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WO2024012496A1 - Composé récepteur cannabinoïde et son utilisation - Google Patents

Composé récepteur cannabinoïde et son utilisation Download PDF

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Publication number
WO2024012496A1
WO2024012496A1 PCT/CN2023/107046 CN2023107046W WO2024012496A1 WO 2024012496 A1 WO2024012496 A1 WO 2024012496A1 CN 2023107046 W CN2023107046 W CN 2023107046W WO 2024012496 A1 WO2024012496 A1 WO 2024012496A1
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phenyl
formula
alkyl
compound
ring
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Chinese (zh)
Inventor
马彦彬
金磊
王思勤
张宏学
陆爱军
卢华君
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Changchun Genescience Pharmaceutical Co Ltd
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Changchun Genescience Pharmaceutical Co Ltd
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

Definitions

  • the invention belongs to the field of medical technology, and specifically relates to cannabinoid receptor compounds and their uses.
  • Cannabinoid receptors CB1 and CB2 are key components of the endocannabinoid system and the primary target of D9-tetrahydrocannabinol (D9-THC).
  • D9-THC is a psychoactive chemical extracted from cannabis that has a wide range of uses in treating diseases (Lemberger, 1980).
  • cannabinoid receptor 1 CB1 is associated with psychoactive, neuromodulatory, and analgesic effects.
  • Cannabidiol (CBD) has received widespread attention due to its pharmacological effects or effects such as neuroprotection, analgesia, anti-inflammatory, antioxidant, and anti-epilepsy.
  • Endocannabinoid receptors are mainly highly expressed in the central nervous system, fat cells, liver cells (liver cells) and musculoskeletal tissues.
  • Endocannabinoid agonists include: anandamide (AEA) and 2-arachidonoyl glycerol (2- AG).
  • CB1 and CB2 play important roles in a variety of physiological processes, including appetite, pain perception, memory, and immune regulation (Manuel Guzmán, Nat Rev Cancer. 2003 Oct; 3(10):745-55).
  • the two cannabinoid receptors share 44% total sequence homology and 68% sequence similarity in the transmembrane region (Munro et al., 1993).
  • CB1 and CB2 are mainly expressed in the central nervous system and immune system, respectively. Due to the high sequence similarity between the two, the development of therapeutic applications is limited by selectivity for a single target.
  • Rimonabant developed by the French company Sanofi-Synthelabo is the world's first type 1 cannabinoid receptor (CB1) inhibitor weight loss drug, which has a good weight loss effect. It also has the effect of sensitizing insulin and improving lipid metabolism disorders, and has a certain effect in assisting smoking cessation. It was approved for marketing in the EU in 2006 as a new weight loss drug.
  • CBD1 cannabinoid receptor
  • Rimonabant is effective for weight loss, it also works against two other risk factors associated with heart disease - smoking and high cholesterol. Since clinically obese patients are often accompanied by heart damage, treatment with this drug will bring greater benefits to patients. Therefore, rimonabant has become one of the most promising weight loss drugs currently available. Rimonabant reduces visceral fat and improves fatty liver index. However, clinical and post-marketing studies found that rimonabant can increase serious psychiatric adverse reactions, namely depression and anxiety, and also increase the risk of suicide in users, so rimonabant was withdrawn from the European market. Through the process from new drug discovery to marketing, this is a target that has been verified for clinical efficacy.
  • the present invention provides compounds represented by the following formula I, their racemates, stereoisomers, tautomers, isotope labels, solvates, polymorphs, and pharmaceutically acceptable compounds. salt or its prodrug,
  • n 1 or 2;
  • Ring A is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rb: C 6-20 aryl, 5-20 membered heteroaryl, C 3-20 cycloalkenoC 6-20 aryl, 3-20 membered heterocyclyl and C 6-20 aryl;
  • Rb are independently selected from CN, amino, nitro, halogen, C 1-12 alkyl, halogenated C 1-12 alkyl, C 1-12 alkoxy, and halogenated C 1-12 alkoxy;
  • Z is N, CH or C
  • --Y-- is absent or represents a vinylidene group optionally substituted by Rb, provided that, when Z is N or CH, --Y-- is absent;
  • R 1 is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rc: C 6 - 20 aryl, 5-20 membered heteroaryl, C 3-20 cycloalkyl, 3 -20-membered heterocyclyl;
  • Rc are independently selected from C 1-12 alkyl, C 1-12 alkoxy, halogen, halo C 1-12 alkyl, halo C 1-12 alkoxy, C 3-20 cycloalkyl, CN, amino, nitro;
  • R 2 means -NHRd
  • Rd independently represents H, unsubstituted or carboxyl-substituted C 1-12 alkyl, C 1-12 alkylamino, amino, nitro, CN, C 1-12 alkylcarbonylamino.
  • X can be selected from the following groups that are unsubstituted or optionally substituted by one, two or more Ra: C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl;
  • n 1 or 2;
  • Ring A can be selected from the following ring systems that are unsubstituted or optionally substituted by one, two or more Rb: C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkenyl C 6-12 aryl, 3-12 membered heterocyclyl and C 6-12 aryl;
  • Rb can be selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy;
  • Z can be N, CH or C
  • --Y-- may be absent or represent a vinylidene group optionally substituted by Rb, provided that, when Z is N or CH, --Y-- is absent;
  • R 1 can be selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rc: C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl with C 6-12 aryl, 3-12 membered heterocyclyl with C 6-12 aryl;
  • Rc may be independently selected from C 1-12 alkyl, C 1-12 alkoxy, halogen, halo C 1-12 alkyl, halo C 1-12 alkoxy, C 3-20 cycloalkyl ,CN;
  • R 2 can represent -NHRd, and / or
  • Rd independently represents H, unsubstituted or carboxyl-substituted C 1-6 alkyl, C 1-6 alkylamino, amino, nitro, CN, C 1-6 alkylcarbonylamino.
  • the carbon atom connected to X may be a chiral carbon atom, so the compound represented by formula I has the structure represented by the following formula Ia or formula Ib:
  • X, ring A, n, Z, --Y--, R 1 and R 2 are as defined in Formula I.
  • n 1 or 2
  • --Y-- is absent and Z is N
  • the compound represented by formula I has the following formula Ic or formula Id Structure shown:
  • X, ring A, R 1 and R 2 are as defined in formula I;
  • Rb replaces ring A', so the compound represented by formula Ie has the structure represented by the following formula If:
  • X, Rb, R1 , R2 , ring A' and m are as defined in formula Ie.
  • X, Rb, R 1 , R 2 and m are as defined in formula Ie or If.
  • ⁇ means oxo, CN, C 1-6 alkyl (such as methyl or ethyl).
  • X is selected from phenyl, cyclohexyl, pyridin-2-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl or 4-cyanobenzene base.
  • Ring A is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rb: five- or six-membered heteroaryl, phenyl, 2,3- Dihydro-1H-indenyl, 2,3-dihydrobenzofuryl; Rb independently represent C 1-6 alkyl, C 1-6 alkoxy, halogen or halogenated C 1-6 alkyl.
  • Ring A is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rb: pyridyl, pyrimidinyl, phenyl, 1H-imidazolyl, thiazolyl , 2,3-dihydro-1H-indenyl, 2,3-dihydrobenzofuryl; Rb independently represent fluorine, chlorine, difluoromethyl, trifluoromethyl, methyl, and methoxy.
  • Ring A is selected from 5-chloropyridin-2-yl, 5-methylpyridin-2-yl, 6-methylpyridin-3-yl, 3-fluoro-5-chloropyridin- 2-yl, 5-chloropyrimidin-2-yl, 6-difluoromethylpyridin-3-yl, 6-trifluoromethylpyridin-3-yl, 5-trifluoromethylpyridin-2-yl, 3 -Chloropyridin-6-yl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 1-methyl-2-trifluoromethyl-1H-imidazol-4-yl , 2-trifluoromethylthiazol-5-yl, 2,3-dihydro-1H-inden-5-yl, 2,3-dihydrobenzofuran-5-yl.
  • R 1 is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rc: C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 bicycloalkyl, 5-12 membered heterocyclyl;
  • Rc may be independently selected from C 1-12 alkyl, C 1-12 alkoxy, halogen, halo C 1-12 alkyl, halo C 1-12 alkoxy, C 3-20 cycloalkyl ,CN.
  • R 1 is selected from the following groups that are unsubstituted or optionally substituted by one, two or more Rc: phenyl, pyridyl, bicyclo[1.1.1]pentyl, 1H -pyrazolyl, thiazolyl, 2,3-dihydrobenzofuranyl, pyrazolo[1,5-a]pyridyl, Rc are independently selected from chlorine, fluorine, cyclopropyl, CN, trifluoro Methyl, difluoromethyl, tert-butyl, methoxy, methyl, ethyl, trifluoromethoxy.
  • R 1 is selected from 4-chlorophenyl, 4-fluorophenyl, 4-cyclopropylphenyl, 4-cyanophenyl, 3-trifluoromethylphenyl, 4- Trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl, 4-difluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-tert-butylphenyl, 6-trifluoromethylphenyl Fluoromethylpyridin-3-yl, 6-methoxypyridin-3-yl, 5-trifluoromethylpyridin-2-yl, 6-chloropyridin-3-yl, 3-trifluoromethylbicyclo[1.1 .1]penta-1- base, 1-ethyl-1H-pyrazol-4-yl, 2-trifluoromethylthiazol-5-yl, 2,3-dihydrobenzofuran-5-yl, pyrazolo[1,5- a]pyr
  • R 2 represents -NHRd, Wherein, Rd independently represent H, unsubstituted C 1-6 alkyl, amino, C 1-6 alkylcarbonylamino, carboxyl C 1-12 alkyl; in some embodiments, Rd independently represent H , methyl, amino, acetamido, 2-carboxymethyl-4-methylpent-1-yl, pivaloylamino.
  • the compound represented by formula I has a structure represented by formula If, wherein ring A' represents a 2,3-dihydrofuran ring or a benzene ring, and Rb independently represents a C 1-6 alkane Oxygen, halogen or halogenated C 1-6 alkyl preferably independently of each other represent fluorine, chlorine or methoxy.
  • the compound represented by formula I has a structure represented by formula Ig, wherein Rb independently represents each other C 1-6 alkoxy group, halogen or halogenated C 1-6 alkyl group, preferably each other independently represents fluorine, chlorine or methoxy.
  • the compound represented by Formula I can be selected from the following compounds:
  • the present invention also provides a pharmaceutical composition, which includes the compound represented by formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable At least one of the salts or prodrugs thereof is accepted.
  • the pharmaceutical composition is used to prevent or treat cannabinoid receptor-mediated diseases or conditions.
  • the pharmaceutical composition is used to prevent or treat cannabinoid receptor type 1 (CB1) mediated diseases or conditions.
  • CBD1 cannabinoid receptor type 1
  • the cannabinoid receptor mediated disease or condition is selected from the group consisting of: obesity, PWS syndrome, diabetes, non-alcoholic steatohepatitis, fibrosis, diabetic nephropathy, diabetic gastroparesis, Tobacco dependence, high cholesterol.
  • the pharmaceutical composition further includes one, two or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable auxiliary material is selected from one, two or more types of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
  • suitable routes of administration of the pharmaceutical composition include, but are not limited to, oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, intravenous and transdermal administration.
  • the pharmaceutical composition is for oral administration, and the pharmaceutical composition may be tablets, pills, lozenges, sugar-coated agents, capsules, etc.
  • the pharmaceutical composition is for topical administration, and the pharmaceutical composition can be an ointment, cream, paste, tincture, plaster, gel, film, or liniment. , aerosols, sprays, foams, micro sponges, etc.
  • the present invention provides the compound represented by the above formula I, its racemate, stereoisomer, tautomer, isotope label, solvate, polymorph, pharmaceutically acceptable salt or its prodrug, Or the use of the pharmaceutical composition in the preparation of a medicament for the treatment or prevention of cannabinoid receptor mediated disorders.
  • the present invention also provides a method of treating or preventing a disease or condition mediated by a cannabinoid receptor, preferably cannabinoid receptor type 1 (CB1), or alleviating symptoms thereof, comprising administering the prevention or treatment to an individual in need thereof
  • a cannabinoid receptor preferably cannabinoid receptor type 1 (CB1)
  • CBD1 cannabinoid receptor type 1
  • the cannabinoid receptor mediated disease or condition is selected from the group consisting of: obesity, PWS syndrome, diabetes, non-alcoholic steatohepatitis, fibrosis, diabetic nephropathy, diabetic gastroparesis, Tobacco dependence, high cholesterol.
  • the daily dosage is 0.01 to 200 mg/kg body weight.
  • dosing regimens may be adjusted to provide the optimal desired response.
  • a single oral dose may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as the exigencies of the therapeutic situation indicate.
  • dosage values may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that, for any particular individual, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
  • the compound of the present invention has good binding ability and inverse agonistic activity to human CB1 receptors, and at the same time shows almost no inverse agonistic activity to human CB2 receptors. Therefore, the compound has good selectivity for CB1 and can be used in Obtain expected pharmacological activity while reducing side effects related to CB2 receptors. Moreover, the compound of the present invention also has the advantages of short synthetic route, convenient preparation process and simple product post-processing.
  • Truncated chemical bonds represent attachment sites for corresponding groups.
  • halogen includes F, Cl, Br or I.
  • C 1-12 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1 to 12 carbon atoms.
  • C 1-6 alkyl refers to straight and branched chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-Methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers.
  • C 1-12 alkoxy is understood to mean -OC 1-12 alkyl, wherein C 1-12 alkyl has the above definition.
  • C 3-20 cycloalkyl is understood to mean a saturated monovalent monocyclic, bicyclic or polycyclic hydrocarbon ring (also called fused hydrocarbon ring) having 3 to 20 carbon atoms.
  • Bicyclic or polycyclic cycloalkyl groups include pendant cycloalkyl, bridged cycloalkyl, and spirocycloalkyl; the pendant ring refers to two or more cyclic structures sharing two adjacent ring atoms.
  • the bridged ring refers to a fused ring structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other.
  • the spiro ring refers to a fused ring structure formed by two or more ring structures sharing one ring atom with each other.
  • the C 3-20 cycloalkyl group can be a C 3-8 monocyclic cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or C 7 -12- branched cycloalkyl group, such as decalin ring; it can also be C 7-12 bridged cycloalkyl group, such as norbornane, adamantane, and bicyclo[2,2,2]octane.
  • the term "cycloalkenyl” refers to a cycloalkyl group containing one or more intracyclic double bonds.
  • heterocyclyl means a partially saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, preferably “3-10 "Heterocyclic group”.
  • heterocyclyl means a partially saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclyl group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom, if present.
  • the heterocyclyl group may include, but is not limited to: 4-membered rings, such as azetidinyl, oxetanyl; 5-membered rings, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as Tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or 7-membered ring, such as diazepanyl.
  • the heterocyclyl group may be benzo-fused.
  • the heterocyclyl group may be bicyclic, such as but not limited to a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing nitrogen atoms may be partially unsaturated, i.e.
  • the heterocyclyl group is nonaromatic.
  • C 6-20 aryl is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably “C 6-14 aryl”.
  • C 6-14 aryl is understood to mean preferably a monovalent or partially aromatic monocyclic, bicyclic or Tricyclic hydrocarbon rings (“C 6-14 aryl”), especially rings with 6 carbon atoms ("C 6 aryl”), such as phenyl; or biphenyl, or with 9 carbon atoms a ring (“C 9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring with 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring with 14 carbon atoms ("C 14 atoms).
  • 5-20 membered heteroaryl is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 independently selected from N, O and S heteroatoms, such as "5-14 membered heteroaryl".
  • the term “5-14 membered heteroaryl” is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, additionally in each case The following can be benzo-fused.
  • the heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl, thi-4H-pyrazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzene Triazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinoline base, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • heteroaryl group may also include a heteroaryl group formed by the fusion of two any of the aforementioned heteroaryl groups, such as a pyrazole-fused pyridyl group, especially a pyrazolo[1,5-a]pyridyl group.
  • C 1-12 alkyl is also applicable to other groups containing C 1-12 alkyl, such as C 1-12 alkoxy, etc.
  • C 6-20 aryl, 5-20 membered heteroaryl, and C 3-20 cycloalkyl have the same definitions throughout the text.
  • Example 1 (E)-N-((E)-1-aminoethylene)-3-(5-chloropyridin-2-yl)-4-phenyl-N'-[4-(trifluoro Methyl)benzenesulfonyl]-4,5-dihydropyrazole-1-carboxylimideamide (compound 1), (R,E)-N-((E)-1-aminoethylene)- 3-(5-chloropyridin-2-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole- 1-Carboxylimide amide (compound 2) and (S,E)-N-((E)-1-aminoethylene)-3-(5-chloropyridin-2-yl)-4-phenyl Preparation of -N'-((4-(trifluoromethyl)phenyl)sulfonyl)
  • Step 4 Synthesis of compound 5-chloro-2-(4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)pyridine (5)
  • Step 5 Compound (Z)-3-(5-chloropyridin-2-yl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-di Synthesis of hydrogen-1H-pyrazole-1-thiocarboxylic acid methyl ester (6)
  • reaction mixture was cooled to room temperature, then diluted with water (50 mL), and extracted with dichloromethane (3 ⁇ 40 mL). The organic phases were combined, backwashed with saturated brine (1 ⁇ 60 mL), and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Step 6 Compound (E)-N-[(1E)-1-aminoethylene]-3-(5-chloropyridin-2-yl)-4-phenyl-N'-[4-(trifluoro Synthesis of methyl)benzenesulfonyl]-4,5-dihydropyrazole-1-carboxylimide amide (compound 1)
  • the system was continued to stir at 100°C for 1 hour. Liquid quality monitoring showed that the reaction was complete, the reaction solution was cooled to room temperature, distilled water (20 mL) was added to the reaction mixture, and extracted with ethyl acetate (3 ⁇ 20 mL). The organic phases were combined, backwashed with saturated brine (1 ⁇ 20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate obtained was concentrated under reduced pressure.
  • the crude product was purified by preparative HPLC using the following conditions: chromatography column specifications: XBridge Shield RP18OBD Column, 19*150mm, 5 ⁇ m; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL /min; elution gradient: 27% B to 70% B, within 8 minutes, 70% B; detection wavelength: UV 254nm/220nm.
  • Step 7 (R,E)-N-((E)-1-aminoethylene)-3-(5-chloropyridin-2-yl)-4-phenyl-N'-((4-( Trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide amide (compound 2) and (S,E)-N-((E)-1 -Aminoethylene)-3-(5-chloropyridin-2-yl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-di
  • Compound 3 Compound 3
  • Step 1-3 Synthesis of compound 5-chloro-2-(4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)pyridine (10)
  • Steps 1-3 are carried out in a similar manner to steps 2-4 in Example 1 (the starting material is replaced with 5-chloropyridyl cyanide) to obtain 5-chloro-2-(4-phenyl-4,5-dihydro- 1H-pyrazol-3-yl)pyridine (22g, 94.16%) was a dark brown oil and was directly added to the next step without further purification.
  • Step 4 Synthesis of compound 3-(5-chloropyridin-2-yl)-4-phenyl-4,5-dihydropyrazole-1-carbonyl chloride (11)
  • the reaction system was quenched by adding water (30 mL) at 0°C and diluted with water (60 mL).
  • the reaction mixture was extracted with dichloromethane (3 ⁇ 60 mL).
  • the organic phases were combined, backwashed with saturated sodium chloride solution (2 ⁇ 60 mL), and dried over anhydrous sodium sulfate.
  • the resulting mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography to obtain 3-(5-chloropyridin-2-yl)-4-phenyl-4,5-dihydropyrazole-1-carbonitrile (1.5 g, 59.09%).
  • Step 7 Compound (E)-N-(1-aminoethylene)-3-(5-chloropyridin-2-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1 -Synthesis of carboxyimide amide (14)
  • Step 8 Compound (E)-3-(5-chloropyridin-2-yl)-N-acetylimido-4-phenyl-N'-[6-(trifluoromethyl)pyridin-3-yl Synthesis of sulfonyl]-4,5-dihydropyrazole-1-carboxylimide amide (compound 14)
  • reaction solution was quenched with water (20 mL) and diluted with water (60 mL).
  • the reaction mixture was extracted with dichloromethane (3 ⁇ 60 mL).
  • the organic phases were combined, backwashed with saturated sodium chloride aqueous solution (2 ⁇ 60 mL), and dried over anhydrous sodium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure.
  • the crude product was purified by preparative HPLC using the following conditions: chromatography column specifications: XBridge Shield RP18 OBD Column, 30*150mm, 5 ⁇ m; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL/min; elution solvent: 10% B to 70% B; detection wavelength: UV 254nm/220nm.
  • Step 9 Compound (R,E)-N-((E)-1-aminoethylene)-3-(5-chloropyridin-2-yl)-4-phenyl-N'-((6- (Trifluoromethyl)pyridin-3-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximide amide (compound 15) and (S,E)-N-(( E)-1-Aminoethylene)-3-(5-chloropyridin-2-yl)-4-phenyl-N'-((6-(trifluoromethyl)pyridin-3-yl)sulfonyl Synthesis of )-4,5-dihydro-1H-pyrazole-1-carboxylimide amide (compound 16)
  • Step 1-4 Synthesis of compound 5-(4-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-2-(trifluoromethyl)pyridine (19)
  • the first four steps adopt a similar method to Example 1 (the starting material is replaced with 6-(trifluoromethyl)nicotinic acid) to obtain 5-(4-phenyl-4,5-dihydro-1H-pyrazole-3) -(yl)-2-(trifluoromethyl)pyridine (2g, 95.19%) was directly used in the next step without further purification.
  • Step 5 Compound 4-phenyl-N-[4-(trifluoromethyl)benzenesulfonyl]-3-[6-(trifluoromethyl)pyridin-3-yl]-4,5-dihydropyridine Synthesis of azole-1-carboxamide (20)
  • Step 6 Compound (Z)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(6-(trifluoromethyl)pyridin-3-yl)- Synthesis of 4,5-dihydro-1H-pyrazole-1-carbonimide acid chloride (21)
  • Step 7 Compound (E)-N-((E)-1-aminoethylene)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-3- Synthesis of (6-(trifluoromethyl)pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboximide amide (compound 36)
  • Step 8 (R,E)-N-(1-iminoethyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(6- (Trifluoromethyl)pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboximide amide (compound 37) and (S,E)-N-(1-imino Ethyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(6-(trifluoromethyl)pyridin-3-yl)-4,5 -Synthesis of dihydro-1H-pyrazole-1-carboximide amide (compound 38)
  • the reaction mixture was quenched by adding ice water (200 mL) at 0°C, and extracted with dichloromethane (3 ⁇ 100 mL). The organic phases were combined, backwashed with saturated brine (1 ⁇ 100 mL), and dried over anhydrous sodium sulfate. After the resulting mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1-(2,3-dihydro-1H-inden-5-yl)-2-phenylacetone (7 g, 23.34%). LCMS:(ESI,m/z):237.00[M+H] + .
  • Step 2 Synthesis of compound 1-(2,3-dihydro-1H-inden-5-yl)-2-phenylprop-2-en-1-one (24)
  • Step 3 Synthesis of compound 3-(2,3-dihydro-1H-inden-5-yl)-4-phenyl-4,5-dihydro-1H-pyrazole (25)
  • Step 4 Synthesis of compound 3-(2,3-dihydro-1H-inden-5-yl)-4-phenyl-4,5-dihydropyrazole-1-carboximide amide (26)
  • Step 5 N-[(1E)-1-aminoethylene]-3-(2,3-dihydro-1H-inden-5-yl)-4-phenyl-4,5-dihydropyrazole -Synthesis of 1-carboxylimide amide (27)
  • the obtained residue was purified by preparative HPLC under the following conditions: chromatography column specifications: Xselect CSH C18 OBD Column 30*150mm 5 ⁇ m, n; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate :60mL/min; elution solvent: 40% B to 67% B; detection wavelength: UV 254nm/220nm; retention time (minutes): 8.67.
  • Example 5 Referring to the methods of Example 4 and Example 5, the compounds in Table 5 below were prepared. The structural characterization data of these compounds are listed in Table 5.
  • Step 1 Synthesis of compound 1-(4-toluenesulfonyl)-2-phenylaniline (31)
  • Step 2 Synthesis of compound 7-chloro-3-(4-methylbenzenesulfonyl)-1-phenyl-1H,2H-benzo[e]indole (32)
  • Example 7 (E)-N-((E)-1-aminoethylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl) )phenyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxylimide amide (compound 61), compound (S,E)-N-((E)-1-aminoimide Ethyl)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine-1( 4H)-carboxamide (compound 62) and (R,E)-N-((E)-1-aminoethylene)-3-(4-chlorophenyl)-4-phenyl-N'-( Preparation of (4-(trifluoromethyl)phenyl)sul
  • Step 1 Synthesis of compound 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid methyl ester (36)
  • aqueous phase was extracted with ethyl acetate (3 ⁇ 100 mL), the organic phases were combined, backwashed with saturated brine (1 ⁇ 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography to obtain 4-(4-chlorophenyl)-4-oxo-3-phenylbutyric acid methyl ester (3.5 g, 53.34%).
  • Step 4 Synthesis of compound 3-(4-chlorophenyl)-4-phenyl-1,4,5,6-tetrahydropyridazine (39)
  • Step 5 Compound (Z)-3-(4-chlorophenyl)-4-phenyl-N-((4-(trifluoromethyl)phenyl)sulfonyl)-5,6-dihydropyridazine -Synthesis of 1(4H)-carmine thiocarbonate (40)
  • Step 6 (E)-N-((E)-1-aminoethylene)-3-(4-chlorophenyl)-4-phenyl-N'-((4-(trifluoromethyl)) benzene Synthesis of methyl)sulfonyl)-5,6-dihydropyridazine-1(4H)-carboxylimide amide (compound 61)
  • the crude product was purified by preparative HPLC using the following conditions: chromatography column specifications: XBridge Prep BEH130 C18 Column, 19X100mm, 5 ⁇ m; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60mL/min ; Elution solvent: 25% B to 75% B; Detection wavelength: UV 220nm; Retention time (minutes): 6.85.
  • Step 7 Synthesis of Compound 62 and Compound 63
  • Example 8 N-((E)-N'-((E)-(3-(4-chlorophenyl)-4-phenyl-5,6-dihydropyridazine-1(4H)-yl Preparation of )(((4-(trifluoromethyl)phenyl)sulfonyl)imino)methyl)aminoamido)acetamide (compound 67)
  • the UNIFILTER-96GF/C plate added with 0.5% PEI solution and incubated for 1 hour at 4°C was washed twice with washing solution (50mM Tris-HCl, 2.5mM EDTA, 5mM MgCl 2 , 0.5mg/ml BSA, pH 7.4). 50mL wash solution each time. Transfer the reaction system in the 96-well deep-well experimental plate to the UNIFILTER-96GF/C plate, wash it 4 times with washing solution, 900 ⁇ L of washing solution per well. Place the cleaned UNIFILTER-96GF/C board in a 55°C oven and dry for 10 minutes.
  • the compounds of the present invention have good binding ability to human CB1 receptors, and the binding data of some compounds are shown in Table 9 below.
  • Flp-In-CHO-human CB1/2, Flp-In-CHO-mouse CB1/2 and Flp-In-CHO-rat CB1/2 cells were cultured in F12K, 10% fetal bovine serum, 1% penicillin-streptococci The cells were cultured in a complete medium containing 600 ⁇ g/ml hygromycin and 600 ⁇ g/ml hygromycin in a 37°C, 5% CO2 cell culture incubator. On the day of the experiment, the cells were digested and resuspended in HBSS experimental buffer containing 20mM HEPES, 0.1% BSA and 500 ⁇ M IBMX, and then seeded into a 384-well cell culture plate.
  • the seeding density of human and mouse CB1/2 cells is 8000 cells per well, and the seeding density of rat CB1/2 cells is 2000 cells per well, and the seeding volume is 15 ⁇ L. Subsequently, a cAMP production assay was used to detect the inverse agonistic activity of the compounds on human CB1 and CB2 receptors.
  • the compounds of the present invention show good human CB1 inverse agonistic activity.
  • the human CB1 inverse agonistic activity of some compounds is shown in Table 10 below.
  • Exemplary compounds of the present invention show good selectivity for human CB2 inverse agonism.
  • the inverse agonistic activity of some compounds on human CB2 is shown in Table 11 below.

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Abstract

La présente invention concerne un composé récepteur cannabinoïde tel que représenté par la formule I. Le composé présente une bonne capacité de liaison et une bonne activité agoniste sur un récepteur CB1 humain, et ne présente presque pas d'activité agoniste inverse sur un récepteur CB2 humain. Par conséquent, le composé présente une bonne sélectivité vis-à-vis de CB1, et des effets secondaires associés au récepteur CB2 peuvent être réduits et l'activité pharmacologique attendue peut être obtenue.
PCT/CN2023/107046 2022-07-15 2023-07-12 Composé récepteur cannabinoïde et son utilisation Ceased WO2024012496A1 (fr)

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WO2025103493A1 (fr) * 2023-11-16 2025-05-22 西藏海思科制药有限公司 Antagoniste du récepteur cannabinoïde 1 et son utilisation

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