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WO2021047581A1 - Dérivé d'hexahydrobenzopyrazole et sa préparation - Google Patents

Dérivé d'hexahydrobenzopyrazole et sa préparation Download PDF

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Publication number
WO2021047581A1
WO2021047581A1 PCT/CN2020/114448 CN2020114448W WO2021047581A1 WO 2021047581 A1 WO2021047581 A1 WO 2021047581A1 CN 2020114448 W CN2020114448 W CN 2020114448W WO 2021047581 A1 WO2021047581 A1 WO 2021047581A1
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alkyl
compound
pain
ring
group
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Chinese (zh)
Inventor
李瑶
陈雷
王文晶
张国彪
石宗军
王亚军
赵剑飞
唐平明
林洪军
叶飞
冯清伟
张晨
倪佳
严庞科
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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Priority to CN202080061781.9A priority Critical patent/CN114391011A/zh
Publication of WO2021047581A1 publication Critical patent/WO2021047581A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof

Definitions

  • the invention relates to a hexahydrobenzopyrazole compound and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides, prodrugs and pharmaceutical compositions thereof, preparation methods, and Use in the prevention and treatment of diseases mediated by the cannabinoid CB2 receptor.
  • Neuropathic pain is caused by damage to the peripheral or central nerve pathways. This pain leads to persistent spontaneous pain and hypersensitivity reactions to pain and harmless stimuli.
  • the underlying causes of neuropathic pain vary widely, but usually have similar clinical features. Some of the most common pathologies that cause neuropathic pain are diabetic neuropathy, amputation, surgery, and postherpetic neuralgia. Studies have shown that up to 7-8% of adults suffer from neuropathic pain, and the prevalence is rising, and it is expected to further increase in the aging population. In addition to personal pain, unemployment and loss of social ability have led to an increase in treatment costs. At the same time, it is often accompanied by complications such as anxiety and depression.
  • the main symptoms of Crohn's disease include abdominal pain, diarrhea and fatigue, weight loss, fever, growth retardation, anemia, recurrent anal fistulas or other extraintestinal manifestations.
  • Drug treatments include aminosalicylic acid preparations, glucocorticoids, immunosuppressants, antibacterial drugs, and anti-TNF- ⁇ monoclonal antibodies. There are currently no drugs to manage Crohn's disease-related abdominal pain.
  • painkillers widely used in the market can cause harmful side effects and have unsatisfactory therapeutic effects. Therefore, the development of new analgesics cannot be delayed.
  • Cannabis extract has been used for pain relief for centuries.
  • cannabidiol CBD
  • CBD cannabidiol
  • cannabinoid cannabinoid
  • cannabinoid receptor 1 cannabinoid receptor 1
  • CB2 cannabinoid receptor 2
  • CB1 is most expressed in neurons of the CNS, but it is also present in a variety of peripheral tissues and cells at lower concentrations (Matsuda, L.A. et al. (1990) Nature 346: 561-564).
  • CB2 is mainly but not absolutely expressed in non-neural tissues such as hematopoietic cells, endothelial cells, osteoblasts, osteoclasts, endocrine pancreas and cancer cell lines (Munro, S. et al. (1993) Nature 365 :61-65; and Pache, P. etal. (2006) Pharmacol. Rev. 58(3):389-462).
  • Central CB1 is distributed in the cerebral cortex and limbic system, and is responsible for the analgesic effect and causing behavioral changes after being activated by cannabinoid. Although CB1 can mediate a powerful analgesic effect, it can cause euphoria, ataxia, dizziness and other mental symptoms. At the same time, it may produce addiction and tolerance, so it limits its use in the field of analgesia.
  • Peripheral CB2 is mainly distributed in immune cells and plays a role in pain and inflammation signals. In addition, CB2 is also distributed in peripheral nerve fibers and injured nerve endings.
  • CB2 After CB2 is excited, it exerts analgesic effect by inhibiting the production of toxins and inflammatory mediators by neutrophils and macrophages, and can also block the excitatory conduction of injured nerves.
  • CB2 is expressed in the brainstem, cerebral cortex and cerebellum of mice, but the expression level is very low, about 3.4% of the spleen.
  • CB2 selective CB2 agonists can theoretically avoid CB1R-related central psychiatric side effects, and show good analgesic effects in multiple preclinical models.
  • CB2 selective agonists have been discontinued in the field of analgesia due to insufficient analgesic efficacy in clinical trials, including JBT-101, LY2828360, etc. The reasons may be as follows: Although it shows a certain selectivity, it still has an agonistic effect on CB1, so it may cause adverse events at the effective dose and insufficient efficacy at a safe dose; agonistic effects on CB1 may lead to significant drug effects in animal models. Insufficient efficacy after transformation.
  • CB2 agonists will have functional selectivity.
  • the downstream of CB1/2 includes adenosine cyclase synthesis, ERK signaling pathway activation, ion current changes, internalization, ⁇ -arrestin, etc. Different drugs have functional biases to downstream activation .
  • the purpose of the present invention is to introduce a new type of cannabinoid CB2 agonist which is effective, safe, highly selective, long-acting and good in pharmacokinetic characteristics.
  • the present invention relates to a hexahydrobenzopyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs:
  • R 1 is selected from -L 1 -L 2 -L 3 -L 4 ;
  • L 1 is selected from C 1-6 alkylene, C 3-7 cycloalkenylene, C 3-7 cycloalkylene, C 3-6 unsaturated cycloalkylene, C 3-6 heterocyclylene, C 6-10 arylene group, C 5-10 heteroarylene group, C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring or not present, the alkylene group, cycloalkylene group Group, cycloalkylene, unsaturated cycloalkylene, heterocyclylene, arylene, heteroarylene, bridged ring, fused ring, and spiro ring are each independently optionally substituted with the following substituents: halogen, cyano, Hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 2-6 alkynyl-C 3-6 cycloalkyl, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, halogenated C
  • L 2 is selected from C 1-6 alkylene, C 3-7 cycloalkylene, C 3-6 heterocyclylene, C 5-10 heteroarylene, -C(O)NH-, -C( O)-, -C(O)O- or not present, the alkylene, cycloalkylene, heterocyclylene, and heteroarylene are each independently optionally substituted by the following substituents: C 1-6 Alkyl or halogen;
  • L 3 is selected from C 1-6 alkylene or absent
  • L 4 is selected from H, halogen, hydroxyl, amino, ureido, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 3-6 heterocyclyl, C 2-6 alkynyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) C 1-6 alkyl, -NHC(O )C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -NH-C 6-10 aryl, -NH-C 3-7 cycloalkyl, -C(O)-C 6- 10 aryl, -OC 6-10 aryl, -OC 6-10 heteroaryl, -OC 1-6 alkylene-COOH, -C(O)NH 2 , -COOH, C 4-12 bridged ring, C 4-12 parallel ring or C 5-10 spiro ring, the alkyl, al
  • R 2 and R 3 are each independently selected from H, F, Cl, cyano, hydroxyl or C 1-6 alkyl;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 8 and R 9 are each independently selected from H, F, Cl, C 1-6 alkyl, and the alkyl is optionally substituted by the following substituents: cyano, F or Cl, or R 8 and R 9 together form C 2-6 alkenyl or C 3-6 cycloalkyl;
  • R 10 is selected from H or C 1-6 alkyl
  • R 11 is selected from aryl or heteroaryl, said aryl or heteroaryl is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl or C 1-6 alkoxy, said Heteroaryl groups include heteroatoms selected from N, O, S and their oxidation states;
  • the present invention relates to a hexahydrobenzopyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs:
  • R 1 is selected from -L 1 -L 2 -L 3 -L 4 ;
  • L 1 is selected from C 1-6 alkylene, C 3-7 cycloalkenylene, C 3-7 cycloalkylene, C 3-6 unsaturated cycloalkylene, C 3-6 heterocyclylene, C 6-10 arylene group, C 5-10 heteroarylene group, C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring or not present, the alkylene group, cycloalkylene group Group, cycloalkylene, unsaturated cycloalkylene, heterocyclylene, arylene, heteroarylene, bridged ring, fused ring, and spiro ring are each independently optionally substituted with the following substituents: halogen, cyano, Hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 alkynyl-C 3-6 cycloalkyl, C 1-6 alkoxy, hydroxy substituted C 1-6 alkyl, halo C 1-6 alky
  • L 2 is selected from C 1-6 alkylene, C 3-7 cycloalkylene, C 3-6 heterocyclylene, C 5-10 heteroarylene, -C(O)NH-, -C( O)-, -C(O)O- or not present, the alkylene, cycloalkylene, heterocyclylene, and heteroarylene are each independently optionally substituted by the following substituents: C 1-6 Alkyl or halogen;
  • L 3 is selected from C 1-6 alkylene or absent
  • L 4 is selected from H, halogen, hydroxyl, amino, ureido, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, C 3-6 heterocyclyl, C 1-6 haloalkyl, C 2-6 alkynyl, C 6-10 aryl, C 5-10 heteroaryl, -NHC 1-6 alkyl, -N (C 1-6 alkyl) C 1-6 Alkyl, -NHC(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -NH-C 6-10 aryl, -NH-C 3-7 cycloalkyl, -C (O)-C 6-10 aryl, -OC 6-10 aryl, -OC 6-10 heteroaryl, -OC 1-6 alkyl-COOH, -C(O)NH 2 , -COOH, C 4-12 bridged ring, C 4-12 parallel ring or C 5-10 spiro
  • R 2 and R 3 are each independently selected from H, F, Cl, cyano, hydroxyl or C 1-6 alkyl;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 8 and R 9 are each independently selected from H, F, Cl, C 1-6 alkyl, and the alkyl is optionally substituted by the following substituents: cyano, F or Cl, or R 8 and R 9 together form C 2-6 alkenyl or C 3-6 cycloalkyl;
  • R 10 is selected from H or C 1-6 alkyl
  • R 11 is selected from aryl or heteroaryl, said aryl or heteroaryl is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl or C 1-6 alkoxy, said Heteroaryl groups include heteroatoms selected from N, O, S and their oxidation states;
  • the present invention relates to a hexahydrobenzopyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs:
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 3-6 unsaturated cyclic hydrocarbon group, C 6-10 aryl, C 5-10 heteroaryl Group, C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring, the alkyl group, cycloalkyl group, unsaturated cyclic hydrocarbon group, heterocycloalkyl group, aryl group, heteroaryl group, The bridged ring, fused ring or spiro ring is optionally substituted by the following substituents: F, Cl, hydroxy, cyano, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy, Halogenated C 1-6 alkyl, benzene ring, -C (O) OC 1-6 alkyl, -C 1-6 alkyl-OC 1-6 alkyl or C 3-6 cycloalkyl; R 1 is selected From
  • R 2 and R 3 are each independently selected from H, F, Cl, cyano, hydroxyl, C 1-6 alkoxy or C 1-6 alkyl; in some embodiments, R 2 and R 3 are each independently selected From H, F, Cl, cyano, hydroxy, or C 1-6 alkyl; in some embodiments, R 2 and R 3 are each independently selected from H, F, Cl, methyl, ethyl, isopropyl , Tert-butyl; In certain embodiments, R 2 and R 3 are each independently selected from H, F or methyl;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl; in certain embodiments, R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, cyano, hydroxyl, or C 1-6 alkyl; R 4 , R 5 , R 6 , and R 7 are each independently selected from H or C 1- 6 Alkyl; In certain embodiments, R 4 , R 5 , R 6 , and R 7 are each independently selected from H, methyl, ethyl, and isopropyl;
  • R 8 and R 9 are each independently selected from H, F, Cl, cyano, hydroxyl, C 1-6 alkoxy or C 1-6 alkyl; R 8 , R 9 are each independently selected from H, F, Cl, C 1-6 alkyl, said alkyl is optionally substituted by the following substituents: cyano, F or Cl, or R 8 and R 9 together form a C 2-6 alkenyl or C 3-6 cycloalkyl;
  • R 10 is selected from H or C 1-6 alkyl
  • R 11 is selected from aryl or heteroaryl, said aryl or heteroaryl is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl or C 1-6 alkoxy; in some In the embodiment, R 11 is selected from or In certain embodiments, R 11 is selected from
  • the present invention relates to a hexahydrobenzopyrazole compound represented by formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs:
  • R 1 is selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 3-6 unsaturated cyclic hydrocarbon group, C 6-10 aryl, C 5-10 heteroaryl Group, C 4-12 bridged ring, C 4-12 parallel ring, C 5-10 spiro ring, the alkyl group, cycloalkyl group, unsaturated cyclic hydrocarbon group, heterocycloalkyl group, aryl group, heteroaryl group, The bridged ring, fused ring or spiro ring is optionally substituted by the following substituents: F, Cl, hydroxy, cyano, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 heterocycloalkyl, benzene ring, -C (O) OC 1-6 alkyl, -C 1-6 alkyl-OC 1-6 alkyl or C 3-6 cycloalkyl; in some In an embodiment
  • R 2 and R 3 are each independently selected from H, F, Cl, cyano, hydroxyl, C 1-6 alkoxy or C 1-6 alkyl; in some embodiments, R 2 and R 3 are each independently selected From H, F, Cl, cyano, hydroxy, or C 1-6 alkyl; in some embodiments, R 2 and R 3 are each independently selected from H, F, Cl, methyl, ethyl, isopropyl , Tert-butyl; In certain embodiments, R 2 and R 3 are each independently selected from H, F or methyl;
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, Cl, amino, cyano, hydroxyl, C 1-6 alkyl or C 1-6 haloalkyl; in certain embodiments, R 4 , R 5 , R 6 , and R 7 are each independently selected from H, F, cyano, hydroxyl, or C 1-6 alkyl; R 4 , R 5 , R 6 , and R 7 are each independently selected from H or C 1- 6 Alkyl; In certain embodiments, R 4 , R 5 , R 6 , and R 7 are each independently selected from H, methyl, ethyl, and isopropyl;
  • R 8 and R 9 are each independently selected from H, F, Cl, cyano, hydroxyl, C 1-6 alkoxy or C 1-6 alkyl; R 8 , R 9 are each independently selected from H, F, Cl, C 1-6 alkyl, said alkyl is optionally substituted by the following substituents: cyano, F or Cl, or R 8 and R 9 together form a C 2-6 alkenyl or C 3-6 cycloalkyl;
  • R 10 is selected from H or C 1-6 alkyl
  • R 11 is selected from aryl or heteroaryl, said aryl or heteroaryl is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl or C 1-6 alkoxy; in some In the embodiment, R 11 is selected from or In certain embodiments, R 11 is selected from
  • R 1 is selected from Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl, or
  • R 1 is selected from
  • R 1 is selected from Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl, or
  • R 1 is selected from Indolyl, pyrrolyl, pyridyl, piperidinyl, phenyl, cyclohexyl, cyclopentyl, pyrazine, adamantyl, piperazine, morpholinyl, or
  • R 11 is selected from or
  • the condition is: when R 11 is selected from When, R 1 is selected from
  • R 11 is selected from
  • R 11 is selected from or
  • the condition is: when R 11 is selected from When, R 1 is selected from
  • R 11 is selected from
  • R 1 is selected from C 1-6 alkyl or C 3-6 cycloalkyl, said alkyl or cycloalkyl is optionally substituted by the following substituents: F, Cl, C 1-6 alkyl or hydroxy;
  • R 2 and R 3 are each independently selected from H, F, Cl or C 1-6 alkyl
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H or C 1-6 alkyl;
  • R 8 and R 9 are each independently selected from H, F, Cl, C 1-6 alkyl, and the alkyl is optionally substituted by the following substituents: cyano, F or Cl, or R 8 and R 9 together form C 2-6 alkenyl or C 3-6 cycloalkyl;
  • R 10 is selected from H
  • R 11 is selected from or
  • the condition is: when R 11 is selected from When, R 1 is selected from
  • R 1 is selected from or
  • R 2 and R 3 are each independently selected from H, F or methyl
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H;
  • R 8 and R 9 are each independently selected from H, F, isopropyl, Or R 8 and R 9 together form 2-methpropenyl or cyclopropyl;
  • R 10 is selected from H
  • R 11 is selected from
  • R 1 is selected from or
  • R 2 and R 3 are each independently selected from H, F or methyl
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H;
  • R 8 and R 9 are each independently selected from H, F, isopropyl, or R 8 and R 9 together form 2-methpropenyl or cyclopropyl;
  • R 10 is selected from H
  • R 11 is selected from
  • R 1 is selected from or
  • R 2 and R 3 are each independently selected from H, F or methyl
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H;
  • R 8 and R 9 are each independently selected from H, F, isopropyl, Or R 8 and R 9 together form 2-methpropenyl or cyclopropyl;
  • R 10 is selected from H
  • R 11 is selected from
  • R 1 is selected from or
  • R 2 and R 3 are each independently selected from H, F or methyl
  • R 4 , R 5 , R 6 , and R 7 are each independently selected from H;
  • R 8 and R 9 are each independently selected from H, F, and isopropyl
  • R 10 is selected from H
  • R 11 is selected from
  • hexahydrobenzopyrazole compound of the present invention and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, wherein the compound structure is as follows:
  • hexahydrobenzopyrazole compound of the present invention and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, wherein the compound structure is as follows:
  • hexahydrobenzopyrazole compound of the present invention and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs, wherein the compound structure is as follows:
  • the present invention also relates to a pharmaceutical composition, said composition comprising: an effective dose of any compound of the present invention and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides Or prodrugs, or further include one or more other therapeutic agents and pharmaceutically acceptable carriers or excipients.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention Use of the compound composition in the preparation of a medicament for the treatment of diseases mediated by CB2 receptors.
  • the present invention relates to a hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the compounds of the present invention
  • the composition is used in the preparation of a medicine for the treatment of pain.
  • the pain can be selected from: bone pain, arthralgia, muscle pain, toothache, migraine, headache, inflammatory pain, neuropathic pain, Crohn’s disease-related abdominal pain, and dysfunction due to the therapeutic agent Pain caused by the action and pain associated with diseases selected from: osteoarthritis, cancer, multiple sclerosis, allergic response, nephritis syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia , HIV-related neuropathy, sciatica and autoimmune diseases.
  • diseases selected from: osteoarthritis, cancer, multiple sclerosis, allergic response, nephritis syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia , HIV-related neuropathy, sciatica and autoimmune diseases.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention Use of the compound composition in the preparation of a medicament for treating neuropathic pain.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention Use of the compound composition in the preparation of a medicament for treating Crohn's disease-related abdominal pain.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention
  • the composition of the compound is used in a method of treating diseases mediated by CB2 receptors.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention
  • the composition of the compound is used in a method of treating pain.
  • the pain may be selected from: bone pain, arthralgia, muscle pain, toothache, migraine, headache, inflammatory pain, neuropathic pain, Crohn’s disease-related abdominal pain due to adverse effects of the therapeutic agent
  • the pain caused and the pain associated with diseases selected from: osteoarthritis, cancer, multiple sclerosis, allergic response, nephritis syndrome, scleroderma, thyroiditis, diabetic neuropathy, fibromyalgia, Neuropathy, sciatica and autoimmune diseases associated with HIV.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention A method of treating neuropathic pain with a combination of compounds.
  • the present invention also relates to the hexahydrobenzopyrazole compound represented by the general formula (I) and its stereoisomers, pharmaceutically acceptable salts, solvates, hydrates, N-oxides or prodrugs or containing the present invention A method for the treatment of Crohn's disease-related abdominal pain with a combination of compounds.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H) and deuterium (D, also known as heavy hydrogen).
  • tritium T, also known as superheavy hydrogen
  • oxygen isotopes include 16 O, 17 O and 18 O
  • sulfur isotopes include 32 S, 33 S, 34 S and 36 S
  • nitrogen isotopes include 14 N and 15 N
  • the isotope of fluorine is 19 F
  • the isotope of chlorine includes 35 Cl and 37 Cl
  • the isotope of bromine includes 79 Br and 81 Br.
  • Alkyl refers to a linear and branched monovalent saturated hydrocarbon group, the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 Straight and branched groups of up to 4 carbon atoms, most preferably 1 to 2 carbon atoms, examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isopropyl Butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl Group, n-octyl, n-nonyl, n-decyl, etc.; the alkyl group may be further substituted with any substituent.
  • Alkylene refers to straight and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v- (v is an integer from 1 to 10).
  • alkylene include, but are not limited to, methylene, methylene, and Ethyl, propylene, butylene, etc.; the alkylene group may be optionally further substituted with any substituent. When the number of substituents in the alkylene group is greater than or equal to 2, the substituents may be fused together to form a cyclic structure.
  • Alkoxy refers to a monovalent group of O-alkyl (-O-alkyl), where alkyl is as defined herein, and examples of alkoxy include but are not limited to methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy Group, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl ⁇ -1-Butoxy and so on.
  • alkenyl refers to straight and branched monovalent unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 Up to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain
  • alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl , 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2- Methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-hepten
  • Alkynyl refers to a linear and branched monovalent unsaturated hydrocarbon group, which has at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 To 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include but are not limited to ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl Alkynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3 -Hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl and 4-decynyl, etc.; the alkynyl
  • Cycloalkyl refers to a monovalent saturated carbocyclic hydrocarbon group, a single ring, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl Base and so on.
  • the cycloalkyl group may be optionally further substituted with any substituent.
  • Unsaturated cyclic hydrocarbon group refers to a carbocyclic hydrocarbon group that contains unsaturated bonds (such as double bonds) and does not have aromaticity. Non-limiting examples include cyclopropenyl, cyclobutenyl, and 1,4-cyclohexanyl. Ene, 1,3-cyclopentadiene, etc.
  • the cycloalkyl group may be optionally further substituted with any substituent.
  • Heterocyclic group refers to a saturated or unsaturated cyclic hydrocarbon group containing at least one heteroatom, a single ring, and the heteroatoms are N, O, S, P and their oxidized forms.
  • Non-limiting examples include aza Cyclopropyl, oxetanyl, thietanyl, azetidinyl, oxetanyl, thietanyl, azetidine (also known as azetidinyl), pyrrolyl, Pyrrolinyl, 3-pyrrolinyl, 1-pyrrolinyl, pyrrolidinyl, pyrazolidinyl, 2-pyrazolinyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, tetrahydrothienyl, 1,2 , 4-Triazolyl and so on.
  • the heterocyclic group may be optionally further substituted with any substituent.
  • the spiro ring may be further substituted with any substituent.
  • the ring atom contains 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12, and still more preferably 5 to 10 atoms.
  • Non-limiting examples include And adamantane.
  • the bridged ring may be further substituted with any substituent.
  • Aryl refers to a substituted or unsubstituted 6 to 14-membered cyclic aromatic group, including monocyclic aromatic groups and condensed ring aromatic groups.
  • a 6 to 14 membered aromatic ring is preferred, and a 6 to 10 membered aromatic ring is more preferred, and non-limiting examples thereof include phenyl, naphthyl, anthryl, phenanthryl and the like.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.
  • Non-limiting examples include: The aryl group may be further substituted with any substituent.
  • the ring is more preferably 5 to 6 members.
  • heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include
  • the heteroaryl group may be further substituted with any substituent.
  • “Pharmaceutically acceptable salt” refers to maintaining the biological effectiveness and characteristics of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or organic base, or the free base is passed through with the non-toxic inorganic base or organic base. Those salts obtained by the reaction of toxic inorganic or organic acids.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, ingredients Granules, lubricants, binders, disintegrants, etc.
  • Prodrug refers to a compound that can be converted into a compound of the present invention with biological activity under physiological conditions or by solvolysis.
  • the prodrug of the present invention is prepared by modifying the phenol group in the compound, 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 individual, the prodrug is split to form free hydroxyl groups.
  • Examples of prodrugs include, but are not limited to, the phenolic hydroxyl group of the compound of the present invention and sodium salt derivatives of phosphoric acid.
  • Effective dose refers to the amount of a compound that causes a physiological or medical response in a tissue, system, or subject. This amount is sought and includes one or more of the compounds that are sufficient to prevent the disease or condition being treated when administered to the subject. The amount of the compound that occurs or alleviates the symptoms to a certain degree.
  • solvents refer to the compounds of the present invention or their salts, and they also include stoichiometric or non-stoichiometric solvents bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.
  • “Optional” or “optionally” means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur.
  • “Alkyl group optionally substituted by F” means that the alkyl group may but need not be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • Optionally substituted by R means that it can be substituted or unsubstituted by R.
  • the number of R is not limited, as long as the principle of chemical bond is satisfied, preferably 1-5, 1-3, 1-2, One; when replaced by two or more Rs, R can be independently and freely selected, can be the same, can be different, and are independent of each other.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • the NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
  • NMR is measured with (Bruker ADVANCE III 400) nuclear magnetic instrument, the solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard is Tetramethylsilane (TMS), 1 HNMR information is listed in the following format: chemical shift (multiple peaks (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), Number of protons).
  • DMSO-d6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Tetramethylsilane
  • 1 HNMR information is listed in the following format: chemical shift (multiple peaks (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), Number of protons).
  • HPLC determination uses Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18 100 x 4.6mm).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • TEA triethylamine
  • LHMDS Lithium bis(trimethylsilyl)amide
  • m-CPBA m-chloroperoxybenzoic acid
  • DIPEA N,N-diisopropylethylamine
  • PE petroleum ether
  • EA ethyl acetate
  • NIS N-iodosuccinimide
  • dichloromethane 100 mL was added to the known compound 1a (5.0 g, 32.0 mmol), and under water bath cooling, Dess Martin oxidant (13.6 g, 32 mmol) was added in batches, and the mixture was stirred at room temperature for 2 hours.
  • a saturated aqueous sodium bicarbonate solution 100 mL was added to the reaction to quench the reaction, and then stirred at room temperature for 30 minutes.
  • the first step (4R)-1-(2,4-difluorophenyl)-7-isopropyl-4-methyl-4,5,6,7-tetrahydro-1H-indazole-3- Formic acid (2a).
  • the first step 3-((4R)-3-carboxy-7-isopropyl-4-methyl-4,5,6,7-tetrahydro-1H-indazol-1-yl)pyrazine-1 -Oxide (3a).
  • the second step 3-((4R)-3-((1-hydroxy-2-methylpropanol-2-yl)carbamoyl)-7-isopropyl-4-methyl-4,5, 6,7-Tetrahydro-1H-indazol-1-yl)pyrazine 1-oxide (Compound 3).
  • Dissolve compound 5b (3.0g, 21.4mmol) in tetrahydrofuran (30mL), cool to minus 78 degrees Celsius, add LHMDS (1M, 23.5mL) to it, and then add diethyl oxalate (3.4g) to it after half an hour , 23.5mmol), warm to room temperature and react overnight.
  • Preparative HPLC separation method 1. Instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phase A and B: mobile phase A: acetonitrile; mobile phase B: water (containing 0.1% ammonium acetate); b. gradient elution, the content of mobile phase A ranges from 5% to 50% ; C. Flow rate 12mL/min; d Elution time 20min. Compound 6 retention time: 13.5min.
  • the first step 7,7-difluoro-N-(1-(hydroxymethyl)cyclopentyl)-1-(pyrazin-2-yl)-4,5,6,7-tetrahydro-1H- Indazole-3-carboxamide (8b)
  • compound 8b is obtained by reacting compound 5g.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Composition of mobile phase A and B: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20%-75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.8min.
  • the first step 3-(7,7-difluoro-3-((4,4,4-trifluoro-1-hydroxy-3,3-dimethylbutan-2-yl)carbamyl)- 4,5,6,7-tetrahydro-1H-indazol-1-yl)-1-oxopyrazine
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.2min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.8min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.7min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.9min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.6min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.5min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.3min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 12.4min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.1min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.3min.
  • Preparation method 1. Instrument: waters 2767 preparation liquid phase; Chromatographic column: SunFire@Prep C18 (19mm ⁇ 250mm). 2. The sample is dissolved in DMF and filtered with a 0.45 ⁇ m filter to make a sample solution. 3. Preparative chromatographic conditions: a. Mobile phase A, B composition: mobile phase A: acetonitrile, mobile phase B: water; b. Gradient elution, mobile phase A content from 20% to 75%; c. Flow rate 12ml/min ; D. Elution time 20min. Peak time: 13.5min.
  • APD-371 is compound 699 in patent document WO2011025541.
  • the compounds of the present invention especially 1, 4, 5, 6, 7, 8, 19, 20 show high agonistic activity for CB 2 receptors.
  • Some compounds, especially compound 5 and compound 8 have a higher agonistic activity on CB 2 /CB. 1 receptor shows high selectivity.
  • Experimental purpose to administer the test substance to SD rats by a single dose intravenously and intragastrically, determine the concentration of the test substance in the rat's plasma, and evaluate the pharmacokinetic characteristics and bioavailability of the test substance in the rat.
  • Test animals Male SD rats, about 220 g, 6-8 weeks old, 6 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Test method On the day of the test, 6 SD rats were randomly grouped according to their body weight. One day before administration, fasting without water for 12-14 hours, and 4 hours after administration. Dosing according to Table 2.
  • 0.1ml of blood was taken from the orbit with isoflurane anesthetized and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma.
  • Plasma collection time points in group G1 0, 2, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h.
  • Plasma collection time points in group G2 0,5,15,30min,1,2,4,6,8,24h.
  • APD-371 is compound 699 in patent document WO2011025541.
  • the compound of the present invention especially compound 5, has high bioavailability, good pharmacokinetic characteristics, and long half-life.
  • Pot dihydrogen phosphate buffer solution weigh 1.3961 g of potassium dihydrogen phosphate, dissolve in water, dilute to 100 ml, and adjust the pH to 6.8 with 0.1 mol/L sodium hydroxide solution.
  • Test animals Male SD rats, about 200g, 6-8 weeks old, 12 rats/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Test method On the day of the test, 24 SD rats were randomly grouped according to their body weight. One day before administration, fasting without water for 12-14 hours, and 4 hours after administration. Dosing according to Table 6.
  • APD-371MTD is 300mg/kg; compound 5MTD is 1000mg/kg.

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Abstract

L'invention concerne un composé d'hexahydrobenzopyrazole représenté par la formule (I), et un stéréoisomère, un sel pharmaceutiquement acceptable, un solvate, un hydrate, un N-oxyde, un promédicament, et une composition pharmaceutique de celui-ci, son procédé de préparation et son utilisation dans la prévention et le traitement de maladies médiées par le récepteur cannabinoïde CB2. (I)
PCT/CN2020/114448 2019-09-12 2020-09-10 Dérivé d'hexahydrobenzopyrazole et sa préparation Ceased WO2021047581A1 (fr)

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