement de maladies
WO2023141595A2 (fr) * 2022-01-20 2023-07-27 Terran Biosciences, Inc. Alkylamines fonctionnalisées

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009039461A2 (fr) * 2007-09-21 2009-03-26 Acadia Pharmaceuticals, Inc. Dérivés de pipéridine n-substitués en tant qu'agents récepteurs de la sérotonine
WO2019040106A2 (fr) * 2017-08-21 2019-02-28 Acadia Pharmaceuticals Inc. Composés, sels associés et méthodes pour le traitement de maladies
WO2023141595A2 (fr) * 2022-01-20 2023-07-27 Terran Biosciences, Inc. Alkylamines fonctionnalisées

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 28 January 2016 (2016-01-28), XP093292943, Database accession no. 1854317-04-6 *

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