WO2020035070A1 - 3-芳氧基-3-芳香基-丙胺类化合物及其用途 - Google Patents

3-芳氧基-3-芳香基-丙胺类化合物及其用途 Download PDF

Info

Publication number
WO2020035070A1
WO2020035070A1 PCT/CN2019/101197 CN2019101197W WO2020035070A1 WO 2020035070 A1 WO2020035070 A1 WO 2020035070A1 CN 2019101197 W CN2019101197 W CN 2019101197W WO 2020035070 A1 WO2020035070 A1 WO 2020035070A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
unsubstituted
compound
atom
Prior art date
Application number
PCT/CN2019/101197
Other languages
English (en)
French (fr)
Inventor
王友鑫
林锦霞
陈志亮
蓝文良
张玲玲
曲振林
Original Assignee
漳州片仔癀药业股份有限公司
上海璃道医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 漳州片仔癀药业股份有限公司, 上海璃道医药科技有限公司 filed Critical 漳州片仔癀药业股份有限公司
Priority to JP2021532507A priority Critical patent/JP7283669B2/ja
Priority to EP19849974.1A priority patent/EP3838900A4/en
Priority to US17/268,763 priority patent/US20220119375A1/en
Priority to CN201980053661.1A priority patent/CN112654616B/zh
Publication of WO2020035070A1 publication Critical patent/WO2020035070A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/4015—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 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to the fields of medicinal chemistry and medicinal therapy, in particular to a 3-aryloxy-3-aryl-propylamine compound and use thereof.
  • Pain is an unpleasant feeling and emotional experience caused by tissue damage or potential tissue damage. It is a warning signal issued by the body, but severe or long-term pain forms an intolerable torture on the body, which seriously affects the patient. life. Therefore, the International Society of Pain has set October 11th each year as the "Global Day of Conquering Pain" since 2004.
  • pain can be divided into acute pain and chronic pain.
  • Acute pain is mostly nociceptive pain caused by tissue trauma, while chronic pain is mainly a neuropathic pain disease.
  • Traditional analgesics include opioids and non-steroidal anti-inflammatory drugs.
  • Opioids have strong analgesic effects, but long-term use can easily lead to tolerance, dependence, and addiction, and have adverse reactions such as respiratory depression and central sedation.
  • Non-steroidal anti-inflammatory drugs exert only moderate analgesic effects, and have reactions such as gastrointestinal bleeding and cardiac toxicity.
  • TRPA1 also known as ANKTM1
  • ANKTM1 is a member of the TRP ion channel superfamily.
  • TRPA1 is mainly distributed in the primary sensory neurons of the dorsal root nerve (DRG), trigeminal nerve (TG), and vagus nerve (VG), and it is peptide-rich (rich in neuropeptides CGRP and SP and neurotrophic factor receptor TrkA) and Peptidergic neurons (co-expressing purine receptors P2X3, Neuroturin, Artemin, G protein-coupled receptors in the Mrg family and GFR ⁇ 1 and GFR ⁇ 2 in the GDNF receptor family) are all expressed. From the perspective of the distributed human system, TRPA1 is highly expressed in the peripheral nervous system, respiratory system, gastrointestinal system, and urinary system. When these organs and tissues have abnormal functions, the expression and function of TRPA1 channels usually also occur simultaneously. TRPA1 can convert cold, chemical, and mechanical stimuli into inward currents, trigger a series of physiological functions, and participate in the formation
  • Inflammation is a defensive response of living tissues with vascular system to injury factors. Among them, the stimulation of inflammatory mediators such as prostaglandin, serotonin, bradykinin, etc. is the main cause of local pain in inflammation. Inflammatory pain is a common problem of some chronic diseases, and there is still a lack of effective treatments in clinical practice. Animal experiments have shown that TRPA1 participates in inflammatory reactions and plays an important role in inflammatory pain. By using TRA1 specific blockers, inflammatory pain reactions in rats can be significantly reduced. The pathogenesis of asthma and cough has become more and more clear as the research continues. From current research, TRPA1 plays an important role in the occurrence of asthma and cough. Asthma and cough-inducing compounds, both endogenous and exogenous factors, can activate TRPA1. TRPA1 antagonists reduce asthma symptoms and block airway hyperresponsiveness.
  • Visceral pain is often caused by stimuli such as mechanical traction, spasms, ischemia, or inflammation.
  • TRPA1 is involved in the regulation of visceral hypersensitivity through different visceral hypersensitivity animal models such as colitis, rectal expansion, or stress.
  • Neuropathic pain is a pain syndrome caused by injury or disease of the central or peripheral nervous system. It is mainly manifested as hyperalgesia, abnormal hyperalgesia, and spontaneous pain. Unlike inflammatory pain, neurogenic pain has nothing to do with the vascular response of the central link of inflammation, but depends on damage and dysfunction of the nervous system, often caused by damage to peripheral nerves.
  • TRPA1 channel plays an important role in different neurogenic pain, such as diabetic neuropathy and neuropathy caused by chemotherapeutics. Recent studies have also shown that TRPA1 also mediates in pain such as toothache and migraine. The administration of antagonists of TRPA1 can significantly alleviate the occurrence of pain symptoms.
  • TRPA1 is widely distributed and expressed in the human system, the importance of its function is self-evident. In addition to the physiological functions involved in the above TRPA1, the development of the currently reported TRPA1 inhibitor indications also involves inflammatory bowel disease, chronic obstructive pulmonary disease, antitussive, itching, allergic rhinitis, ear disease, anti-diabetes, Urinary incontinence etc. TRPA1 is a new target for pain therapy that has been proven. There is currently no marketed drug for this target. Pain is a refractory disease.
  • the purpose of the present invention is to provide a compound with a novel structure and a TRP channel as a target (especially a TRPA1 target) and its use.
  • a compound, or a pharmaceutically acceptable salt thereof, or the use of a prodrug thereof for (a) preparing a transient receptor potential channel protein (TRP) inhibitor; (b) preparing Drugs for preventing and / or treating diseases related to transient receptor potential channel protein (TRP);
  • A is Group; wherein ring B is a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 5-7 membered heteroaryl, a substituted or unsubstituted C 6 -C 12 aryl; ring D is a substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted C 6 -C 12 aryl; and when A is a substituted or unsubstituted aromatic structure, A contains 1-3 heteroatoms selected from N, O and S;
  • heterocyclic ring or heteroaryl group contains 1-3 heteroatoms selected from N, O and S;
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 2 -C 4 acyl, substituted Or an unsubstituted C 2 -C 6 ester group, or R 1 , R 2 and a connected N atom to form a substituted or unsubstituted C 3 -C 7 heterocycloalkyl group, wherein the heterocycloalkyl group contains 1 -2 N atoms and 0-1 O or S atoms;
  • X is a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom
  • Y is a carbon atom or a nitrogen atom
  • At least one of X and Y is a heteroatom
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
  • n 1, 2, 3, 4 or 5;
  • any “substitution” means that one to four (preferably 1, 2, 3) hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: C 1 -C 6 alkyl , C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxyl, C 2 -C 4 ester, C 2 -C 4 amido , C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, benzyl, five- or six-membered aryl or heteroaryl (preferably C 6 aryl or C 5 heteroaryl).
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is not a naphthalene ring.
  • A is a substituted or unsubstituted C 6 -C 12 bicyclic heteroaryl group, a substituted or unsubstituted 5-6 membered heterocyclic phenyl group, and a substituted or unsubstituted 5-6 membered heterocyclic ring.
  • 5- and 6-membered heteroaryl, or substituted or unsubstituted C 6 -C 12 benzoalicyclic.
  • the C 6 -C 12 bicyclic heteroaryl is quinolinyl, isoquinolinyl, phthalimido, benzofuranyl, benzothienyl, indole Radical, benzoxazolyl, benzothiazolyl, quinoxaline, imidazopyridyl or benzimidazolone.
  • the C 6 -C 12 benzoalicyclic group includes indanyl, tetrahydronaphthyl or dihydronaphthyl.
  • A is a substituted or unsubstituted benzofuranyl group, a benzothienyl group, or an indanyl group.
  • At least one of X and Y is a hetero atom.
  • X is S or O.
  • X is S.
  • the heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O or S.
  • said Is a heteroaryl group which is unsubstituted or has 1 to 5 R 3 substituents.
  • the substitution refers to substitution with one to four substituents (preferably 1, 2, 3) selected from the group consisting of: C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, carboxyl, C 2 -C 4 ester, C 2 -C 4 amido, C 1 -C 4 alkoxy, C 1 -C 6 haloalkoxy, benzyl, five- or six-membered aryl or heteroaryl (preferably C 6 aryl or C 5 heteroaryl).
  • substituents preferably 1, 2, 3
  • the transient receptor potential channel protein is TRPA1.
  • A is a substituted or unsubstituted C 6 -C 12 bicyclic heteroaryl group, a substituted or unsubstituted 5-6 membered heterocyclic phenyl group, and a substituted or unsubstituted 5-6 membered heterocyclic ring.
  • 5- and 6-membered heteroaryl, or substituted or unsubstituted C 6 -C 12 benzoalicyclic.
  • R 1 and R 2 are each independently a hydrogen atom, a C 1 -C 3 alkyl group, or a C 2 -C 4 acyl group; or R 1 , R 2 and a connected N atom form a carboxyl group or C 2- C 4 ester substituted tetrahydropyrrolyl.
  • R 3 is a hydrogen atom, a halogen, a substituted or unsubstituted C 1 -C 3 alkyl group.
  • A is quinolinyl, isoquinolinyl, phthalimido, benzofuranyl, benzothienyl, indolyl, benzoxazolyl, benzothiazole Radical, quinoxalinyl, imidazopyridyl, benzimidazolone, indanyl, tetrahydronaphthyl or dihydronaphthyl.
  • R 1 and R 2 are each independently a hydrogen atom, a methyl group, an acetyl group, or R 1 , R 2 and N atoms constitute a proline group or a proline methyl group.
  • R 3 is a hydrogen atom, a chlorine atom or a methyl group.
  • the compound is selected from the following group:
  • the transient receptor potential channel protein is TRPA1.
  • the disease associated with transient receptor potential channel protein is selected from the group consisting of pain, epilepsy, inflammation, respiratory disorders, pruritus, urinary tract disorders, or inflammatory bowel disease.
  • the pain includes acute inflammatory pain, chronic inflammatory pain, visceral pain, neurogenic pain, myofiberic pain, headache, neuralgia or cancer-induced pain.
  • the headache is migraine or muscle pain.
  • the neuralgia is trigeminal neuralgia, diabetic pain or post-zoster neuralgia.
  • the pain is selected from the group consisting of acute pain, myofiberic pain, visceral pain, inflammatory pain, neuralgia, or a combination thereof.
  • the other pain is myofiberic pain.
  • a compound, or a pharmaceutically acceptable salt thereof, or a prodrug thereof characterized in that the compound has the structure of Formula I:
  • A is Group; wherein ring B is a substituted or unsubstituted 5-7 membered carbocyclic ring, a substituted or unsubstituted 5-7 membered heterocyclic ring, a substituted or unsubstituted 5-7 membered heteroaryl, a substituted or unsubstituted C 6 -C 12 aryl; ring D is a substituted or unsubstituted 5-7 membered heteroaryl, substituted or unsubstituted C 6 -C 12 aryl; and when A is a substituted or unsubstituted aromatic structure, A contains 1-3 heteroatoms selected from N, O and S;
  • heterocyclic ring or heteroaryl group contains 1-3 heteroatoms selected from N, O and S;
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 2 -C 4 acyl, substituted Or an unsubstituted C 2 -C 6 ester group, or R 1 , R 2 and a connected N atom to form a substituted or unsubstituted C 3 -C 7 heterocycloalkyl group, wherein the heterocycloalkyl group contains 1 -2 N atoms and 0-1 O or S atoms;
  • X is a carbon atom, an oxygen atom, a sulfur atom or a nitrogen atom
  • Y is a carbon atom or a nitrogen atom
  • At least one of X and Y is a heteroatom
  • R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl;
  • n 1, 2, 3, 4 or 5;
  • any “substitution” means that one to four (preferably 1, 2, 3) hydrogen atoms on the group are replaced by a substituent selected from the group consisting of: C 1 -C 6 alkyl , C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, C 1 -C 4 carboxyl, C 2 -C 4 ester, C 2 -C 4 amido , C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, benzyl, five- or six-membered aryl or heteroaryl (preferably C 6 aryl or C 5 heteroaryl).
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is not a naphthalene ring.
  • A is a substituted or unsubstituted C 6 -C 12 bicyclic heteroaryl group, a substituted or unsubstituted 5-6 membered heterocyclic phenyl group, and a substituted or unsubstituted 5-6 membered heterocyclic ring.
  • 5- and 6-membered heteroaryl, or substituted or unsubstituted C 6 -C 12 benzoalicyclic.
  • the C 6 -C 12 bicyclic heteroaryl is quinolinyl, isoquinolinyl, phthalimido, benzofuranyl, benzothienyl, indole Radical, benzoxazolyl, benzothiazolyl, quinoxaline, imidazopyridyl or benzimidazolone.
  • the C 6 -C 12 benzoalicyclic group includes indanyl, tetrahydronaphthyl or dihydronaphthyl.
  • A is a substituted or unsubstituted benzofuranyl group, a benzothienyl group, or an indanyl group.
  • At least one of X and Y is a hetero atom.
  • X is S or O.
  • X is S.
  • the heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O or S.
  • said Is a heteroaryl group which is unsubstituted or has 1 to 5 R 3 substituents.
  • the substitution refers to substitution with one to four substituents (preferably 1, 2, 3) selected from the group consisting of: C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl, halogen, nitro, cyano, hydroxyl, carboxyl, C 2 -C 4 ester, C 2 -C 4 amido, C 1 -C 4 alkoxy, C 1 -C 6 haloalkoxy, benzyl, five- or six-membered aryl or heteroaryl (preferably C 6 aryl or C 5 heteroaryl).
  • substituents preferably 1, 2, 3
  • A is a substituted or unsubstituted C 6 -C 12 bicyclic heteroaryl group, a substituted or unsubstituted 5-6 membered heterocyclic phenyl group, and a substituted or unsubstituted 5-6 membered heterocyclic ring.
  • 5- and 6-membered heteroaryl, or substituted or unsubstituted C 6 -C 12 benzoalicyclic.
  • R 1 and R 2 are each independently a hydrogen atom, a C 1 -C 3 alkyl group, or a C 2 -C 4 acyl group; or R 1 , R 2 and a connected N atom form a carboxyl group or C 2- C 4 ester substituted tetrahydropyrrolyl.
  • R 3 is a hydrogen atom, a halogen, a substituted or unsubstituted C 1 -C 3 alkyl group.
  • A is quinolinyl, isoquinolinyl, phthalimido, benzofuranyl, benzothienyl, indolyl, benzoxazolyl, benzothiazole Radical, quinoxalinyl, imidazopyridyl, benzimidazolone, indanyl, tetrahydronaphthyl or dihydronaphthyl.
  • R 1 and R 2 are each independently a hydrogen atom, a methyl group, an acetyl group, or R 1 , R 2 and N atoms constitute a proline group or a proline methyl group.
  • R 3 is a hydrogen atom, a chlorine atom or a methyl group.
  • the compound is selected from the following group:
  • a pharmaceutical composition comprising the compound described in the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and a pharmaceutically acceptable carrier .
  • a method for preparing the compound according to the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a prodrug thereof includes the steps of: in an inert solvent, Body II reacts with a R 1 -NH-R 2 compound to form the compound:
  • the method includes steps:
  • the method includes steps:
  • the method further includes the steps:
  • the method further includes the steps:
  • an intermediate is provided.
  • the intermediate for example, has a structure of Formula II or Formula III:
  • a sixth aspect of the present invention there is provided a method for preparing the intermediate according to the fifth aspect of the present invention, characterized in that:
  • the method includes steps:
  • a non-therapeutic and non-diagnostic method for inhibiting the activity of a transient receptor potential channel protein in vitro comprising the steps of: combining a transient receptor potential channel protein or a cell expressing the protein with the first The compound according to the second aspect, or a pharmaceutically acceptable salt thereof, or a prodrug thereof is contacted to inhibit the activity of the transient receptor potential channel protein.
  • a method for inhibiting transient receptor potential channel protein or preventing and / or treating a disease related to transient receptor potential channel protein comprising the step of administering a second aspect of the present invention to a subject in need thereof
  • the compound according to the aspect, or a pharmaceutically acceptable salt thereof, or a prodrug thereof comprising the step of administering a second aspect of the present invention to a subject in need thereof.
  • Figure 3 is the analgesic activity induced pain model in mice results in the hot plate Compound I C -23 disclosure.
  • FIG 5 Compound I C -1, duloxetine, indomethacin and the analgesic activity of choline mountain buttercup pain model in mice results torsion acetate.
  • FIG 6 Compound I C -1 and gabapentin analgesic activity results in the model SNL rats.
  • FIG. 7 is a statistical result of adding time of compound Ic-1 and duloxetine in phase II (10-60min) period at different dosages in a mouse formalin model.
  • the present inventors unexpectedly developed a compound, or a pharmaceutically acceptable salt thereof, or a prodrug thereof for the first time, the compound having the structure of Formula I.
  • the compounds of the present invention have a significant inhibitory effect on TRP channels.
  • the compounds of the present invention are effective in treating pain and the like associated with TRP (especially TRPA1) targets. Based on this, the present invention has been completed.
  • the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed, and open definitions. In other words, the term includes “consisting of”, “consisting essentially of”.
  • R1 the same “R 1” and “R1" meaning, are interchangeable, the same as other similarly defined meanings.
  • C 1 -C 6 alkyl or “C 1 -C 3 alkyl” refers to straight or branched chain alkyl group having 1-6 or 1-3 carbon atoms such as methyl, ethyl Group, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
  • C 1 -C 6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy , Butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, or similar groups.
  • C 6 -C 12 benzoalicyclic group refers to a group having 6 to 12 carbon atoms, including indanyl, tetrahydronaphthyl, or dihydronaphthyl and the like.
  • C 3 -C 7 cycloalkyl refers to a cycloalkyl (including monocyclic, bicyclic, or polycyclic ring systems) having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, Methylcyclobutyl, cyclopentyl, cycloheptyl, or similar groups.
  • C 2 -C 6 ester group refers to a group having a C 1 -C 5 alkyl-COO- structure or a group having a -COO-C 1 to C 5 alkyl structure, wherein the alkyl group Can be straight or branched, for example CH 3 COO-, C 2 H 5 COO-, C 3 H 8 COO-, (CH 3 ) 2CHCOO-, -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 8 or similar.
  • C 2 -C 4 amido refers to a group having a C 1 -C 3 alkyl-CO-NH- structure or a group having a -CO-NH-C 1 -C 3 alkyl structure Where the alkyl group can be straight or branched, such as CH 3 -CO-NH-, C 2 H 5 -CO-NH-, C 3 H 8 -CO-NH-, -COOCH 3 , -CO-NH -C 2 H 5 , -CO-NH-C 3 H 8 , or a similar group.
  • C 2 -C 4 acyl refers to a group having a C 1 -C 3 alkyl-CO- structure in which the alkyl group may be straight or branched, such as CH 3 -CO-, C 2 H 5 -CO-, C 3 H 8 -CO-, or similar groups.
  • C 3 -C 7 heterocycloalkyl refers to having 3-7 ring carbon atoms and 1-3 heteroatoms (preferably containing 1 nitrogen atom, that is, co-adjacent to R 1 and R 2 Monocyclic and polycyclic heterocycles (preferably monocyclic heterocycles), such as piperidine groups, tetrahydropyrrolyl groups, or similar groups.
  • the term "5- to 7-membered carbocyclic ring” is any stable 5, 6, or 7-membered monocyclic, bicyclic, or polycyclic ring.
  • the carbocyclic ring may be a saturated, partially unsaturated, unsaturated ring, but Cannot be an aromatic ring.
  • carbocyclic ring examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantane Alkyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, bicyclo [4.4.0] decane, bicyclo [2.2.2] Octane, fluorenyl, indanyl.
  • heterocycle is any stable monocyclic, bicyclic, or polycyclic (e.g., 5, 6, or 7 membered) ring containing one or more (e.g., 1-3) selected from N, O With S heteroatoms, heterocycles may be saturated, partially unsaturated, unsaturated rings, but not aromatic rings.
  • C 1 -C 6 haloalkyl and “C 1 -C 3 haloalkyl” refer to one or more of straight or branched chain alkyl groups having 1-6 and 1-3 carbon atoms. Each hydrogen atom is replaced by a halogen group, such as monochloromethane, dichloroethane, trichloropropane, or similar groups.
  • C 1 -C 4 carboxyl refers to a group of C 1 -C 3 alkyl-COOH structure, wherein the alkyl group may be linear or branched, such as CH 3 COOH, C 2 H 5 COOH, C 3 H 8 COOH, (CH 3 ) 2 CHCOOH, or similar groups.
  • C 6 -C 12 aryl refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl, or similar Group.
  • heteroaryl refers to an optionally substituted aromatic group, such as a 5- to 7-membered monocyclic ring system having a ring containing at least one heteroatom and at least one carbon atom, such as Pyrrolyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, furan, imidazole, thiazole, oxazole, triazole, or similar groups.
  • halogen refers to F, Cl, Br, and I.
  • substitution is when a hydrogen atom on a group is replaced by a non-hydrogen atom group, but needs to meet its valence requirements and generate a chemically stable compound from substitution. In this specification, all substituents are to be interpreted as unsubstituted, unless explicitly described herein as “substituted.”
  • a substituent may be attached to the parent group or substrate on any atom, unless the connection violates the valence requirement; the hydrogen atom of the parent group or substrate may be on the same atom, It can also be on a different atom.
  • the range includes not only the endpoints P1 and P2, but also any numerical point between the endpoints P1 and P2.
  • the value range includes any integer value point between the endpoints P1 and P2.
  • the value range is 1-10, including 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the value range 3-7 includes 3, 4, 5, , 6, 7.
  • C3-C7 includes C3, C4, C5C6, and C7.
  • the compounds of the present invention have inhibitory effects not only on TRPA1, but also on other members of the TRP family.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention and an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred type of salt is the salt formed by the compound of the present invention with an acid.
  • Suitable acids for forming the salt include (but are not limited to): hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid , Propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid and other organic acids; And acidic amino acids such as aspartic acid and glutamic acid.
  • a preferred type of salt is a metal salt formed by a compound of the present invention with a base.
  • Suitable bases for forming the salt include (but are not limited to): inorganic hydroxides such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, Organic bases such as ammonia, triethylamine, and diethylamine.
  • Preferred compounds of the invention include any one selected from Table 1 below:
  • the invention also provides a method for preparing the 3-aryloxy-3-aryl-propylamine compounds I A to I F of the present invention.
  • the present invention also provides a method for preparing intermediates II to III for preparing the above compounds.
  • the compound represented by formula I according to the present invention can be converted into a pharmaceutically acceptable salt thereof by a conventional method.
  • a solution of the corresponding acid can be added to the solution of the above compound, and the solvent can be removed under reduced pressure after salt formation is completed.
  • the corresponding salt of the compound of the present invention is obtained.
  • TRP Transient receptor potential channel protein
  • Transient receptor potential channel proteins are a type of protein superfamily composed of important cation channels existing on the cell membrane.
  • Transient receptor potential channel proteins include multiple subfamilies, such as the TRPA, TRPC, TRPM, TRPV, TRPML, and TRPP subfamilies.
  • TRPA1 channel protein is associated with pain, epilepsy, inflammation, respiratory disorders, pruritus, urinary tract disorders, inflammatory bowel disease and other diseases.
  • TRPA1 is used to treat pain, epilepsy, inflammation, respiratory disorders, pruritus, urinary tract disorders, inflammatory diseases.
  • Targets for diseases such as bowel disease.
  • the invention also provides a method for inhibiting transient receptor potential channel protein (TPR), and a method for treating diseases related to the transient receptor potential channel protein.
  • TPR transient receptor potential channel protein
  • the above-mentioned compound of formula I of the present invention can be used to inhibit transient receptor potential channel proteins, thereby preventing or treating diseases related to transient receptor potential channel proteins.
  • examples of diseases related to transient receptor potential channel proteins include (but are not limited to): pain, epilepsy, inflammation, respiratory disorders, itching, urinary tract disorders, and inflammatory bowel disease.
  • the pain includes (but is not limited to): acute inflammatory pain, chronic inflammatory pain, visceral pain, neurogenic pain, myofiberic pain, headache (such as migraine, myalgia, etc.), nerve Pain (such as trigeminal neuralgia, diabetic pain, post-zoster neuralgia, etc.), or cancer causing pain.
  • the present invention provides a method for non-therapeutic inhibition of transient receptor potential channel protein activity in vitro, including, for example, in vitro culture system, the transient receptor potential channel protein or a protein expressing said protein
  • the cell is contacted with a compound of formula I, or a pharmaceutically acceptable salt thereof, or a prodrug thereof according to the present invention, thereby inhibiting the activity of a transient receptor potential channel protein.
  • the invention also provides a method for inhibiting transient receptor potential channel proteins, which method can be therapeutic or non-therapeutic.
  • the method includes the step of administering to a subject in need thereof a compound of formula I, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • the subject includes human and non-human mammals (rodents, rabbits, monkeys, domestic animals, dogs, cats, etc.).
  • rodents rodents, rabbits, monkeys, domestic animals, dogs, cats, etc.
  • the present invention provides a composition for inhibiting transient receptor potential channel protein activity.
  • the composition includes (but is not limited to): a pharmaceutical composition, a food composition, a dietary supplement, a beverage composition, and the like.
  • the composition is a pharmaceutical composition
  • the pharmaceutical composition includes a compound of formula I according to the present invention, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the dosage forms of the pharmaceutical composition include, but are not limited to, oral preparations, injections, and external preparations.
  • Representative include (but are not limited to): tablets, injections, infusions, pastes, gels, solutions, microspheres, films.
  • pharmaceutically acceptable carrier refers to one or more compatible solid, semi-solid, liquid, or gel fillers that are suitable for human or animal use and must be of sufficient purity and low enough. toxicity. "Compatibility” means that each component in the pharmaceutical composition and the active ingredients of the drug and each other are blended with each other without significantly reducing the efficacy.
  • the carrier is not particularly limited, and materials commonly used in the art may be selected, or may be prepared by conventional methods, or may be purchased from the market.
  • examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc.), gelatin, talc, and solid lubricants.
  • stearic acid such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • buffers such as chelating agents, thickeners, pH adjusters, transdermal enhancers, colorants, flavoring agents, stabilizers, antioxidants, preservatives , Bacteriostat, pyrogen-free water, etc.
  • the liquid dosage form may include an inert diluent such as water or other solvents, solubilizers, and emulsifiers commonly used in the art, such as ethanol, isopropanol, ethyl carbonate, acetic acid Ethyl esters, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof.
  • the composition may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents.
  • the pharmaceutical preparation should match the mode of administration.
  • the agents of the invention may also be used with other synergistic therapeutic agents (including before, during, or after).
  • a safe and effective amount of the drug is administered to a desired subject (such as a human or non-human mammal).
  • the safe and effective amount is usually at least about 10 ⁇ g / kg body weight, and in most cases Not more than about 8 mg / kg body weight, preferably the dose is about 10 micrograms / kg body weight to about 1 mg / kg body weight.
  • the specific dosage should also consider factors such as the route of administration, the patient's health, etc., which are all within the skill of a skilled physician.
  • the present invention provides a class of compounds of formula I which are novel in structure and have excellent TRP channel inhibitory activity.
  • the compound of the present invention has excellent in vivo pharmacological effects such as analgesia.
  • the compounds of the invention are less toxic and more active, and therefore have a larger safety window.
  • the compounds of the present invention have excellent pharmacokinetic properties.
  • the compounds of the present invention are suitable for oral administration.
  • intermediate II-1 600 mg was dissolved in an acetone solution of saturated sodium iodide and refluxed overnight. After the reaction, the solvent was spin-dried, water was added to the system, and extracted with ethyl acetate three times, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in 20 ml of tetrahydrofuran solution, and 2 ml of 40 was added. % Methylamine aqueous solution was reacted overnight. After the reaction, the solvent was spin-dried.
  • Example 8-9 Except that 7-hydroxybenzofuran was replaced with 4-hydroxybenzofuran, the rest of the required raw materials, reagents and preparation methods were the same as those in Example 8-9. 15 mg of the title compound was obtained as a yellow oil with a yield of 1.40%.
  • Example 18 Except that the methylamine aqueous solution was replaced with dimethylamine, the other required raw materials, reagents and preparation methods were the same as those in Example 18 to obtain 21 mg of the title compound as a brown oil with a yield of 10.1%.
  • Example 8-9 Except that 7-hydroxybenzofuran was replaced with 5-indanol, the other required raw materials, reagents and preparation methods were the same as those in Example 8-9. 15 mg of the title compound was obtained as a yellow oil with a yield of 9.7%.
  • Example 8-9 Except that 7-hydroxybenzofuran was replaced with 5,8-dihydronaphthol, the other required raw materials, reagents and preparation methods were the same as those in Example 8-9, and 65 mg of the title compound was obtained as a brown oil with a yield of 25.3%.
  • Example 8-9 Except that 7-hydroxybenzofuran was replaced with 8-hydroxyimidazo [1,2-a] pyridine, the rest of the required raw materials, reagents, and preparation methods were the same as in Example 8-9. 43 mg of the title compound was obtained as a brown oil. The rate is 11.7%.
  • Example 8-9 Except that 7-hydroxybenzofuran was replaced with 5-fluoroquinoxaline, the other required raw materials, reagents and preparation methods were the same as those in Example 8-9, to obtain 230 mg of the title compound as a brown oil, with a yield of 40.5%.
  • Example 8-9 Except that 7-hydroxybenzofuran was replaced with benzo [b] thiophen-5-ol, the other required raw materials, reagents, and preparation methods were the same as those in Example 8-9. 20 mg of the title compound was obtained as a yellow oil with a yield of 3.30. %.
  • the positive control compound is a compound of formula A (WO2010075353):
  • Test method by IonWorks Barracuda (IWB) automated patch clamp detection HEK293 cells stably expressing TRPA1, DMEM medium containing 15 ⁇ g / mL Blasticidin S HCl, 200 ⁇ g / mL Hygromycin B and 10% FBS serum was placed in T175 In a culture flask, place in a 37 ° C, 5% CO 2 incubator. When the cell density grows to ⁇ 80%, remove the culture solution, rinse it with calcium-magnesium-free phosphate buffer solution (PBS), and add 3 mL. Trypsin was digested for 2 minutes, and 7 mL of culture medium was added to terminate the digestion.
  • IWB IonWorks Barracuda
  • IWB experiments use population and clamp (PPC) plates.
  • the entire detection process is automatically completed by the instrument, that is, extracellular fluid is added to the 384 wells of the PPC plate, and intracellular fluid is added to the plenum under the PPC plate.
  • the sealing solution was subjected to sealing test.
  • the intracellular solution in plenum was changed to an intracellular solution containing amphotericin B, so that the sealed cells were perforated to form a whole-cell recording mode.
  • the sampling frequency for recording TPRA1 current is 10kHz
  • the cell is clamped at 0mV
  • the voltage stimulation command (channel protocol) is a ramp voltage from -100mV to + 100mV for 300ms. This voltage stimulation is given every 10s. .
  • IWB IonWorks Barracuda
  • compound I C -10 (containing heteroaryl
  • the specific activity) and Compound C1 (phenyl containing) (compound C1 is IC 50 / Compound I IC C -10 50) is about 2.5 times, which shows that the compounds of the present invention containing a heteroaryl group (e.g., I C - 10) Higher inhibitory activity on TRPA1.
  • a heteroaryl group e.g., I C - 10
  • the A group is a compound having a naphthalene ring (e.g. duloxetine) compared to the compound I C -10 (A benzo group is an aliphatic ring) and the compounds I C -3, compounds and compound I C -23
  • the IC 50 value of I C -1 (where the A groups are all benzoheteroaryl) is significantly reduced.
  • S-type duloxetine the IC 50 of the compound I C -10, Compound I C -3, I or Compound C -23 the ratio of compound I IC C -1 in a compound according to any of from about 2.8 50 to 6.8 (Note: The IC 50 of duloxetine type R is 48.5 ⁇ M, and the IC 50 of duloxetine type S is 24.74 ⁇ M).
  • the IC 50 of duloxetine type R is 48.5 ⁇ M
  • the IC 50 of duloxetine type S is 24.74 ⁇ M.
  • the compound of the present invention in which the A group is a benzoalicyclic ring or a heteroaryl group has a higher inhibitory activity on TRPA1 (an increase of about 2.8-6.8 times).
  • the present inventors also measured TRPA1 inhibitory activity on Compound I C -1 by a manual patch clamp test method as follows:
  • HEK293 stably transfected cell line stably expressing human TRPA1 channel, DMEM medium containing 15 ⁇ g / mL Blasticidin pH HCl, 200 ⁇ g / mL Hygromycin B, and 10% FBS serum was placed in a T75 culture flask, placed at 37 ° C., 5 Cultivate in a% CO2 incubator.
  • the cell density grows to ⁇ 80%, remove the culture medium, rinse it with calcium-magnesium-free phosphate buffered saline (PBS), add 2 mL of Trypsin for 2 minutes, and terminate by adding 8 mL of culture medium. digestion.
  • the cells were collected in a 15 mL centrifuge tube and centrifuged at 800 rpm for 3 minutes. After removing the supernatant, the cells were resuspended by adding an appropriate volume of extracellular fluid.
  • the manual patch clamp detection was performed at room temperature using the HEKA system (Patch Master software) combined with an EPC-10 amplifier to record the whole cell current of TRPA1 stably transformed cell lines.
  • Internal cell formula for whole cell recording (mM): 140CsCl, 10HEPES, 5EGTA, 0.1CaCl2, 1MgCl2 (pH7.2, osmotic pressure 295–300mOsm); external solution for recording uses Ca2 + -free setting (mM): 140NaCl, 5KCl, 0.5 EGTA, 1MgCl2, 10Glucose, 10HEPES (pH 7.4, osmotic pressure 300-310mOsm).
  • the patch clamp records the glass microelectrode resistance used by 2-4M ⁇ , the sampling frequency is 10kHz, the filtering frequency is 2.9kHz, the cell is clamped at 0mV, and the voltage stimulation command (channel protocol) is a 300ms linear voltage from -100mV to + 100mV, and then recovered To the clamp potential of 0mV, this recording is performed every 2s.
  • the hTRPA1 current is induced by 100 ⁇ M AITC. To ensure the accuracy of the current recording, the series resistance is compensated by 60% during the recording.
  • HepG-2 and SH-SY5Y cells culture in 10cmdish at 37 ° C, 5% CO 2 cell incubator; trypsinize and resuspend the cells and count. Transfer the cells to 8000 cells in a 100 ⁇ l / well system. 96-well plate. Incubate at 37 ° C for 24 hours in a 5% CO 2 cell incubator; prepare a compound gradient concentration system, 2-fold dilution, and the system is 100 ⁇ l / well. Remove the supernatant from the 96-well plate cell culture system on the first day, and add the newly configured drug concentration system to the wells of the culture cells (double duplicate wells are set). The cells were cultured in a 5% CO 2 cell incubator at 37 ° C for 72 hours.
  • cytotoxicity (%) [A (0 plus drug) -A (plus drug)] / [A (0plus drug) -A (Blank)) ⁇ 100
  • Duloxetine hepatocyte toxicity and neurotoxicity were 33 ⁇ M and 28 ⁇ M, and I C-1 of the present invention and the compounds I C -10 hepatocyte toxicity and neurotoxicity (IC 50, ⁇ M) is about 60-120 ⁇ M, which indicates that the toxic and side effects of the compound of the present invention are significantly lower, and the compound is only about 1/2 or 1/3 of the toxic and side effects of duloxetine). This suggests that the compounds of the present invention have excellent safety.
  • the compound I C -10 mouse formalin pain model testing of the present invention the analgesic activity of the test compound, as follows:
  • mice Male, 9 weeks were selected, and the mice were randomly divided into 3 groups: the solvent control group (vehicle, physiological saline), the duloxetine group (Duloxetine, 5-HT reuptake, and NE Reuptake inhibitors) and Ic-10 groups (Compound Ic-10 of the invention). Before the experiment, the mice were allowed to acclimate to the experimental environment for 72 hours, without fasting or watering.
  • the solvent control group vehicle, physiological saline
  • duloxetine group Duloxetine, 5-HT reuptake, and NE Reuptake inhibitors
  • Ic-10 groups Compound Ic-10 of the invention.
  • the test drug was administered by intraperitoneal injection at a dose of 20 mg / kg, and then the mice were placed in a transparent, ventilated plexiglass cylinder for 1 hour, and then injected into the left hind plantar of each group by microinjector 4% 20 ⁇ l of formalin solution was used to record the foot pain response of mice in real time with a micro camera. Take the number of times that the mouse lifts (1 minute / time), shakes (2 minutes / time), and licks (3 minutes / time) and licks the left foot and the length of time that the left foot is licked as indicators of pain response. Observe and record 0-10min (phase I , Acute pain period) and 10-60min (Phase II, inflammatory pain period) cumulative score and licking time in two periods, and statistical analysis.
  • Compound I C -10 analgesic activity according to the invention results in the formalin pain model in mice as shown in FIG. From the results, it can be known that in the statistical detection index of the full time, the compound I C- 10 of the present invention shows a clear phase I (0-10min) and phase II (10-60min) at a dose of 20mg / kg. And the potent analgesic activity, compared with the normal saline group, almost completely suppressed the foot-adding behavior caused by pain in mice, and was comparable to the clinical analgesic activity of duloxetine.
  • the analgesic activity test of the compounds IC, C- 23, Ic-10, Ic-1 and the like of the present invention is tested by a C57 mouse hot plate pain model, the method is as follows:
  • mice Take SPF C57 male mice, adjust the hot plate temperature to be 55 ⁇ 0.1 ° C, and select the mice that have painful reactions such as foot licking within 10-30s (abandon those who escape and jump). Remove any painful reactions immediately to prevent burns in mice.
  • the screened 40 animals were weighed, and the animals were randomly divided into 4 groups at random: saline control group (blank control), duloxetine group (positive control group), and gabapentin group (positive control group). And Ic-23 (compounds of the invention).
  • test compound is freshly prepared on the day of administration.
  • a 0.9% NaCl physiological saline solution was configured as a vehicle for backup, and an appropriate amount of a test compound was added to a required volume of physiological saline, and the suspension was sufficiently suspended to prepare a drug concentration of 1 mg / ml.
  • the dose standard for mice is 10 ml / kg (ie, 0.1 ml / 10 g).
  • Intraperitoneal administration animals do not need to fast or water before administration.
  • the administration volume was 10 ml / kg.
  • I duloxetine dose and C -23 was 10mg / kg, gabapentin dose of 100mg / kg.
  • Hot plate observation index the reaction time (Time latency) of the mouse on the hot plate of 55 ⁇ 0.1 ° C. Measure 3h before and 15min, 30min, and 60min each time and record.
  • Compound I C-23 of the present invention analgesic activity induced pain model in mice results in the hot plate 3 as shown in FIG. From the results, compared with the control group, the compounds of the present invention exhibit I C -23 at 10mg / kg dose of an analgesic effect it is very potent, with significant difference. Compared to the positive control group, in 60 minutes compounds of the invention I C -23 analgesic activity is much better than 100mg / kg gabapentin and better than 10mg / kg of the analgesic effect of duloxetine.
  • the hot plate pain model is a classic model for evaluating the efficacy of a drug for acute pain, so the compound of the present invention has an excellent therapeutic effect on acute pain.
  • rat pharmacokinetic properties of compounds such as duloxetine and Ic-1 were tested as follows:
  • a certain amount of sample was weighed and dissolved in deionized water, and a solution with a concentration of 1 mg / mL was prepared.
  • Male SD rats were used as test animals.
  • a single intravenous (IV) injection dose was 2 mg / kg, and an oral (PO) dose was 10 mg / kg, with three rats in each group.
  • the oral group was fasted for 10-14 hours before administration. Food was resumed 4 hours after administration.
  • Blood collection time points for animals are: intravenous, before administration, 5, 15, 30min, 1, 2, 4, 6, 8h, and 24h; oral, before administration, 15, 30min, 1, 2, after administration, 4, 6, 8 and 24h.
  • Linear regression analysis uses the peak area as the y-axis and the drug concentration as the x-axis.
  • the linear relationship between the peak area ratio and the concentration is expressed by the correlation coefficient (R) obtained from the regression equation of the compound.
  • R correlation coefficient
  • the pharmacokinetic calculation software WinNonlin7.0 non-compartment model was used to calculate the pharmacokinetic parameters of the test substances.
  • Internal standard working solution Pipette a certain amount of tolbutamide internal standard stock solution into a volumetric flask with a concentration of 490,000ng / mL, make up to volume with methanol, and mix to obtain a 200ng / mL concentration. Internal standard working solution.
  • the peak concentration (C max , 177 ng / mL) was reached in 0.083 h
  • the elimination half-life (T 1/2 ) was 1.77 h
  • the AUC (0- ⁇ ) was 449h * ng / mL
  • the peak concentration ( Cmax , 76ng / mL) was reached in 0.83h
  • the elimination half-life (T1 / 2 ) was 1.81h
  • the AUC ( 0- ⁇ ) is 222 h * ng / mL. Based on AUC (0- ⁇ ), the oral bioavailability was 9.9%.
  • the compounds of the present invention having a structure of formula I have better pharmacokinetic properties than duloxetine, have a longer half-life, and are exposed to plasma. Higher, better bioavailability, suitable for development for oral administration, and has good prospects for medicine.
  • the experimental groups were: solvent control group, 10 mg / kg duloxetine group (positive control group) and 10 mg / kg compound Ic-1 group (the compound was prepared in Example 9)
  • mice Male C57BL / 6 mice were used. The weight of the mice at the beginning of the experiment was 18-22 grams. Four mice were allocated to each cage, and they could eat and drink freely. Twelve mice of each experimental group were labeled with animal tails.
  • mice were placed in a plexiglass box with a stainless steel mesh, and then the plexiglass box was placed in a cold storage (temperature 4 ⁇ 2 ° C) overnight. Feed freely and replace water with agar blocks.
  • mice were transferred to a room temperature (temperature 24 ⁇ 2 ° C) environment and left for 30 minutes, and then transferred to a cold room for 30 minutes. The above steps were repeated until 4:30 pm, and the mice were placed in a cold storage overnight.
  • the compound was administered orally at the experimentally scheduled time at a dose of 10 mg / kg.
  • test method for mechanical hyperalgesia is as follows:
  • mice were placed individually in a plexiglass box with a grid at the bottom to ensure that the mouse feet could be tested. Mice will acclimate for 15 minutes before testing. After the acclimatization was completed, the test fiber was used to test the center of the sole of the left hind foot of the mouse. Test fiber includes 8 test strengths: 2.36 (0.02g), 2.44 (0.04g), 2.83 (0.07g), 3.22 (0.16g), 3.61 (0.4g), 3.84 (0.6g), 4.08 (1g), 4.17 (1.4g). During the test, the test fiber is pressed vertically against the skin and a force is applied to bend the fiber for 6-8 seconds, and the test interval is 5 seconds. During the test, the animal's rapid withdrawal was recorded as a pain response.
  • test fiber with a higher strength was 4.17 (1.4 g).
  • test results are recorded in Table 4 below, with pain response record X, and no pain response record O.
  • the compound Ic-1 of the present invention exhibits a very strong analgesic effect at a dose of 10 mg / kg, and it has been shown to inhibit ICS at 1 and 2 hours after oral administration Model-induced mechanical hyperalgesia.
  • the analgesic effect of Compound Ic-1 was better than duloxetine at the three test times of 0.5h, 1h and 2h.
  • the mouse ICS model is a classic pharmacodynamic model for evaluating the treatment of myofiberic pain by the drug. Therefore, the compound Ic-1 of the present invention has an excellent therapeutic effect on myofiberic pain.
  • ICR mice male, 22-25g, were fasted for 2 h before administration and could not help but water. All ICR mice were weighed and randomly divided into groups with more than 10 animals in each group.
  • the negative control group was a saline group (vehicle, blank control), and the positive control group was set to a dose of 10 mg / kg indomethacin (a non-steroidal anti-inflammatory drug) and a dose of 10 mg / kg anisodamine. (An antispasmodic drug with clinical analgesic activity), duloxetine was administered at doses of 10 mg / kg and 20 mg / kg.
  • Test compound I C -1 (the compound prepared in Example 9 embodiment), the dose is set to 5mg / kg and 10mg / kg.
  • mice were administered by gavage according to the weight of the mice.
  • 1.5% acetic acid solution (0.1ml / 10g) was injected intraperitoneally, and the number of visceral pain in the mice in each group was observed within 30min.
  • the mice showed abdominal depression, the trunk and hind legs extended, and the hips were recorded as Once, finally count the number of occurrences of the above phenomenon within 30min.
  • FIG. 5 A test of a mouse model of writhing pain in acetic acid is shown in FIG. 5.
  • a single intragastric administration of the compound I C -1 (5 mg / kg and 10 mg / kg) of the present invention can significantly reduce the effects of acetic acid.
  • the number of writhing reactions in mice was significantly different from the normal saline group (vehicle, blank control) (49 times).
  • the number of writhing reactions in mice was 20, which was 50% lower than 49 times in the physiological salt control group, suggesting that compound I C -1 was effective in half of the model
  • the dose (ED 50 ) is less than 5 mg / kg.
  • SD rats were taken for surgery, male, SPF grade, mass 150g-180g.
  • the surgical procedure is performed aseptically. Animals were anesthetized with pentobarbital sodium (50 mg / kg, intraperitoneally). The animal's waist surgery area was shaved, and the skin was disinfected three times with iodophor and 70% ethanol. Start surgery after the skin is dry. A scalpel was used to make a longitudinal incision in the back of the animal's sacrum to expose the left paravertebral muscle, and a spreader was used to separate the muscle tissue to expose the spine. The left spinal nerves L5 and L6 were separated and ligated with a 6-0 silk suture to close the wound. After the operation, the animals were placed on an electric blanket and subcutaneously injected with 5 mL of physiological saline to prevent dehydration. After the animal is fully awakened (free to move), return the animal to its cage.
  • mice were acclimatized in an experimental environment for 15 minutes / day for 3 days.
  • the rats were subjected to a baseline test of mechanical hyperalgesia. Animals that did not show mechanical hyperalgesia (foot withdrawal threshold greater than 5 g) were randomly divided into 1 control group and 2 experimental groups.
  • the animals were weighed, and the two experimental groups were administered with 100 mg / kg gabapentin (gabapentin is currently the first-line treatment for neuralgia clinically) and 10 mg / kg compound I C -1 (Example 9) Prepared compound), and the control group was an intragastrically administered equal volume of physiological saline.
  • a mechanical hyperalgesia test was performed. Place the rats individually in a plexiglass box with a grid at the bottom to ensure that the rat's feet can be tested. Rats will acclimate for 15 minutes before testing. After the acclimatization is completed, the test fiber is used to test the center of the sole of the left hind foot of the rat.
  • the test fibers include 8 test strengths: 3.61 (0.4 g), 3.84 (0.6 g), 4.08 (1 g), 4.31 (2 g), 4.56 (4 g), 4.74 (6 g), 4.93 (8 g), 5.18 (15 g).
  • the test fiber is pressed vertically against the skin and a force is applied to bend the fiber for 6-8 seconds, and the test interval is 5 seconds.
  • the animal's rapid withdrawal was recorded as a pain response.
  • Withdrawal of the test fiber as it left the animal's skin was also recorded as a pain response. If the animal moves or walks without remembering the pain response, the test should be repeated.
  • 4.31 (2g) When testing, first use 4.31 (2g).
  • test fiber with a lower strength If the animal has a painful reaction, the next test will use a test fiber with a lower strength; if the animal does not have a pain response, the next test will use a test fiber with a higher strength.)
  • the maximum strength of the test fiber was 5.18 (15 g).
  • PWT withdrawal footing threshold
  • the compounds of the present invention I C -1 exhibited very potent analgesic effect at 10mg / kg dose, with a significant difference.
  • the present invention is one hour analgesic activity of the compounds I C-1 and 100mg / kg gabapentin considerable analgesic effect after administration.
  • the rat SNL model is a classic pharmacodynamic model for evaluating drugs for treating neuropathic pain. Therefore, the compound I C -1 of the present invention has an excellent therapeutic effect on neuropathic pain.
  • mice 100 C57BL / 6 mice (male, 9 weeks) were taken, and each group of 10 mice was randomly divided into 10 groups for the analgesic activity test of 2 compounds in a mouse formalin pain model: respectively and the compound is duloxetine group I C -1 (the compound prepared in Example 9 embodiment). Before the experiment, the mice were allowed to acclimate to the experimental environment for 72 hours, without fasting or watering. Test drugs are given by intraperitoneal injection, and the dose settings are:
  • Duloxetine group Blank Vehicle (blank saline control), 1mg / kg, 5mg / kg, 10mg / kg and 20mg / kg;
  • Compound I C -1 groups Vehicle (saline control blank, with the blank group duloxetine), 0.1mg / kg, 0.5mg / kg, 1mg / kg, 5mg / kg and 10mg / kg.
  • ED 50 refers to the dose of the drug which is reduced by half compared to the blank control group. The smaller the ED 50 value, the lower the analgesic effective dose of the compound, and the better its analgesic effect.
  • the compound IIc-1 of the present invention has a phase II (10-60min) addition time that has been reduced by more than 50% compared to the blank Vehicle at a dose of 1 mg / kg
  • the analgesic ED 50 for phase II pain is 2.22 mg / kg
  • duloxetine has an ED 50 for phase II pain of 8.00 mg / kg.
  • the analgesic activity of the compound Ic-1 of the present invention is significantly better than duloxetine. From the above data, it can be known that the compound Ic-1 of the present invention exhibits extremely strong analgesic activity in a mouse formalin pain model.
  • the mouse formalin model is a classic model for evaluating the efficacy of drugs for acute pain and inflammatory pain. Therefore, the compound Ic-1 of the present invention has an excellent therapeutic effect on acute pain and inflammatory pain.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Furan Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

一类3-芳氧基-3-芳香基-丙胺类化合物或其药学上可接受的盐，或其前药及其用途，所述化合物具有式I结构，所述的化合物，或其药学上可接受的盐，或其前药对瞬时受体电位通道蛋白(TPR)具有优异的抑制作用，并对瞬时受体电位通道蛋白相关的疾病具有良好的治疗作用。

Description

3-芳氧基-3-芳香基-丙胺类化合物及其用途 技术领域
本发明涉及药物化学和药物治疗学领域，具体地涉及一种3-芳氧基-3-芳香基-丙胺类化合物及其用途。
背景技术
疼痛是由组织损伤或潜在的组织损伤引起的一种不愉快的感觉和情绪体验，是机体发出的一种警告信号，但是剧烈或长期的疼痛对机体形成一种难以忍受的折磨，严重影响患者的生活。因此国际疼痛学会从2004年起将每年的10月11日定为“全球征服疼痛日”。
根据持续时间的不同，疼痛可分为急性疼痛和慢性疼痛。急性疼痛多是由组织创伤引起的伤害性疼痛，而慢性疼痛是以神经病理性疼痛为主的疾病。传统镇痛药物主要包括阿片类药物和非甾体抗炎药。阿片类药物镇痛作用强，但长期使用易导致耐受性、依赖性和成瘾性，并且有呼吸抑制、中枢镇静等不良反应。非甾体抗炎药仅发挥中等程度镇痛作用，同时具有消化道出血和心脏毒性等反应。
TRPA1又称ANKTM1，是TRP离子通道超家族中的一员。TRPA1主要分布在背根神经(DRG)、三叉神经(TG)和迷走神经(VG)的初级感觉神经元上，且在肽能(富含神经肽CGRP和SP以及神经营养因子受体TrkA)和非肽能神经元(共表达嘌呤受体P2X3、Neurturin、Artemin、Mrg家族的G蛋白耦联受体以及GDNF受体家族中的GFR α1和GFR α2)均有表达。从分布的人体系统来看，TRPA1高表达在外周神经系统、呼吸系统、胃肠系统和泌尿系统，当这些器官组织出现功能异常时，TRPA1通道的表达和功能通常也同步发生异常。TRPA1可以将冷刺激、化学刺激以及机械刺激转化为内向电流，引发一系列生理功能，并参与多种痛觉的形成。
炎症是具有血管系统的活体组织对损伤因子所发生的防御反应，其中炎症介质诸如前列腺素、5-羟色胺、缓激肽等的刺激是引起炎症局部疼痛的主要原因。炎性痛是某些慢性疾病的共同困扰，临床上尚缺乏很有效的治疗手段。动物实验研究显示，TRPA1参与炎性反应，并在炎性疼痛中发挥重要作用，通过使用TRA1特异性阻断剂，可以明显减轻大鼠炎性疼痛反应。哮喘与咳嗽的发病机制，随着研究的不断深入越来越清晰。从目前的研究来看，TRPA1在哮喘和咳嗽的发生中扮演一个重要的作用。诱导哮喘与咳嗽的化合物，无论是细胞内源因子，还是外 源因子，都能激活TRPA1。TRPA1的拮抗剂能够减轻哮喘症状，能阻断气道高反应性。
内脏痛作为一种主要的内脏感觉，常由内脏受到机械性牵拉、痉挛、缺血或炎症等刺激所引起。通过不同的内脏高敏感动物模型如结肠炎、直结肠扩张或应激，证实TRPA1参与内脏高敏感的调控。神经源性疼痛是由中枢或外周神经系统损伤或者疾病引起的疼痛综合征，主要表现为痛觉过敏、异常痛敏和自发性疼痛等。与炎性痛不同，神经源性疼痛与炎症的中心环节血管反应无关，而取决于神经系统的损伤和功能紊乱，常常是由于外周神经的损伤引起的。近年来越来越多的研究显示，TRPA1通道在不同的神经源性疼痛中起到重要作用，例如糖尿病性神经病变和化疗药引起的神经病变等。最近研究还表明，TRPA1在牙痛、偏头痛等疼痛中也有介导作用，通过给予TRPA1的拮抗剂能明显缓解疼痛症状的产生。
由于TRPA1在人体系统中广泛分布和表达，其功能的重要性不言而喻。除以上TRPA1参与的生理功能外，目前已报道的TRPA1抑制剂适应症的开发还涉及到炎症性肠病、慢性阻塞性肺疾病、镇咳、止痒、过敏性鼻炎、耳疾病、抗糖尿病、尿失禁等。TRPA1是已经被证实了的疼痛治疗的新靶点，目前还没针对该靶点的上市药物，疼痛属于难治性疾病。
因此，本领域迫切需要开发一种针对TRP靶点(尤其是TRPA1靶点)的治疗药物，从而提高疾病的治疗效果。
发明内容，
本发明的目的在于提供一种结构新颖的以TRP通道为靶点(尤其是TRPA1靶点)的化合物及其用途。
本发明的第一方面，提供一种化合物，或其药学上可接受的盐、或其前药的用途，用于(a)制备瞬时受体电位通道蛋白(TRP)抑制剂；(b)制备预防和/或治疗与瞬时受体电位通道蛋白(TRP)相关的疾病的药物；
其中，所述化合物具有式I结构：
Figure PCTCN2019101197-appb-000001
式中：
A为
Figure PCTCN2019101197-appb-000002
基团；其中，环B为取代或未取代的5-7元碳环、取代或未取代的5-7元杂环、取代或未取代的5-7元杂芳基、取代或未取代的C 6-C 12芳基；环D为取代或未取代的5-7元杂芳基、取代或未取代的C 6-C 12芳基；并且当A为取代或未取代的芳香结构时，A含有1-3个选自N、O和S的杂原子；
其中，所述的杂环或杂芳基含有1-3个选自N、O和S的杂原子；
R 1和R 2各自独立为氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基、取代或未取代的C 2-C 4酰基、取代或未取代的C 2-C 6酯基，或R 1、R 2和相连的N原子组成取代或未取代的C 3-C 7杂环烷基；其中，所述的杂环烷基含有1-2个N原子以及0-1个O或S原子；
X为碳原子、氧原子、硫原子或氮原子；
Y为碳原子或氮原子；
X和Y中至少一个是为杂原子；
R 3为氢、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基；
n为1、2、3、4或5；
“*”表示手性碳原子，所述手性碳原子绝对构型为S型；
其中，所述的任一“取代”是指基团上的一个到四个(优选为1、2、3个)氢原子被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、羟基、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、五元或六元的芳基或杂芳基(优选C 6芳基或C 5杂芳基)。
在另一优选例中，A为
Figure PCTCN2019101197-appb-000003
在另一优选例中，A不为萘环。
在另一优选例中，A为取代或未取代的C 6-C 12双环杂芳基、取代或未取代的5-6元杂环并苯基、取代或未取代的5-6元杂环并5-6元杂芳基、或取代或未取代的C 6-C 12苯并脂肪环基。
在另一优选例中，所述的C 6-C 12双环杂芳基为喹啉基、异喹啉基、邻苯二甲酰亚胺基、苯并呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并噻唑基、喹喔啉基、咪唑并吡啶基或苯并咪唑酮基。
在另一优选例中，所述的C 6-C 12苯并脂肪环基包括茚满基、四氢萘基或二氢 萘基。
在另一优选例中，A为取代或未取代的苯并呋喃基、苯并噻吩基、或茚满基。
在另一优选例中，X和Y中至少一个为杂原子。
在另一优选例中，X为S或O。
在另一优选例中，X为S。
在另一优选例中，所述的杂芳基含有1-3个选自下组的杂原子：N、O或S。
在另一优选例中，所述的
Figure PCTCN2019101197-appb-000004
为具有未取代的或具有1-5个R 3取代基的杂芳基。
在另一优选例中，所述的取代是指被选自下组的一个到四个取代基(优选为1、2、3个)所取代：C 1-C 3烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、羟基、羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 4烷氧基、C 1-C 6卤代烷氧基、苄基、五元或六元的芳基或杂芳基(优选C 6芳基或C 5杂芳基)。
在另一优选例中，所述瞬时受体电位通道蛋白(TRP)为TRPA1。
在另一优选例中，A为取代或未取代的C 6-C 12双环杂芳基、取代或未取代的5-6元杂环并苯基、取代或未取代的5-6元杂环并5-6元杂芳基、或取代或未取代的C 6-C 12苯并脂肪环基。
在另一优选例中，R 1和R 2各自独立为氢原子、C 1-C 3烷基、C 2-C 4酰基；或者R 1、R 2和相连的N原子组成羧基或C 2-C 4酯基取代的四氢吡咯基。
在另一优选例中，R 3为氢原子、卤素、取代或未取代的C 1-C 3烷基。
在另一优选例中，A为喹啉基、异喹啉基、邻苯二甲酰亚胺基、苯并呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并噻唑基、喹喔啉基、咪唑并吡啶基、苯并咪唑酮基、茚满基、四氢萘基或二氢萘基。
在另一优选例中，R 1和R 2各自独立为氢原子、甲基、乙酰基，或R 1、R 2和N原子组成脯氨酸基或脯氨酸甲酯基。
在另一优选例中，R 3为氢原子、氯原子或甲基。
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2019101197-appb-000005
Figure PCTCN2019101197-appb-000006
Figure PCTCN2019101197-appb-000007
在另一优选例中，所述的瞬时受体电位通道蛋白(TRP)为TRPA1。
在另一优选例中，与瞬时受体电位通道蛋白(TRP)相关的疾病选自下组：疼痛、癫痫、炎症、呼吸障碍、瘙痒、尿路障碍或炎症性肠病。
在另一优选例中，所述的疼痛包括急性炎性疼痛、慢性炎性疼痛、内脏痛、神经源性疼痛、肌纤维痛、头痛、神经痛或癌症引起疼痛。
在另一优选例中，所述的头痛为偏头痛或肌紧张性疼痛。
在另一优选例中，所述的神经痛为三叉神经痛、糖尿病性疼痛或带状孢疹后神经痛。
在另一优选例中，所述的疼痛选自下组：急性疼痛、肌纤维痛、内脏疼痛、炎症疼痛、神经痛，或其组合。
在另一优选例中，所述他疼痛为肌纤维痛。
本发明第二方面，提供一种化合物，或其药学上可接受的盐、或其前药，其特征在于，所述化合物具有式I结构：
Figure PCTCN2019101197-appb-000008
式中：
A为
Figure PCTCN2019101197-appb-000009
基团；其中，环B为取代或未取代的5-7元碳环、取代或未取代的5-7元杂环、取代或未取代的5-7元杂芳基、取代或未取代的C 6-C 12芳基；环D为取代或未取代的5-7元杂芳基、取代或未取代的C 6-C 12芳基；并且当A为取代或未取代的芳香结构时，A含有1-3个选自N、O和S的杂原子；
其中，所述的杂环或杂芳基含有1-3个选自N、O和S的杂原子；
R 1和R 2各自独立为氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基、取代或未取代的C 2-C 4酰基、取代或未取代的C 2-C 6酯基，或R 1、R 2和相连的N原子组成取代或未取代的C 3-C 7杂环烷基；其中，所述的杂环烷基含有1-2个N 原子以及0-1个O或S原子；
X为碳原子、氧原子、硫原子或氮原子；
Y为碳原子或氮原子；
X和Y中至少一个是为杂原子；
R 3为氢、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基；
n为1、2、3、4或5；
“*”表示手性碳原子，所述手性碳原子绝对构型为S型；
其中，所述的任一“取代”是指基团上的一个到四个(优选为1、2、3个)氢原子被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、羟基、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、五元或六元的芳基或杂芳基(优选C 6芳基或C 5杂芳基)。
在另一优选例中，A为
Figure PCTCN2019101197-appb-000010
在另一优选例中，A不为萘环。
在另一优选例中，A为取代或未取代的C 6-C 12双环杂芳基、取代或未取代的5-6元杂环并苯基、取代或未取代的5-6元杂环并5-6元杂芳基、或取代或未取代的C 6-C 12苯并脂肪环基。
在另一优选例中，所述的C 6-C 12双环杂芳基为喹啉基、异喹啉基、邻苯二甲酰亚胺基、苯并呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并噻唑基、喹喔啉基、咪唑并吡啶基或苯并咪唑酮基。
在另一优选例中，所述的C 6-C 12苯并脂肪环基包括茚满基、四氢萘基或二氢萘基。
在另一优选例中，A为取代或未取代的苯并呋喃基、苯并噻吩基、或茚满基。
在另一优选例中，X和Y中至少一个为杂原子。
在另一优选例中，X为S或O。
在另一优选例中，X为S。
在另一优选例中，所述的杂芳基含有1-3个选自下组的杂原子：N、O或S。
在另一优选例中，所述的
Figure PCTCN2019101197-appb-000011
为具有未取代的或具有1-5个R 3取代基的杂芳基。
在另一优选例中，所述的取代是指被选自下组的一个到四个取代基(优选为 1、2、3个)所取代：C 1-C 3烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、羟基、羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 4烷氧基、C 1-C 6卤代烷氧基、苄基、五元或六元的芳基或杂芳基(优选C 6芳基或C 5杂芳基)。
在另一优选例中，A为取代或未取代的C 6-C 12双环杂芳基、取代或未取代的5-6元杂环并苯基、取代或未取代的5-6元杂环并5-6元杂芳基、或取代或未取代的C 6-C 12苯并脂肪环基。
在另一优选例中，R 1和R 2各自独立为氢原子、C 1-C 3烷基、C 2-C 4酰基；或者R 1、R 2和相连的N原子组成羧基或C 2-C 4酯基取代的四氢吡咯基。
在另一优选例中，R 3为氢原子、卤素、取代或未取代的C 1-C 3烷基。
在另一优选例中，A为喹啉基、异喹啉基、邻苯二甲酰亚胺基、苯并呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并噻唑基、喹喔啉基、咪唑并吡啶基、苯并咪唑酮基、茚满基、四氢萘基或二氢萘基。
在另一优选例中，R 1和R 2各自独立为氢原子、甲基、乙酰基，或R 1、R 2和N原子组成脯氨酸基或脯氨酸甲酯基。
在另一优选例中，R 3为氢原子、氯原子或甲基。
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2019101197-appb-000012
Figure PCTCN2019101197-appb-000013
本发明第三方面，提供一种药物组合物，所述的组合物包括本发明第二方面所述的化合物，或其药学上可接受的盐，或其前药；和药学上可接受的载体。
本发明第四方面，提供一种制备本发明第二方面所述的化合物，或其药学上可接受的盐，或其前药的方法，所述的方法包括步骤：在惰性溶剂中，将中间体II与R 1-NH-R 2化合物进行反应，形成所述化合物：
Figure PCTCN2019101197-appb-000014
其中，X、Y、A、R 1、R 2、R 3和“*”的定义如本发明第二方面所述。
在另一优选例中，所述的方法包括步骤：
Figure PCTCN2019101197-appb-000015
在惰性溶剂中，单氟取代的喹啉或单氟取代的异喹啉与3-(甲基氨基)-1-(噻吩-2-基)丙-1-醇反应，形成化合物I A或I B；
在另一优选例中，所述的方法包括步骤：
Figure PCTCN2019101197-appb-000016
其中，X、Y、A、R 1、R 2、R 3和“*”的定义如本发明第二方面所述；
(a)在惰性溶剂中，在缩合剂的存在下，将化合物A-OH和1-(R 3-五元芳杂基)-3- 氯-丙醇进行反应，形成中间体II；
(b)进行选自下组的任一反应，从而形成化合物I C或I E：
(b-1)在惰性溶剂中，将中间体II与R 1-NH-R 2反应，形成化合物Ic；或
(b-2)在惰性溶剂中，将中间体II与邻苯二甲酰亚胺进行反应，形成中间体III，中间体III进行肼解反应，形成化合物Ic；或
(b-3)在惰性溶剂中，将中间体II与脯氨酸甲酯进行反应，形成化合物I E。
在另一优选例中，所述方法还包括步骤：
(c1)在惰性溶剂中，在缩合剂的存在下，将Ic与醋酸进行反应，形成化合物I D；
在另一优选例中，所述方法还包括步骤：
(c2)在惰性溶剂中，在碱的存在下，化合物I E发生水解反应，形成化合物I F。
本发明第五方面，提供一种中间体，所述的中间体如具有式II或式III结构：
Figure PCTCN2019101197-appb-000017
其中，X、Y、A、R 3和“*”的定义如本发明第二方面所述。
本发明第六方面，提供一种制备如本发明第五方面所述的中间体的方法，其特征在于，
Figure PCTCN2019101197-appb-000018
其中，X、Y、A、R 1、R 2、R 3和“*”的定义如本发明第二方面所述；
(1)所述的方法包括步骤：
(i)在惰性溶剂中，在缩合剂的存在下，将化合物A-OH和1-(R 3-五元芳杂基)-3- 氯-丙醇进行反应，形成中间体II；
或(2)所述的方法包括步骤：
(i)在惰性溶剂中，在缩合剂的存在下，将化合物A-OH和1-(R 3-五元芳杂基)-3-氯-丙醇进行反应，形成中间体II；和
(ii)在惰性溶剂中，将中间体II与邻苯二甲酰亚胺进行反应，形成中间体III。
本发明第七方面，提供一种体外非治疗性和非诊断性的抑制瞬时受体电位通道蛋白活性的方法，包括步骤：将瞬时受体电位通道蛋白或表达所述蛋白的细胞与本发明第二方面所述的化合物，或其药学上可接受的盐、或其前药进行接触，从而抑制瞬时受体电位通道蛋白的活性。
本发明第八方面，提供一种抑制瞬时受体电位通道蛋白或预防和/或治疗与瞬时受体电位通道蛋白(TRP)相关的疾病的方法，包括步骤：给需要的对象施用本发明第二方面所述所述的化合物，或其药学上可接受的盐，或其前药。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1A-1E为本发明化合物I C-3、I C-4、I C-8I C-23和I C-24抑制TRPA1活性的量效关系曲线图。
图2为本发明化合物I C-10在小鼠福尔马林疼痛模型中的镇痛活性结果。
图3为本发明化合物I C-23在小鼠热板致痛模型中的镇痛活性结果。
图4为化合物Ic-1和度洛西汀在小鼠肌纤维痛模型中的镇痛活性结果，Mean±SD,n＝12,**p<0.01，***p<0.001与溶剂对照组比较。
图5为化合物I C-1、度洛西汀、吲哚美辛和山莨胆碱在小鼠醋酸扭体痛模型中的镇痛活性结果。
图6为化合物I C-1和加巴喷丁在大鼠SNL模型中的镇痛活性结果。
图7为化合物Ic-1和度洛西汀在小鼠福尔马林模型中不同给药剂量下在II相(10-60min)期添足时间统计结果。
具体实施方式
本发明人通过广泛而深入的研究，首次意外地开发了一种化合物，或其药学上可接受的盐，或其前药，所述化合物具有式I结构。实验表明，本发明化合物对TRP通道具有显著的抑制效果。本发明的化合物可有效治疗与TRP(尤其是TRPA1)靶点相关的疼痛等。在此基础上，完成了本发明。
术语
如本文所用，术语“包含”、“包括”、“含有”可互换使用，不仅包括封闭式定义，还包括半封闭、和开放式的定义。换言之，所述术语包括了“由……构成”、“基本上由……构成”。
如本文所用，“R1”、“R 1”和“R1”的含义相同，可相互替换，其它类似定义的含义相同。
如本文所用，术语“C 1-C 6烷基”或“C 1-C 3烷基”指具有1-6或1-3个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基，或类似基团。
如本文所用，术语“C 1-C 6烷氧基”指具有1-6碳原子的直链或支链的烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基，或类似基团。
如本文所用，术语“C 6-C 12苯并脂肪环基”指具有6-12个碳原子的基团，包括茚满基、四氢萘基或二氢萘基等类似基团。
如本文所用，术语“C 3-C 7环烷基”指具有3-7个碳原子的环烷基(包括单环、二环或多环环系)，例如环丙基、环丁基、甲基环丁基、环戊基、环庚基，或类似基团。
如本文所用，术语“C 2-C 6酯基”指具有C 1-C 5烷基-COO-结构的基团或者具有-COO-C 1～C 5烷基结构的基团，其中烷基可以为直链或支链的，例如CH 3COO-、C 2H 5COO-、C 3H 8COO-、(CH 3)2CHCOO-、-COOCH 3、-COOC 2H 5、-COOC 3H 8，或类似基团。
如本文所用，术语“C 2-C 4酰胺基”指具有C 1-C 3烷基-CO-NH-结构的基团或者具有-CO-NH-C 1-C 3烷基结构的基团，其中烷基可以为直链或支链的，例如CH 3-CO-NH-、C 2H 5-CO-NH-、C 3H 8-CO-NH-、-COOCH 3、-CO-NH-C 2H 5、-CO-NH-C 3H 8，或类似基团。
如本文所用，术语“C 2-C 4酰基”指具有C 1-C 3烷基-CO-结构的基团其中烷基可以为直链或支链的，例如CH 3-CO-、C 2H 5-CO-、C 3H 8-CO-，或类似基团。
如本文所用，术语“C 3-C 7杂环烷基”指具有3-7个环碳原子和1-3个杂原子(优选含有1个氮原子，即与R 1和R 2共同相邻的氮原子)的单环和多环杂环(优选单环杂环)，例如哌啶基团、四氢吡咯基，或相似基团。
如本文所用，术语“5-7元碳环”为任何稳定的5、6或7元单环、二环或多环，碳环可以是饱和的、部分不饱和的、不饱和的环，但不能为芳族的环。所述碳环的实例包括但不限于环丙基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环庚烯基、金刚烷基、环辛基、环辛烯基、环辛二烯基、二环[3.3.0]辛烷、二环[4.3.0]壬烷、二环[4.4.0]癸烷、二环[2.2.2]辛烷、芴基、茚满基。
如本文所用，术语“杂环”为任何稳定的单环、二环或多环(例如5、6或7元)，杂环上含有一个或多个(如1-3)选自N、O和S的杂原子，杂环可以是饱和的、部分不饱和的、不饱和的环，但不能为芳族的环。
如本文所用，术语“C 1-C 6卤代烷基”和“C 1-C 3卤代烷基”是指具有1-6和1-3个碳原子的直链或支链的烷基的一个或多个氢原子被卤素基团取代，如一氯甲烷、二氯乙烷、三氯丙烷，或类似基团。
如本文所用，术语“C 1-C 4羧基”是指C 1-C 3烷基-COOH结构的基团，其中烷基可以为直链或支链的，例如CH 3COOH、C 2H 5COOH、C 3H 8COOH、(CH 3) 2CHCOOH，或类似基团。
如本文所用，术语“C 6-C 12芳基”是指在环部分中具有6至12个碳原子的单环或二环芳族烃基，诸如苯基、萘基、联苯基，或相似基团。
如本文所用，术语“杂芳基”是指任选取代的芳香基，例如其为5至7元单环环系，所述环系具有的环含有至少一个杂原子和至少一个碳原子，例如吡咯基、噻吩基、吡啶基、哒嗪基、嘧啶基、吡嗪基、呋喃、咪唑、噻唑、噁唑、三氮唑，或类似基团。
如本文所用，术语“卤素”指F、Cl、Br和I。
如本文所用，术语“取代”是基团上的氢原子被非氢原子基团，但需要满足其化合价要求并且由取代生成化学稳定的化合物。在本说明书中，应解释为所有取代基为未取代的，除非在本文中明确描述为“取代的”。
如本文所用，
Figure PCTCN2019101197-appb-000019
与
Figure PCTCN2019101197-appb-000020
含义相同，均表示具有未取代的或具有1-5个(优选1-3个)R 3取代基的杂芳基。
同样，应当理解的是，在本发明中，取代基可以在任何原子上与母体基团或底 物连接，除非其连接违反化合价要求；母体基团或底物的氢原子可以在同一原子上，也可以在不同的原子上。
如本文所用，对于一个数值范围P1至P2,则该范围不仅包括端点P1和P2，还包括介于端点P1和P2的任何数值点。此外，对于P1和P2均为正数时，则对于一个整数n，该数值范围包括介于端点P1和P2的任何整数数值点。例如，对于一个整数n，当其数值范围为1-10时，包括1、2、3、4、5、6、7、8、9、和10；数值范围3-7包括3、4、5、6、7。代表性地，对于基团而言，C3-C7包括C3、C4、C5C6、和C7。
活性成分
如本文所用，“本发明化合物”、“本发明的3-芳氧基-3-芳香基-丙胺类化合物”、或“式I化合物”可互换使用，指具有式I结构的化合物，或其药学上可接受的盐、或其前药。应理解，该术语还包括上述组分的混合物。
本发明化合物不仅对TRPA1具有抑制作用，对TRP家族中其它成员也有一定的抑制作用。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐，适合形成盐的酸包括(但并不限于)：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。一类优选的盐是本发明化合物与碱形成的金属盐，适合形成盐的碱包括(但并不限于)：氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、磷酸钠等无机碱、氨水、三乙胺、二乙胺等有机碱。
本发明优选的化合物包括选自下表1的任一化合物：
表1
Figure PCTCN2019101197-appb-000021
Figure PCTCN2019101197-appb-000022
Figure PCTCN2019101197-appb-000023
Figure PCTCN2019101197-appb-000024
Figure PCTCN2019101197-appb-000025
Figure PCTCN2019101197-appb-000026
制备方法
本发明还提供了本发明式I所示的3-芳氧基-3-芳香基-丙胺类化合物I A～I F的制备方法。
本发明还提供了用于制备上述化合物的中间体II～III的制备方法。
具体合成策略分别如下：
I A和I B的合成：
Figure PCTCN2019101197-appb-000027
将叔丁醇钾加入(S)-3-(甲基氨基)-1-(噻吩-2-基)丙-1-醇的二甲基亚砜溶液中，搅拌10～20分钟后加入不同位置氟取代的喹啉或异喹啉，80～120℃反应过夜。反应结束后，向反应体系中加入水，用乙酸乙酯萃取三次，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离得到化合物I A和I B。
Ic的合成：
Figure PCTCN2019101197-appb-000028
式中，A、X、Y、R 1、R 2、R 3和“*”定义如上所述。
1)将C 6-C 12双环杂芳基酚或含脂肪环苯酚，1-(R 3-五元芳杂基)-3-氯-丙醇和三苯基膦溶于无水四氢呋喃中，在冰浴条件下慢慢往体系中滴加偶氮二甲酸二异丙酯，滴加完毕后，将体系转移至20～25℃反应过夜。反应完毕后，体系直接旋干，残余物经柱层析分离纯化，得到中间体II。
2)将中间体II溶解于饱和碘化钠的丙酮溶液中，50～70℃温度下反应过夜。反应结束后，旋干溶剂，向体系中加入水，用乙酸乙酯萃取三次，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物溶于四氢呋喃溶液中，加入40％的甲胺水溶液，20～25℃反应过夜。反应结束后，旋干溶剂，向体系中加入氢氧化钠水溶液，用乙酸乙酯萃取三次，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离，得到化合物I。
3)将中间体II，邻苯二甲酰亚胺钾盐和碘化钠溶解于N,N-二甲基甲酰胺溶液中，70-90℃反应过夜。反应结束后，往体系中加入水，乙酸乙酯萃取三次，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离，得到中间体III.
4)将中间体III溶于甲醇溶液中，加入水合肼，20～25℃反应过夜。反应结束后，旋干溶剂，残余物经柱层析分离，得到化合物I。
5)将醋酸，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，4-二甲氨基吡啶和三乙胺溶于无水二氯甲烷溶液中，室温搅拌一小时后，将I C-23的二氯甲烷溶液加入体系中，室温反应过夜。反应结束后，往体系中加入水，用乙酸乙酯萃取三次，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离，得到化合物I D。
6)将将中间体II，L-脯氨酸甲酯盐酸盐，碳酸钾和碘化钠溶解于乙腈溶液中，氮气保护条件下于60～80℃反应过夜。反应结束后，往体系中加入水，用乙酸乙酯萃取三次，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离，得到化合物I E。
7)将化合物I E，氢氧化钠溶于水和四氢呋喃混合溶液中，30～50℃反应过夜。反应结束后，往体系中加入水，用稀盐酸将反应体系调至pH＝6～8，用乙酸乙酯萃取三次，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到化合物I F。
化合物盐的合成
本发明所述的如式I所示化合物可通过常规方法转化为其药学上可接受的盐，例如，可将相应的酸的溶液加入到上述化合物的溶液中，成盐完全后减压除去溶剂即得本发明所述化合物的相应的盐。
瞬时受体电位通道蛋白(TRP)
瞬时受体电位通道蛋白是一类存在于细胞膜上的重要阳离子通道构成的蛋白超家族。瞬时受体电位通道蛋白包括多个亚族，如TRPA、TRPC、TRPM、TRPV、TRPML和TRPP亚族。
研究发现，TRPA1通道蛋白与疼痛、癫痫、炎症、呼吸障碍、瘙痒、尿路障碍、炎症性肠病等疾病相关，TRPA1是治疗疼痛、癫痫、炎症、呼吸障碍、瘙痒、尿路障碍、炎症性肠病等疾病的靶标。
用途
本发明还提供了一种抑制瞬时受体电位通道蛋白(TPR)的方法，以及治疗与瞬时受体电位通道蛋白相关的疾病的方法。
本发明的上述式I化合物可用于抑制瞬时受体电位通道蛋白，进而预防或治疗与瞬时受体电位通道蛋白相关的疾病。
在本发明中，与瞬时受体电位通道蛋白相关的疾病的例子包括(但并不限于)：疼痛、癫痫、炎症、呼吸障碍、瘙痒、尿路障碍、炎症性肠病。代表性的，所述的疼痛包括(但不限于)：急性炎性疼痛、慢性炎性疼痛、内脏痛、神经源性疼痛、肌纤维痛、头痛(例如偏头痛、肌紧张性疼痛等)、神经痛(例如三叉神经痛、糖尿病性疼痛、带状孢疹后神经痛等)、或癌症引起疼痛。
在一个优选实施例中，本发明提供了一种体外非治疗性的抑制瞬时受体电位通道蛋白活性的方法，包括例如在体外培养体系中，将瞬时受体电位通道蛋白或表达所述蛋白的细胞与本发明所述的式I化合物，或其药学上可接受的盐、或其前药进行接触，从而抑制瞬时受体电位通道蛋白的活性。
本发明还提供了一种抑制瞬时受体电位通道蛋白的方法，该方法可以是治疗性的或非治疗性的。通常，该方法包括步骤：给需要的对象施用本发明所述的式I化合物，或其药学上可接受的盐、或其前药。
优选地，所述对象包括人和非人哺乳动物(啮齿动物、兔、猴、家畜、狗、猫等)。
组合物和施用方法
本发明提供了一种用于抑制瞬时受体电位通道蛋白活性的组合物。所述的组合物包括(但并不限于)：药物组合物、食品组合物、膳食补充剂、饮料组合物等。
典型地，所述的组合物为药物组合物，所述的药物组合物包括如本发明所述的式I化合物，或其药学上可接受的盐；和药学上可接受的载体。
在本发明中，药物组合物的剂型包括(但不限于)口服制剂、注射剂、外用制剂。
代表性的包括(但不限于)：片剂、注射剂、输液剂、膏剂、凝胶剂、溶液剂、微球、膜剂。
术语“药学上可接受的载体”指的是：一种或多种相容性固体、半固体、液体或凝胶填料，它们适合于人体或动物使用，而且必须有足够的纯度和足够低的毒性。“相容性”是指药物组合物中的各组分和药物的活性成分以及它们之间相互掺和，而不明显降低药效。
应理解，在本发明中，所述的载体没有特别的限制，可选用本领域常用材料，或用常规方法制得，或从市场购买得到。药学可接受的载体部分例子有纤维素及其衍生物(如甲基纤维素、乙基纤维素、羟丙甲基纤维素、羧甲基纤维素钠等)、明胶、滑石粉、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油、等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、缓冲剂、螯合剂、增稠剂、pH调节剂、透皮促进剂、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、抑菌剂、无热原水等。
代表性的，液体剂型除了活性药物成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂等
药物制剂应与给药方式相匹配。本发明药剂还可与其他协同治疗剂一起使用(包括之前、之中或之后使用)。使用药物组合物或制剂时，是将安全有效量的药物施用于所需对象(如人或非人哺乳动物)，所述安全有效量通常至少约10微克/千克体重，而且在大多数情况下不超过约8毫克/千克体重，较佳地该剂量是约10微克/千克体重-约1毫克/千克体重。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
(a)本发明提供了一类结构新颖且具有优异TRP通道抑制活性的式I化合物。
(b)本发明化合物具有优异的镇痛等体内药效。
(c)本发明化合物的毒性更小、活性更高，因此安全窗口更大。
(d)本发明化合物的成药性好。
(e)本发明化合物具有优异的药代动力学性质。
(f)本发明化合物适合口服给药。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1
(S)-N-甲基-3-(喹啉-8-基氧基)-3-(噻吩-2-基)丙-1-胺(化合物I A-1)
Figure PCTCN2019101197-appb-000029
将257毫克(S)-3-(甲氨基)-1-(噻吩-2-基)丙-1-醇溶解于10毫升二甲基亚砜溶液中，加入168毫克的叔丁醇钾，室温搅拌15分钟，加入883毫克8-氟喹啉，90℃反应过夜。反应结束后，向反应体系中加入水，用乙酸乙酯萃取三次，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离(甲醇/二氯甲烷＝1:15)，得到标题化合物，217毫克棕色油状物，收率48.5％。
1H-NMR(400MHz,CDCl 3)δ8.97(dd,J＝4.1,1.3Hz,1H),8.17–8.09(m,1H),7.46–7.38(m,2H),7.32(t,J＝7.9Hz,1H),7.24(d,J＝4.9Hz,1H),7.05(d,J＝7.6Hz,1H),7.01(d,J＝3.2Hz,1H),6.94–6.89(m,1H),5.80(dd,J＝8.6,4.8Hz,1H),3.01(dt,J＝12.6,6.9Hz,1H),2.91(dt,J＝12.2,6.2Hz,1H),2.60(dq,J＝14.4,6.2Hz,1H),2.52(s,3H),2.37–2.26(m,1H).MS(ESI,m/z):298.88(M+H) +.
实施例2
(S)-N-甲基-3-(喹啉-6-基氧基)-3-(噻吩-2-基)丙-1-胺(化合物I A-2)
Figure PCTCN2019101197-appb-000030
除了将8-氟喹啉换成6-氟喹啉外，其余所需原料、试剂及制备方法同实施例1，得到161毫克棕色油状标题化合物，收率36.1％。
1H-NMR(400MHz,CDCl 3)δ8.73(dd,J＝4.1,1.2Hz,1H),7.96(t,J＝7.5Hz,2H),7.41(dd,J＝9.2,2.6Hz,1H),7.30(dd,J＝8.3,4.2Hz,1H),7.23(d,J＝5.0Hz,1H),7.14(d,J＝2.6Hz,1H),7.08(d,J＝3.3Hz,1H),6.94(dd,J＝4.8,3.7Hz,1H),5.73(dd,J＝7.4,5.7Hz,1H),2.83–2.74(m,2H),2.45(s,3H),2.37(td,J＝14.0,6.9Hz,1H),2.16(dq,J＝13.7,6.9Hz,1H).MS(ESI,m/z):298.88(M+H) +.
实施例3
(S)-N-甲基-3-(喹啉-4-基氧基)-3-(噻吩-2-基)丙-1-胺(化合物I A-3)
Figure PCTCN2019101197-appb-000031
除了将8-氟喹啉换成4-氟喹啉外，其余所需原料、试剂及制备方法同实施例1，得到157毫克棕色油状标题化合物，收率30.1％。
1H-NMR(400MHz,CDCl 3)δ8.63(d,J＝5.2Hz,1H),8.09(d,J＝8.5Hz,1H),8.03(dd,J＝8.6,1.3Hz,1H),7.66(ddd,J＝8.4,6.9,1.4Hz,1H),7.47(ddd,J＝8.2,6.8,1.2Hz,1H),7.25(dd,J＝4.8,1.7Hz,1H),6.97–6.91(m,2H),6.84(d,J＝5.3Hz,1H),5.09(dd,J＝7.8,5.1Hz,1H),3.50(hept,J＝6.9Hz,2H),3.05(s,3H),2.37–2.19(m,2H).MS(ESI,m/z):298.88(M+H) +.
实施例4
(S)-N-甲基-3-(喹啉-5-基氧基)-3-(噻吩-2-基)丙-1-胺(化合物I A-4)
Figure PCTCN2019101197-appb-000032
除了将8-氟喹啉换成5-氟喹啉外，其余所需原料、试剂及制备方法同实施例1，得到161毫克棕色油状标题化合物，收率35.9％。
1H-NMR(400MHz,CDCl 3)δ8.89(dd,J＝4.2,1.8Hz,1H),8.65(dt,J＝8.5,1.3Hz,1H),7.65(d,J＝8.5Hz,1H),7.50(t,J＝8.1Hz,1H),7.39(dd,J＝8.5,4.2Hz,1H),7.22(dd,J＝5.1,1.2Hz,1H),7.06(dd,J＝3.6,1.2Hz,1H),6.97–6.88(m,2H),5.81(dd,J＝7.6,5.4Hz,1H),2.83(t,J＝6.4Hz,2H),2.54–2.38(m,4H),2.24(dtd,J＝14.0,7.0,5.3Hz,1H).MS(ESI,m/z):298.88(M+H) +.
实施例5
(S)-N-甲基-3-(异喹啉-4-基氧基)-3-(噻吩-2-基)丙-1-胺(化合物I B-1)
Figure PCTCN2019101197-appb-000033
除了将8-氟喹啉换成4-氟异喹啉外，其余所需原料、试剂及制备方法同实施例1，得到141毫克棕色油状标题化合物，收率31.5％。
1H-NMR(400MHz,CDCl 3)δ8.84(s,1H),8.27(d,J＝8.3Hz,1H),8.12(s,1H),7.91(d,J＝8.2Hz,1H),7.71(t,J＝7.6Hz,1H),7.61(t,J＝7.5Hz,1H),7.22(d,J＝4.9Hz,1H),7.11(d,J＝3.3Hz,1H),6.95–6.88(m,1H),5.94–5.86(m,1H),2.96(q,J＝7.3Hz,1H),2.90(t,J＝7.0Hz,1H),2.55(dd,J＝14.0,7.0Hz,1H),2.50(s,3H),2.32(dd,J＝13.5,6.2Hz,1H).MS(ESI,m/z):298.88(M+H) +.
实施例6
(S)-N-甲基-3-(异喹啉-8-基氧基)-3-(噻吩-2-基)丙-1-胺(化合物I B-2)
Figure PCTCN2019101197-appb-000034
除了将8-氟喹啉换成8-氟异喹啉外，其余所需原料、试剂及制备方法同实施例1，得到152毫克棕色油状标题化合物，收率33.9％。
1H-NMR(400MHz,CDCl 3)δ9.72(s,1H),8.53(d,J＝5.7Hz,1H),7.56(d,J＝5.7Hz,1H),7.47(t,J＝8.0Hz,1H),7.33(d,J＝8.2Hz,1H),7.23(d,J＝5.0Hz,1H),7.09(d,J＝3.4Hz,1H),6.99–6.93(m,2H),5.85(dd,J＝7.5,5.5Hz,1H),2.84(q,J＝6.4,6.0Hz,2H),2.54–2.47(m,1H),2.45(s,3H),2.24(dq,J＝13.7,6.9Hz,1H).MS(ESI,m/z):298.88(M+H) +.
实施例7
(S)-N-甲基-3-(异喹啉-5-基氧基)-3-(噻吩-2-基)丙-1-胺(化合物I B-3)
Figure PCTCN2019101197-appb-000035
除了将8-氟喹啉换成5-氟异喹啉外，其余所需原料、试剂及制备方法同实施例1，得到163毫克棕色油状标题化合物，收率36.4％。
1H-NMR(400MHz,CDCl 3)δ9.17(s,1H),8.53(d,J＝5.9Hz,1H),8.07(d,J＝5.8Hz,1H),7.50(d,J＝8.2Hz,1H),7.39(t,J＝8.0Hz,1H),7.22(dd,J＝5.0,1.2Hz,1H),7.08–7.04(m,2H),6.93(dd,J＝5.1,3.5Hz,1H),5.83(dd,J＝7.7,5.4Hz,1H),2.90–2.84(m,2H),2.55–2.44(m,4H),2.30–2.25(m,1H).MS(ESI,m/z):298.88(M+H) +.
实施例8
(S)-7-(3-氯-1-(噻吩-2-基)丙氧基)苯并呋喃(中间体II-1)
Figure PCTCN2019101197-appb-000036
将480毫克(R)-3-氯-1-(噻吩-2-基)丙-1-醇，364毫克7-羟基苯并呋喃和784毫克三苯基膦溶解于20毫升的无水四氢呋喃中，在冰浴条件下慢慢往体系中滴加589微升偶氮二甲酸二异丙酯，滴加完毕将体系转移至室温反应过夜。反应完毕后，体系直接旋干，残余物经柱层析分离纯化，得到标题化合物，600毫克的无色油状，收率75.43％。
1H NMR(500MHz,CDCl 3)δ7.61(t,J＝3.1Hz,1H),7.39(dd,J＝1.7,0.7Hz,1H),7.21(dt,J＝8.2,1.9Hz,1H),7.11–7.06(m,1H),6.88(d,J＝7.9Hz,1H),6.76(dd,J＝8.1,2.1Hz,1H),6.33(d,J＝3.2Hz,1H),6.30(dd,J＝3.3,1.8Hz,1H),5.70(dd,J＝8.4,5.1Hz,1H),3.89(ddd,J＝11.1,8.2,5.4Hz,1H),3.73–3.65(m,1H),2.80–2.70(m,1H),2.51–2.42(m,1H).MS(ESI,m/z):293(M+H) +.
实施例9
(S)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(噻吩-2-基)丙-1-胺(化合物I C-1)
Figure PCTCN2019101197-appb-000037
将600毫克中间体II-1溶于饱和碘化钠的丙酮溶液中，回流过夜。反应结束后，旋干溶剂，向体系中加入水，用乙酸乙酯萃取三次，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物溶解于20毫升的四氢呋喃溶液中，加入2毫升40％的甲胺水溶液，反应过夜。反应结束后，旋干溶剂，向体系中加入氢氧化钠水溶液，用乙酸乙酯萃取三次，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离(甲醇/二氯甲烷＝1:15)，得到标题化合物，200毫克无色油状物，收率33.96％。
1H NMR(400MHz,CDCl 3)δ7.63(d,J＝2.0Hz,1H),7.20(t,J＝6.6Hz,2H),7.08–6.99(m,2H),6.88(dd,J＝4.9,3.6Hz,1H),6.80(d,J＝7.9Hz,1H),6.75(d,J＝2.0Hz,1H),5.93(dd,J＝8.2,4.4Hz,1H),3.30(t,J＝7.0Hz,2H),2.82–2.69(m,4H),2.65–2.54(m,1H).MS(ESI,m/z):287.87(M+H) +.
实施例10
(S)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(噻吩-3-基)丙-1-胺(化合物I C-2)
Figure PCTCN2019101197-appb-000038
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(噻吩-3-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例8-9，得到200毫克黄色油状物标题化合物，收率33.9％。
1H NMR(500MHz,CDCl 3)δ7.63(d,J＝2.1Hz,1H),7.27(dd,J＝5.0,3.0Hz,1H),7.24(d,J＝2.1Hz,1H),7.18–7.11(m,2H),7.01(t,J＝7.9Hz,1H),6.75(d,J＝2.1Hz,1H),6.72(d,J＝7.8Hz,1H),5.64(dd,J＝8.0,5.0Hz,1H),2.94–2.81(m,2H),2.48(s,3H),2.46–2.32(m,1H),2.24–2.13(m,1H).MS(ESI,m/z):287.76(M+H) +.
实施例11
(S)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(呋喃-3-基)丙-1-胺(化合物I C-3)
Figure PCTCN2019101197-appb-000039
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(呋喃-3-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例8-9，得到100毫克无色油状物标题化合物，收率9.89％。
1H NMR(500MHz,CDCl 3)δ7.62(d,J＝2.1Hz,1H),7.40(s,1H),7.35(t,J＝1.7Hz,1H),7.17(dd,J＝7.8,0.8Hz,1H),7.05(t,J＝7.9Hz,1H),6.80(d,J＝7.7Hz,1H),6.75(d,J＝2.1Hz,1H),6.46(d,J＝1.1Hz,1H),5.56(dd,J＝7.7,5.4Hz,1H),2.90–2.78(m,2H),2.46(s,3H),2.35(td,J＝13.9,7.4Hz,1H),2.13(dtd,J＝12.4,7.0,5.5Hz,1H).MS(ESI,m/z):271.88(M+H) +.
实施例12
(S)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(呋喃-2-基)丙-1-胺(化合物I C-4)
Figure PCTCN2019101197-appb-000040
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(呋喃-2-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例8-9，得到30毫克无色油状物标题化合物，收率3.22％。
1H NMR(500MHz,CDCl 3)δ7.61(d,J＝2.1Hz,1H),7.36(d,J＝1.1Hz,1H),7.20(d,J＝7.7Hz,1H),7.06(dd,J＝10.5,5.3Hz,1H),6.82(d,J＝7.7Hz,1H),6.74(dd,J＝7.8,2.1Hz,1H),6.31(d,J＝3.2Hz,1H),6.27(dd,J＝3.2,1.8Hz,1H),5.60(dd,J＝7.9,5.3Hz,1H),3.13–2.99(m,2H),2.63–2.56(m,4H),2.44(ddd,J＝14.1,12.4,7.0Hz,1H).MS(ESI,m/z):271.88(M+H) +.
实施例13
(S)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(5-甲基噻吩-2-基)丙-1-胺(化合物 I C-5)
Figure PCTCN2019101197-appb-000041
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(5-甲基噻吩-2-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例8-9，得到160毫克无色油状物标题化合物，收率14.24％。
1H NMR(500MHz,CDCl 3)δ7.62(d,J＝2.1Hz,1H),7.17(dd,J＝7.8,0.8Hz,1H),7.04(t,J＝7.9Hz,1H),6.82(d,J＝7.6Hz,1H),6.79(d,J＝3.4Hz,1H),6.74(dd,J＝6.6,2.2Hz,1H),6.58–6.51(m,1H),5.71(dd,J＝7.8,5.5Hz,1H),2.93–2.81(m,2H),2.47(s,3H),2.45–2.38(m,4H),2.25–2.16(m,1H).MS(ESI,m/z):301.87(M+H) +.
实施例14
(S)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(5-氯噻吩-2-基)丙-1-胺(化合物I C-6)
Figure PCTCN2019101197-appb-000042
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(5-氯噻吩-2-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例8-9，得到300毫克无色油状物标题化合物，收率20.84％。
1H NMR(500MHz,CDCl 3)δ7.63(d,J＝2.1Hz,1H),7.20(d,J＝7.8Hz,1H),7.05(t,J＝7.9Hz,1H),6.80(dd,J＝12.0,5.7Hz,2H),6.75(t,J＝4.6Hz,1H),6.70(d,J＝3.8Hz,1H),5.75(dd,J＝8.1,5.2Hz,1H),3.04–2.89(m,2H),2.57–2.43(m,4H),2.27(ddd,J＝13.7,12.0,6.7Hz,1H).MS(ESI,m/z):321.78(M+H) +.
实施例15
(S)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(噻唑-2-基)丙-1-胺(化合物I C-7)
Figure PCTCN2019101197-appb-000043
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成3-氯-1-(噻唑-2-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例8-9，得到I C-7的消旋体之后，通过手性拆分的方法得到60毫克黄色油状物标题化合物，收率6.72％。
1H NMR(500MHz,CDCl 3)δ7.76(d,J＝3.2Hz,1H),7.64(d,J＝2.1Hz,1H),7.33(d,J＝3.2Hz,1H),7.25(d,J＝0.9Hz,1H),7.08(t,J＝7.9Hz,1H),6.89(d,J＝7.3Hz,1H),6.78(d,J＝2.2Hz,1H),6.05(t,J＝6.0Hz,1H),3.33(t,J＝6.9Hz,2H),2.81–2.67(m,5H).MS(ESI,m/z):288.77(M+H) +.
实施例16
(S)-3-(苯并呋喃-7-基氧基)-N,N-二甲基-3-(噻吩-2-基)丙-1-胺(化合物I C-8)
Figure PCTCN2019101197-appb-000044
除了将甲胺水溶液换成二甲胺外，其余所需原料、试剂及制备方法同实施例9，得到130毫克无色油状物标题化合物，收率34.67％
1H NMR(400MHz,CDCl 3)δ7.62(d,J＝2.0Hz,1H),7.23(d,J＝5.0Hz,1H),7.17(d,J＝7.8Hz,1H),7.03(t,J＝7.9Hz,2H),6.96–6.87(m,1H),6.82(d,J＝7.9Hz,1H),6.74(d,J＝2.1Hz,1H),5.88–5.79(m,1H),2.60(t,J＝6.9Hz,2H),2.47(dt,J＝21.7,7.4Hz,1H),2.32(s,6H),2.22(dt,J＝20.5,6.8Hz,1H).MS(ESI,m/z):301.88(M+H) +.
实施例17
(S)-3-(苯并呋喃-4-基氧基)-N-甲基-3-(噻吩-2-基)丙-1-胺(化合物I C-9)
Figure PCTCN2019101197-appb-000045
除了将7-羟基苯并呋喃换成4-羟基苯并呋喃外，其余所需原料、试剂及制备方法同实施例8-9，得到15毫克黄色油状物标题化合物，收率1.40％。
1H NMR(400MHz,CDCl 3)δ7.53(d,J＝2.1Hz,1H),7.20(d,J＝5.0Hz,1H),7.14–7.07(m,3H),6.92–6.87(m,2H),6.72(dd,J＝6.6,2.1Hz,1H),5.87(dd,J＝7.7,4.8Hz,1H),3.34–3.19(m,2H),2.78(td,J＝14.6,7.3Hz,1H),2.66(dt,J＝15.1,6.4Hz,4H).MS(ESI,m/z):287.87(M+H) +.
实施例18
(S)-3-(2,3-二氢-1H-茚-4-基)氧基)-N-甲基-3-(2-噻吩基)丙-1-胺(化合物I C-10)
Figure PCTCN2019101197-appb-000046
除了将7-羟基苯并呋喃换成4-茚醇外，其余所需原料、试剂及制备方法同实施例8-9，得到16毫克棕色油状标题化合物，收率是9.9％。
1H NMR(400MHz,CDCl 3)δ7.21(dd,J＝5.0,1.2Hz,1H),7.03–6.96(m,2H),6.92(dd,J＝5.0,3.5Hz,1H),6.81(d,J＝7.3Hz,1H),6.65(d,J＝8.0Hz,1H),5.57(dd,J＝7.8,5.0Hz,1H),2.87(dt,J＝19.9,7.3Hz,6H),2.47(s,3H),2.41–2.30(m,1H),2.25–2.14(m,1H),2.06(p,J＝7.0Hz,2H).MS(ESI,m/z):287.87(M+H) +.
实施例19
(S)-3-(2,3-二氢-1H-茚-4-基)氧基)-N-甲基-3-(3-噻吩基)丙-1-胺(化合物I C-11)
Figure PCTCN2019101197-appb-000047
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(噻吩-3-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例18，得到60毫克棕色油状标题化合物，收率是8.6％。
1H NMR(500MHz,CDCl 3)δ7.27(dd,J＝4.0,2.0Hz,1H),7.20–7.15(m,1H),7.06(dt,J＝3.8,1.9Hz,1H),6.96(t,J＝7.9Hz,1H),6.80(d,J＝7.6Hz,1H),6.54(d,J＝8.2Hz,1H),5.40(dd,J＝7.9,4.7Hz,1H),2.91(dd,J＝16.1,8.4Hz,4H),2.82(ddd,J＝9.8,7.1,3.8Hz,2H),2.47(s,3H),2.31–2.23(m,1H),2.19–2.11(m,1H),2.11–2.03(m,2H).MS(ESI,m/z):287.76(M+H) +.
实施例20
(S)-3-(2,3-二氢-1H-茚-4-基)氧基)-N-甲基-3-(2-呋喃基)丙-1-胺(化合物I C-12)
Figure PCTCN2019101197-appb-000048
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(呋喃-2-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例18，得到10毫克棕色油状标题化合物，收率是4.2％。
1H NMR(500MHz,CDCl 3)δ7.36(dd,J＝1.8,0.8Hz,1H),7.03(dd,J＝14.9,7.1Hz,1H),6.83(d,J＝7.4Hz,1H),6.67(d,J＝8.1Hz,1H),6.30(dd,J＝3.2,1.8Hz,1H),6.25(d,J＝3.2Hz,1H),5.30(dd,J＝7.6,5.4Hz,1H),2.92–2.79(m,6H),2.48(s,3H),2.35(td,J＝14.0,7.2Hz,1H),2.23(ddd,J＝14.0,12.5,7.1Hz,1H),2.08–2.01(m,2H).MS(ESI,m/z):271.88(M+H) +.
实施例21
(S)-3-(2,3-二氢-1H-茚-4-基)氧基)-N-甲基-3-(3-呋喃基)丙-1-胺(化合物I C-13)
Figure PCTCN2019101197-appb-000049
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(呋喃-3-基)丙-1-醇 外，其余所需原料、试剂及制备方法同实施例18，得到13毫克棕色油状标题化合物，收率是4.6％。
1H NMR(500MHz,CDCl 3)δ7.35(d,J＝1.4Hz,2H),7.01(t,J＝7.8Hz,1H),6.81(d,J＝7.4Hz,1H),6.63(d,J＝8.1Hz,1H),6.38(t,J＝1.3Hz,1H),5.29(dd,J＝7.7,5.0Hz,1H),2.94–2.85(m,4H),2.83–2.75(m,2H),2.46(s,3H),2.22(td,J＝13.9,7.4Hz,1H),2.11–2.00(m,3H).MS(ESI,m/z):271.63(M+H) +.
实施例22
(S)-3-(2,3-二氢-1H-茚-4-基)氧基)-N-甲基-3-(2-噻唑基)丙-1-胺(化合物I C-14)
Figure PCTCN2019101197-appb-000050
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成3-氯-1-(噻唑-2-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例18，得到Ic-14的消旋体以后，通过手性拆分的方法，得到35毫克黄色油状标题化合物，收率是5.9％。
1H NMR(400MHz,CDCl 3)δ7.74(d,J＝3.2Hz,1H),7.28(d,J＝3.2Hz,1H),7.01(t,J＝7.8Hz,1H),6.85(d,J＝7.4Hz,1H),6.65(d,J＝8.1Hz,1H),5.70(dd,J＝7.3,5.2Hz,1H),3.01(d,J＝7.5Hz,1H),2.98–2.82(m,5H),2.48(s,3H),2.44–2.24(m,2H),2.14–2.02(m,2H).MS(ESI,m/z):288.87(M+H) +.
实施例23
(S)-3-(2,3-二氢-1H-茚-4-基)氧基)-N,N-二甲基-3-(2-噻吩基)丙-1-胺(化合物I C-15)
Figure PCTCN2019101197-appb-000051
除了将甲胺水溶液换成二甲胺，其余所需原料、试剂及制备方法同实施例18，得到21毫克棕色油状标题化合物，收率是10.1％。
1H NMR(400MHz,CDCl 3)δ7.22(dd,J＝5.0,1.2Hz,1H),7.00(dd,J＝10.5,5.2Hz,2H),6.93(dd,J＝5.0,3.5Hz,1H),6.82(d,J＝7.5Hz,1H),6.65(d,J＝8.1Hz,1H),5.57(dd,J＝7.6,5.3Hz,1H),2.90(dt,J＝20.0,6.5Hz,4H),2.76(s,2H),2.57–2.36(m,7H),2.30(s,1H),2.13–1.98(m,2H).MS(ESI,m/z):301.77(M+H) +.
实施例24
(S)-3-(2,3-二氢-1H-茚-5-基)氧基)-N-甲基-3-(2-噻吩基)丙-1-胺(化合物I C-16)
Figure PCTCN2019101197-appb-000052
除了将7-羟基苯并呋喃换成5-茚醇外，其余所需原料、试剂及制备方法同实施例8-9，得到15毫克黄色油状标题化合物，收率是9.7％。
1H NMR(400MHz,CDCl 3)δ7.21(dd,J＝5.0,1.1Hz,1H),7.06–6.98(m,2H),6.91(dd,J＝5.0,3.5Hz,1H),6.78(s,1H),6.68(d,J＝8.6Hz,1H),5.56(dd,J＝7.8,4.6Hz,1H),3.08(t,J＝7.3Hz,2H),2.79(dt,J＝12.2,7.4Hz,4H),2.61(s,3H),2.03(q,J＝7.6Hz,4H).MS(ESI,m/z):287.88(M+H) +.
实施例25
(S)-3-(四氢萘-1-基)氧基)-N-甲基-3-(2-噻吩基)丙-1-胺(化合物I C-17)
Figure PCTCN2019101197-appb-000053
除了将7-羟基苯并呋喃换成四氢萘酚外，其余所需原料、试剂及制备方法同实施例8-9，得到30毫克黄色油状标题化合物，收率是13.6％。
1H NMR(400MHz,CDCl 3)δ7.19–7.14(m,1H),6.98–6.93(m,2H),6.67 (d,J＝7.9Hz,1H),6.53(d,J＝8.0Hz,1H),4.82(dd,J＝12.5,3.4Hz,1H),2.83–2.64(m,5H),2.56–2.31(m,5H),2.12(m,1H),1.84–1.66(m,4H).MS(ESI,m/z):301.77(M+H) +.
实施例26
(S)-(3-(5,8-二氢萘-1-基)氧基)-N-甲基-3-(2-噻吩基)丙-1-胺(化合物I C-18)
Figure PCTCN2019101197-appb-000054
除了将7-羟基苯并呋喃换成5,8-二氢萘酚外，其余所需原料、试剂及制备方法同实施例8-9，得到65毫克棕色油状标题化合物，收率是25.3％。
1H NMR(400MHz,DMSO)δ9.31(s,1H),7.32(dd,J＝5.1,1.2Hz,1H),7.02(d,J＝8.4Hz,1H),6.93(dd,J＝5.1,3.5Hz,1H),6.88(d,J＝3.1Hz,1H),6.70(d,J＝8.3Hz,1H),5.85(dd,J＝22.1,10.2Hz,2H),4.38(t,J＝7.6Hz,1H),3.42(s,1H),3.15(d,J＝10.1Hz,4H),2.91–2.68(m,3H),2.57–2.52(m,3H),2.30–2.20(m,2H).MS(ESI,m/z):299.76(M+H) +.
实施例27
(S)-2-甲基-4-(3-(甲基氨基)-1-(噻吩-2-基)丙氧基)异吲哚啉-1,3-二酮(化合物I C-19)
Figure PCTCN2019101197-appb-000055
除了将7-羟基苯并呋喃换成4-羟基-2-甲基异吲哚啉-1，3-二酮外，其余所需原料、试剂及制备方法同实施例8-9，得到163毫克棕色油状标题化合物，收率36.4％。
1H NMR(400MHz,CDCl 3)δ7.52(t,J＝7.8Hz,1H),7.43(d,J＝7.3Hz,1H),7.28(d,J＝4.9Hz,1H),7.04(dd,J＝11.3,5.6Hz,2H),6.97(dd,J＝4.9,3.4Hz,1H),6.05(s,1H),3.34(s,2H),3.14(s,3H),3.02(s,1H),2.88(s,3H),2.43(d,J＝15.0Hz,1H).MS(ESI,m/z):330.76(M+H) +.
实施例28
(S)-3-(咪唑并[1,2-a]吡啶-8-氧基)-N-甲基-3-(2-噻吩基)丙-1-胺(化合物I C-20)
Figure PCTCN2019101197-appb-000056
除了将7-羟基苯并呋喃换成8-羟基咪唑并[1,2-a]吡啶外，其余所需原料、试剂及制备方法同实施例8-9，得到43毫克棕色油状标题化合物，收率11.7％。
1H NMR(400MHz,CDCl 3)δ7.95(d,J＝6.4Hz,1H),7.64(s,1H),7.53(d,J＝11.9Hz,1H),7.35–7.28(m,1H),6.91(d,J＝3.4Hz,2H),6.69(t,J＝7.1Hz,1H),6.62(d,J＝7.2Hz,1H),5.85(dd,J＝11.5,2.7Hz,1H),3.55(t,J＝10.1Hz,1H),3.34–3.24(m,1H),2.85(s,3H),2.78(dd,J＝11.1,3.3Hz,1H),2.64–2.52(m,1H).MS(ESI,m/z):287.77(M+H) +.
实施例29
(S)-4-(3-(甲基氨基)-1-(噻吩-2-基)丙氧基)-1,3-二氢-2H苯并[d]咪唑-2-酮(化合物I C-21)
Figure PCTCN2019101197-appb-000057
除了将7-羟基苯并呋喃换成4-羟基-1H-苯并[d]咪唑-2(3H)-酮外，其余所需原料、试剂及制备方法同实施例8-9，得到43毫克棕色油状标题化合物，收率9.4％。
1H NMR(400MHz,CD 3OD)δ7.35(dd,J＝5.1,1.1Hz,1H),7.11(d,J＝2.8Hz,1H),6.95(dd,J＝5.1,3.5Hz,1H),6.88–6.81(m,1H),6.67(dd,J＝8.1,2.8Hz,2H),5.77(dd,J＝8.1,4.8Hz,1H),3.11–2.98(m,2H),2.60(s,3H),2.50–2.39(m,1H),2.32–2.23(m,1H).MS(ESI,m/z):303.88(M+H) +.
实施例30
(S)-N-甲基-3-(喹喔啉-5-基氧基)-3-(噻吩-2-基)丙-1-胺(化合物I C-22)
Figure PCTCN2019101197-appb-000058
除了将7-羟基苯并呋喃换成5-氟喹喔啉外，其余所需原料、试剂及制备方法同实施例8-9，得到230毫克棕色油状标题化合物，收率是40.5％。
1H NMR(400MHz,CDCl 3)δ8.98(d,J＝11.6Hz,2H),7.83(d,J＝8.5Hz,1H),7.58(t,J＝8.1Hz,1H),7.35(d,J＝4.7Hz,1H),7.05–6.95(m,3H),5.67(d,J＝6.1Hz,1H),3.45(s,2H),2.93(s,3H),2.76(s,1H),2.64(s,1H).MS(ESI,m/z):299.88(M+H) +.
实施例31
(S)-2-(3-(苯并呋喃-7-基氧基)-3-(噻吩-2-基)丙基)异吲哚啉-1,3-二酮(中间体III-1)
Figure PCTCN2019101197-appb-000059
将160毫克中间体II-1，303毫克的邻苯二甲酰亚胺钾盐和25毫克的碘化钠溶解于5毫升的N,N-二甲基甲酰胺中，氮气保护条件下90℃反应过夜。反应结束后，向体系中加入水，用乙酸乙酯萃取三次，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离(乙酸乙酯/石油醚＝1:5)，得到标题化合物，140毫克黄色的固体，收率63.49％。
1H NMR(500MHz,CDCl 3)δ7.81–7.78(m,2H),7.68(dd,J＝5.5,3.0Hz,2H),7.45(d,J＝2.1Hz,1H),7.18(dd,J＝5.0,1.1Hz,1H),7.14(dd,J＝7.8,0.8Hz,1H),7.06(d,J＝3.0Hz,1H),7.04–6.97(m,1H),6.86(dt,J＝10.3,5.2Hz,1H),6.78(d,J＝7.4Hz,1H),6.68(d,J＝2.1Hz,1H),5.82(dd,J＝7.8,5.2Hz,1H),4.07–3.89(m,2H),2.66(td,J＝14.4,7.3Hz,1H),2.47–2.36(m,1H).MS(ESI,m/z):404(M+H) +.
实施例32
(S)-3-(苯并呋喃-7-基氧基)-3-(噻吩-2-基)丙-1-胺(化合物I C-23)
Figure PCTCN2019101197-appb-000060
将140毫克中间体III-1和87毫克的水合肼溶解于5毫升的甲醇溶液中，室温反应过夜。反应结束后，旋干溶剂，残余物经柱层析分离(甲醇/二氯甲烷＝1:15)，得到标题化合物，30毫克无色油状物，收率31.63％。
1H NMR(500MHz,DMSO)δ7.97(d,J＝2.1Hz,1H),7.49(dd,J＝5.0,1.1Hz,1H),7.24–7.17(m,2H),7.11–7.03(m,1H),6.99(dd,J＝5.0,3.5Hz,1H),6.95(d,J＝7.5Hz,1H),6.93(d,J＝2.1Hz,1H),6.04(dd,J＝7.8,5.5Hz,1H),2.99–2.86(m,2H),2.44–2.35(m,1H),2.21(ddt,J＝11.5,9.3,5.8Hz,1H).MS(ESI,m/z):273.77(M+H) +.
实施例33
(S)-3-(苯并呋喃-7-基氧基)-3-(呋喃-3-基)丙-1-胺(化合物I C-24)
Figure PCTCN2019101197-appb-000061
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(呋喃-3-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例8、31-32，得到90毫克无色油状物标题化合物，收率是12.71％。
1H NMR(500MHz,CDCl 3)δ7.62(d,J＝2.1Hz,1H),7.42–7.37(m,1H),7.35(t,J＝1.7Hz,1H),7.18(dd,J＝7.8,0.9Hz,1H),7.08–7.01(m,1H),6.79(dd,J＝7.9,0.7Hz,1H),6.75(d,J＝2.2Hz,1H),6.45(dd,J＝1.7,0.7Hz,1H),5.57(dd,J＝8.1,5.0Hz,1H),3.03–2.91(m,2H),2.31(ddt,J＝14.1,8.1,6.4Hz,1H),2.06(dtd,J＝9.4,7.1,5.1Hz,1H).MS(ESI,m/z):257.77(M+H) +.
实施例34
(S)-3-(苯并呋喃-7-基氧基)-3-(呋喃-2-基)丙-1-胺(化合物I C-25)
Figure PCTCN2019101197-appb-000062
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(呋喃-2-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例8、31-32，得到85毫克无色油状物标题化合物，收率是16.53％。
1H NMR(500MHz,CDCl3)δ7.62(d,J＝2.1Hz,1H),7.37(dd,J＝1.6,1.0Hz,1H),7.20(dd,J＝7.8,0.9Hz,1H),7.06(t,J＝7.9Hz,1H),6.87–6.80(m,1H),6.75(d,J＝2.1Hz,1H),6.33–6.24(m,2H),5.59(dd,J＝8.0,5.5Hz,1H),3.09–2.93(m,2H),2.43(dq,J＝7.9,6.4Hz,1H),2.22(qd,J＝12.5,6.9Hz,1H).MS(ESI,m/z):257.64(M+H) +.
实施例35
(S)-3(苯并呋喃-7-基氧基)-3-(噻吩-3-基)丙-1-胺(化合物I C-26)
Figure PCTCN2019101197-appb-000063
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(噻吩-3-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例8、31-32，得到60毫克黄色油状物标题化合物，收率是14.56％。
1H NMR(500MHz,CDCl3)δ7.62(d,J＝1.9Hz,1H),7.25–7.22(m,2H),7.13(t,J＝7.4Hz,1H),7.09(d,J＝4.6Hz,1H),6.97(t,J＝7.9Hz,1H),6.71(d,J＝2.0Hz,1H),6.67(d,J＝8.0Hz,1H),5.65(dd,J＝7.9,4.2Hz,1H),3.30–3.11(m,2H),2.49(dd,J＝14.1,7.4Hz,1H),2.34(dd,J＝12.9,5.8Hz,1H).MS(ESI,m/z):273.77(M+H) +.
实施例36
(S)-3(苯并[b]噻吩-5-基氧基)-N-甲基-3-(噻吩-2-基)丙-1-胺(化合物I C-27)
Figure PCTCN2019101197-appb-000064
除了将7-羟基苯并呋喃换成苯并[b]噻吩-5-醇外，其余所需原料、试剂及制备方法同实施例8-9，得到20毫克黄色油状标题化合物，收率是3.30％。
1H NMR(500MHz,CDCl3)δ7.68(d,J＝8.8Hz,1H),7.39(d,J＝5.4Hz,1H),7.31(d,J＝2.4Hz,1H),7.22(dd,J＝5.0,1.1Hz,1H),7.18(d,J＝5.4Hz,1H),7.04–6.99(m,2H),6.92(dd,J＝5.0,3.5Hz,1H),5.63(dd,J＝7.7,5.2Hz,1H),2.93–2.81(m,2H),2.49(s,3H),2.39(tt,J＝12.5,6.3Hz,1H),2.22(ddd,J＝14.0,12.4,7.0Hz,1H).MS(ESI,m/z):303.76(M+H) +.
实施例37
(S)-3-(苯并呋喃-4-基氧基)-N-甲基-3-(呋喃-3-基)-丙-1-胺(化合物I C-28)
Figure PCTCN2019101197-appb-000065
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(呋喃-3-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例17，得到40毫克无色油状标题化合物，收率是5.08％。
1H NMR(500MHz,CDCl 3)δ7.52(dd,J＝10.8,2.2Hz,1H),7.41(d,J＝0.7Hz,1H),7.35(t,J＝1.7Hz,1H),7.15–7.07(m,2H),6.87(d,J＝2.1Hz,1H),6.70–6.64(m,1H),6.44–6.39(m,1H),5.49(dd,J＝7.6,5.0Hz,1H),2.95(t,J＝7.2Hz,2H),2.53(s,3H),2.42(td,J＝14.3,7.5Hz,1H),2.30–2.23(m,1H).MS(ESI,m/z):271.75(M+H) +.
实施例38
(S)-3-(苯并呋喃-7-基氧基)-N-甲基-3-(噁唑-5-基)丙-1-胺(化合物I C-29)
Figure PCTCN2019101197-appb-000066
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-(噁唑-5-基)丙-1-醇外，其余所需原料、试剂及制备方法同实施例8-9，得到63毫克黄色油状标题化合物，收率是21％。
1H NMR(500MHz,CDCl3)δ7.83(s,1H),7.62(d,J＝2.1Hz,1H),7.23(dd,J＝7.8,0.9Hz,1H),7.08(dd,J＝10.4,5.3Hz,1H),7.03(s,1H),6.87–6.81(m,1H),6.76(d,J＝2.2Hz,1H),5.74(dd,J＝8.0,5.4Hz,1H),3.00–2.87(m,2H),2.53–2.49(m,4H),2.36–2.26(m,1H).MS(ESI,m/z):272.76(M+H) +.
实施例39
(S)-N-(3-(苯并呋喃-7-基氧基)-3-(噻吩-2-基)丙基)乙酰胺(化合物I D)
Figure PCTCN2019101197-appb-000067
将19毫克醋酸，59毫克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，38毫克4-二甲氨基吡啶和52毫克的三乙胺溶于5毫升的无水二氯甲烷溶液中，室温搅拌一小时后，将5毫升溶有70毫克Ic-23的二氯甲烷溶液加入体系中，室温反应过夜。反应结束后，往体系中加入水，用乙酸乙酯萃取三次，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离(甲醇/二氯甲烷＝1:20)，得到标题化合物，18毫克黄色油状物，收率22.29％。
1H NMR(500MHz,CDCl 3)δ7.64(dd,J＝9.8,2.2Hz,1H),7.24(dd,J＝5.0,1.1Hz,1H),7.21(dd,J＝7.8,0.9Hz,1H),7.07–7.02(m,1H),7.01–6.98(m,1H),6.96–6.91(m,1H),6.78(d,J＝2.2Hz,1H),6.75(d,J＝7.9Hz,1H),6.31(s,1H),5.78–5.70(m,1H),3.69–3.59(m,1H),3.55–3.44(m,1H),2.42–2.24(m,2H),1.99(s,3H).MS(ESI,m/z):315.89(M+H) +.
实施例40
((S)-3-(苯并呋喃-7-基氧基)-3-(噻吩-2-基)丙基)-L-脯氨酸甲酯(化合物I E)
Figure PCTCN2019101197-appb-000068
将100毫克中间体II-1，113毫克L-脯氨酸甲酯盐酸盐，283毫克碳酸钾和10毫克碘化钠溶解于5毫升乙腈溶液中，氮气保护条件下于75摄氏度反应过夜。反应结束后，往体系中加入水，用乙酸乙酯萃取三次，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，残余物经柱层析分离(乙酸乙酯/石油醚＝1:5)，得到标题化合物，16毫克无色油状物，收率12.15％。
1H NMR(500MHz,CDCl 3)δ7.62(d,J＝2.1Hz,1H),7.23–7.19(m,1H),7.16(dd,J＝7.0,5.7Hz,1H),7.03(ddd,J＝7.8,6.0,1.5Hz,2H),6.93–6.89(m,1H),6.83(t,J＝8.9Hz,1H),6.74(t,J＝2.1Hz,1H),5.84(dd,J＝15.6,7.6Hz,1H),3.47(s,2H),3.21(s,2H),2.94(d,J＝53.0Hz,1H),2.66(s,1H),2.44(s,2H),2.15(d,J＝49.5Hz,2H),1.95(s,2H),1.83(s,1H).MS(ESI,m/z):386.13(M+H) +.
实施例41
((S)-3-(苯并呋喃-7-基氧基)-3-(噻吩-2-基)丙基)-L-脯氨酸(化合物I F)
Figure PCTCN2019101197-appb-000069
将100毫克化合物I E，50毫克氢氧化钠溶于15毫升水和四氢呋喃混合溶液中，40℃反应过夜。反应结束后，往体系中加入水，用稀盐酸将反应体系调至pH＝7，用乙酸乙酯萃取三次，水洗，饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩得到标题化合物，33.7毫克无色油状物，收率35％。
1H NMR(500MHz,DMSO)δ7.96(d,J＝2.0Hz,1H),7.47(d,J＝4.9Hz,1H),7.19(t,J＝6.1Hz,2H),7.06(td,J＝7.8,2.8Hz,1H),6.94(ddd,J ＝9.9,6.4,2.9Hz,3H),5.98(dd,J＝12.9,7.5Hz,1H),3.45–3.42(m,1H),3.09(ddd,J＝20.6,10.9,5.1Hz,2H),2.92(s,1H),2.82–2.68(m,1H),2.44–2.34(m,1H),2.26–2.08(m,2H),1.94–1.77(m,2H),1.70(dd,J＝18.3,10.6Hz,1H).MS(ESI,m/z):371.94(M+H) +.
对比例1
提供如下式C1化合物的简要制备
Figure PCTCN2019101197-appb-000070
除了将(R)-3-氯-1-(噻吩-2-基)丙-1-醇换成(R)-3-氯-1-苯基丙烷-1-醇外，其余所需原料、试剂及制备方法同实施例18，得到14毫克化合物C1，收率是18％。
1H NMR(400MHz,CDCl 3)δ7.46–7.14(m,5H),6.90(t,J＝7.7Hz,1H),6.77(d,J＝7.4Hz,1H),6.41(d,J＝8.1Hz,1H),5.33(dd,J＝8.0,4.4Hz,1H),3.13(dd,J＝13.5,6.0Hz,2H),2.91(dt,J＝12.3,7.5Hz,4H),2.62(s,3H),2.52–2.36(m,2H),2.13–2.00(m,2H).MS(ESI,m/z):282.20(M+H) +.
实施例42
TRPA1的抑制活性
在本实施例中，测试本发明部分实施例化合物对瞬时受体电位通道蛋白TRPA1的抑制活性。其中，阳性对照化合物采用式A化合物(WO2010075353)：
Figure PCTCN2019101197-appb-000071
式A化合物
方法如下：
通过IonWorks Barracuda(IWB)自动化膜片钳检测的测试方法：稳定表达TRPA1的HEK293细胞，用含有15μg/mL Blasticidin S HCl、200μg/mL Hygromycin B和10％FBS血清的DMEM培养基，置于T175的培养瓶中，放入37℃，5％CO 2的培养箱中培养，待细胞密度生长到～80％时，移走培养液，用无钙镁的磷酸缓冲液(PBS)冲洗一遍，加入3mL的Trypsin消化2分钟，加入7mL培养液终止消化。将细胞收集到15mL的离心管中以800转/每分钟离心3分钟，去除上清液后将细胞加入适当体积的细胞外液重悬，使细胞密度控制在2-3×10 6/mL并用于IWB实验。细胞外液配方(in mM)：140NaCl,5KCl,1MgCl 2,10HEPES,0.5EGTA,10Glucose(pH 7.4)；细胞内液配方(in mM)：140CsCl,10HEPES,5EGTA,0.1CaCl 2,1MgCl 2(pH 7.2)。两性霉素B与实验当天用DMSO新鲜配制成28mg/mL，再用细胞内液配制成0.1mg/mL的终浓度。
IWB实验使用population patch clamp(PPC)板，全部检测过程由仪器自动完成，即在PPC板的384孔中加入细胞外液，并在PPC板下即plenum内加入细胞内液后，加入6L的细胞液进行封接测试，最后将plenum中的细胞内液换成含两性霉素B的细胞内液，使封接的细胞穿孔后形成全细胞记录模式。记录TPRA1电流的采样频率为10kHz，细胞钳制在0mV，电压刺激命令(channel protocol)为一个300ms从-100mV到+100mV的斜坡(ramp)电压，每10s给予此电压刺激，mTRPA1电流由300M AITC诱发。
数据记录和电流幅度测量导出由IWB软件完成(version 2.5.3，Molecular Devices Corporation，Union City，CA)。封接阻抗低于20MΩ的孔将不记录数据统计。原始电流数据由软件进行漏减矫正，TRPA1电流幅度在+100mV时测得。实验的每块PPC板都将有一个HC030031的剂量效应数据作为阳性对照，如HC030031的IC 50值超过以往每块板上得到的IC 50平均值的3倍时，将进行复测。化合物剂量效应曲线和IC 50由GraphPad Prism 5.02(GraphPad Software,San Diego,CA)进行拟合计算。
实验结果
对本发明的部分化合物通过IonWorks Barracuda(IWB)自动化膜片钳检测的测试方法，进行IC 50抑制活性测试，活性数据如表2所示，部分代表性化合物的抑制TRPA1活性的量效关系如图1A-1E所示。
表2.本发明的部分化合物自动化在膜片钳检测测试中对TRPA1的抑制活性数据(IC 50,μM)
Figure PCTCN2019101197-appb-000072
其中活性：IC 50(μM)：
50-100：+
20-50：++
10-20：+++
5-10：++++
1-5：+++++
结果表明，本发明的化合物对TRPA1表现出强效抑制活性，其中有11个化合物对TRPA1的半数有效抑制浓度IC 50在1-10μM之间，从图1A-1E中可以看出，Ic-3、Ic-4、Ic-8、Ic-23、Ic-24化合物对TRPA1的半数有效抑制浓度IC 50<5μM，因此，可以得出本发明式I化合物对TRPA1具有很强的抑制活性。
此外，S构型化合物I C-10和相应R构型化合物(R)-3-(2,3-二氢-1H-茚-4-基)氧基)-N-甲基-3-(2-噻吩基)丙-1-胺，以及S构型I C-23和相应R构型化合物(R)-3-(苯并呋喃-7-基氧基)-3-(噻吩-2-基)丙-1-胺的测试结果表明：R型化合物IC 50与S型化合物的IC 50的比值≥2。这提示，S构型的本发明化合物对TRPA1的抑制活性更高。
此外，化合物I C-10(含有杂芳基
Figure PCTCN2019101197-appb-000073
)和化合物C1(含有苯基)的活性之比(化合物C1的IC 50/化合物I C-10的IC 50)为约2.5倍，这表明，含有杂芳基的本发明化合物(如I C-10)对TRPA1的抑制活性更高。
此外，与A基团为萘环的化合物(如度洛西汀)相比，化合物I C-10(A基团为苯并脂肪环)以及化合物I C-3、化合物I C-23和化合物I C-1(其中A基团均为苯并杂芳基)的IC 50值显著降低。具体地，S型度洛西汀的IC 50与化合物I C-10、化合物I C-3、化合物I C-23或化合物I C-1中任一化合物的IC 50的比值为约2.8～6.8(注：R型度洛西汀的IC 50为48.5μM，S型度洛西汀的IC 50为24.74μM)。这表明，A基团为苯并脂肪环或杂芳基的本发明化合物，对TRPA1的抑制活性更高(提高了约2.8-6.8倍)。
类似地，本发明人还对S型度洛西汀和化合物I C-10，通过手动膜片钳测试法测定了TRPA1抑制活性。与自动膜片钳测试法的测试结果类似，在手动膜片钳测试法中，S型度洛西汀的IC 50与化合物I C-10的IC 50的比值为4.36/1.12＝3.9。
类似地，本发明人还对化合物I C-1，通过手动膜片钳测试法测定了TRPA1抑制活性，测定方法如下：
稳定表达人TRPA1通道的HEK293稳转细胞株，用含有15μg/mL Blasticidin S HCl、200μg/mL Hygromycin B和10％FBS血清的DMEM培养基，置于T75的培养瓶中，放入37℃，5％CO2的培养箱中培养，待细胞密度生长到～80％时，移走培养液，用无钙镁的磷酸缓冲液(PBS)冲洗一遍，加入2mL的Trypsin消化2分钟，加入8mL培养液终止消化。将细胞收集到15mL的离心管中以800转/每分钟离心3分钟，去除上清液后将细胞加入适当体积的细胞外液重悬。
手动膜片钳检测是在室温条件下，采用HEKA系统(Patch Master软件)结合EPC-10放大器记录TRPA1稳转细胞株的全细胞电流。全细胞记录用内液配方(mM)：140CsCl,10HEPES,5EGTA,0.1CaCl2,1MgCl2(pH7.2，渗透压295–300mOsm)；记录用外液采用无Ca2+设置(mM)：140NaCl,5KCl,0.5EGTA,1MgCl2,10Glucose,10HEPES(pH 7.4，渗透压300–310mOsm)。膜片钳记录使用的玻璃微电极电阻2-4MΩ，采样频率10kHz，滤波频率2.9kHz，细胞钳制在0mV，电压刺激命令(channel protocol)为一个300ms从-100mV到+100mV的线性电压，之后恢复至0mV的钳制电位，此记录每2s进行一次，hTRPA1电流由100μM AITC诱发，为确保电流记录的准确，记录时串联电阻进行60％的补偿。
数据记录和电流幅度测量导出由Patch Master软件完成。封接阻抗低于500MΩ的细胞将不纳入数据统计。原始电流数据由软件进行漏减矫正，hTRPA1电流幅度在+100mV时测得。化合物剂量效应曲线和IC50由GraphPad Prism 5.02 (GraphPad Software,San Diego,CA)进行拟合计算。
手动膜片钳测试结果
与自动膜片钳测试法的测试结果类似，在手动膜片钳测试法中，S型度洛西汀的IC 50与化合物I C-1的IC 50的比值为4.36μM/0.43μM＝10.14。
实施例43
细胞毒性试验
在本实施例中，测定I C-10和I C-1化合物的肝细胞毒性和神经细胞毒性实验，方法如下：
准备HepG-2和SH-SY5Y细胞，10cmdish中于37℃，5％CO 2细胞培养箱内培养；胰酶消化重悬细胞并计数，按100μl/孔的体系，8000cells的量将细胞转接至96孔板中。37℃，5％CO 2细胞培养箱内培养24小时；准备化合物梯度浓度体系，2倍稀释，体系为100μl/孔。去掉第一天中96孔板细胞培养体系中的上清，并将新配置好的药物浓度体系对应加入到培养细胞的培养板孔内(设置双复孔)。37℃，5％CO 2细胞培养箱内培养72h。细胞培养结束之后，去掉96孔板细胞培养体系中的上清，每孔加入100μl检测溶液(含10％CCK-8的培养基)，37℃，5％CO 2细胞培养箱内孵育1h，到时取出用酶标仪测定在450nm处的吸光度。进行数据处理，计算细胞毒性，并用GraphPad Prism计算IC50，细胞毒性计算公式如下：细胞毒性(％)＝[A(0加药)-A(加药)]/[A(0加药)-A(空白)]×100
A(加药)：具有细胞、CCK-8溶液和药物溶液的孔的吸光度
A(空白)：具有培养基和CCK-8溶液而没有细胞的孔的吸光度
A(0加药)：具有细胞、CCK-8溶液而没有药物溶液的孔的吸光度
实验结果
I C-10和I C-1化合物的肝细胞毒性(HepG2细胞)和神经细胞(SH-SY5Y)毒性的结果表明：
度洛西汀对肝细胞毒性和神经细胞毒性(IC 50,μM)分别为33μM和28μM，而本发明的I C-1和I C-10化合物对肝细胞毒性和神经细胞毒性(IC 50,μM)为约为60-120μM，这表明，本发明化合物的毒副作用显著更低，化合物仅为度洛西汀毒副作用的约1/2或1/3)。这提示，本发明化合物具有优良的安全性。
实施例44
镇痛活性测试实验
在本实施例中，通过小鼠福尔马林疼痛模型测试本发明的化合物I C-10、化合物的镇痛活性实验，方法如下：
取C57BL/6小鼠(雄性，9周)30只，小鼠随机分为3组：分别为溶剂对照组(vehicle，生理盐水)、度洛西汀组(Duloxetine，5-HT重摄取和NE重摄取抑制剂)和Ic-10组(本发明化合物Ic-10)。实验开始前，让小鼠适应实验环境72h，期间无需禁食禁水。采用腹腔注射方式给予受试药物，剂量为20mg/kg，然后将小鼠置于透明、通气的有机玻璃圆筒内1h后，于各组小鼠左后足底以微量进样器注射4％福尔马林溶液20μl，以微型摄像机实时记录小鼠的足部疼痛反应。以小鼠抬(1分/次)、抖(2分/次)和舔(3分/次)左足的次数以及舔左足的时间长度作为疼痛反应的指标，分别观察记录0-10min(I相，急性疼痛期)和10-60min(II相，炎性疼痛期)两时段内的累积打分和舔足时间，并进行统计学分析。
实验结果
本发明的化合物I C-10在小鼠福尔马林疼痛模型中的镇痛活性结果如图2所示。从结果可知，在添足时间统计检测指标中,在20mg/kg给药剂量下，本发明的化合物I C-10在I相(0-10min)和II相(10-60min)均表现出明确并且强效的镇痛活性，与生理盐水组相比，几乎完全抑制了小鼠由于疼痛导致的添足行为，并且与临床用药度洛西汀镇痛活性相当。
实施例45
小鼠热板痛测试实验
在本实施例中，通过C57小鼠热板致痛模型测试本发明的化合物I C-23、Ic-10、Ic-1等化合物镇痛活性实验，方法如下：
1动物筛选
取SPF级C57雄性小鼠，调节热板温度恒定于55±0.1℃，筛选10-30s内有舔足等疼痛反应的小鼠(对逃避和跳跃者弃之)。发现有疼痛反应立即取出，防止小鼠烫伤。
2动物分组
将筛选到的40只动物进行称重，并将动物随机平均分为4组，分别为生理盐水对照组(空白对照)、度洛西汀组(阳性对照组)、加巴喷丁组(阳性对照组)和Ic-23组(本发明化合物)。
3样品配置
受试化合物于给药当天新鲜配制。配置0.9％NaCl生理盐水溶液作为溶媒备用，将适量的受试化合物加入所需体积的生理盐水中，充分混悬，配制药物浓度为1mg/ml。小鼠的给药体积标准为10ml/kg(即0.1ml/10g)。
4动物给药
腹腔给药，给药前动物无需禁食禁水。给药体积为10ml/kg。度洛西汀和I C-23的给药剂量为10mg/kg,加巴喷丁的给药剂量为100mg/kg。
5热板实验观察
热板观察指标：小鼠在55±0.1℃的热板上的反应时间(Time latency)。给药前3h及给药后15min，30min，60min各测一次并记录。
6.数据统计和分析
使用最大可能镇痛效应％(maximum possible effect，MPE)来评判各化合物的镇痛效应，即MPE％＝[(Post drug latency-baseline latency)/(30-baseline latency)]×100。统计不同时间点的MPE％。MPE％的数值越大，说明化合物的镇痛药效越强。
实验结果
本发明的化合物I C-23在小鼠热板致痛模型中的镇痛活性结果如图3所示。从结果可知，与生理盐水对照组相比，本发明的化合物I C-23在10mg/kg的给药剂量下表现出非常强效的镇痛效果，具有显著性差异。与阳性对照组相比，在60分钟内本发明的化合物I C-23镇痛活性要明显优于100mg/kg的加巴喷丁，并且优于10mg/kg的度洛西汀镇痛效果。
此外，在相同剂量(10mg/kg)下，化合物Ic-10和Ic-1的镇痛活性均优于加巴喷丁和度洛西汀。
热板致痛模型是经典的评价药物急性痛药效的模型，因此本发明的化合物对急性疼痛具有优异的治疗效果。
实施例46
Ic-1药代动力学测试
在本实施例中，测试了度洛西汀和Ic-1等化合物的大鼠药代动力学性质，方法如下：
测试方法：
称取一定量样品溶于去离子水中，配置浓度为1mg/mL的溶液。雄性SD大鼠作为测试动物。单次静脉(IV)注射剂量为2mg/kg，口服(PO)给药剂量为10mg/kg，每组设置三只大鼠。口服组给药前禁食10-14h。给药后4h后恢复给食。动物采血时间点为：静脉，给药前，给药后5，15，30min，1，2，4，6，8h和24h；口服，给药前，给药后15，30min，1，2，4，6，8和24h。每只动物每次经颈静脉采约0.25mL血液，肝素钠抗凝。血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，4℃)。收集的血浆分析前存放于-80℃。取50μL血浆样品至1.5mL离心管中，加入250μL内标溶液(空白组不加内标溶液，补加相同体积的甲醇)，涡旋混匀，14000转/分钟离心5min，取200μL上清液加入到96孔进样板中，LC-MS/MS进样分析。线性回归分析是以峰面积为y轴，以药物浓度为x轴。峰面积比和浓度之间的线性关系用由化合物的回归方程所得的相关系数(R)来表示。根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin7.0非房室模型分别计算受试物的药代动力学参数。
内标工作液：吸取一定量的浓度为490,000ng/mL的甲苯磺丁脲内标储备液至一定体积的容量瓶中，用甲醇定容至刻度后混匀，制得浓度为200ng/mL的内标工作溶液。
实验结果
根据药物各组的平均血药浓度数据，使用药代动力学计算软件WinNonlin7.0非房室模型分别计算化合物各组的药代动力学参数，见表3。
表3 化合物I C-1和度洛西汀主要药代动力学参数
Figure PCTCN2019101197-appb-000074
Figure PCTCN2019101197-appb-000075
从表3可以看出，I C-1以2mg/kg的给药剂量静脉注射后，取样第一个时间点0.083h即至峰浓度(C max,170ng/mL)，消除半衰期(T 1/2)为2.97h，AUC(0-∞)为449h*ng/mL；以5倍剂量(10mg/kg)灌胃口服给药后，3h达到峰浓度(C max，266ng/mL)，消除半衰期(T 1/2)为5.69h，AUC(0-∞)为4016h*ng/mL。以AUC(0-∞)计算，口服生物利用度为179％。
度洛西汀以2mg/kg的给药剂量静脉注射后，0.083h即至峰浓度(C max,177ng/mL)，消除半衰期(T 1/2)为1.77h，AUC(0-∞)为449h*ng/mL；以5倍剂量(10mg/kg)灌胃口服给药后，0.83h达到峰浓度(C max，76ng/mL)，消除半衰期(T 1/2)为1.81h，AUC(0-∞)为222h*ng/mL。以AUC(0-∞)计算，口服生物利用度为9.9％。
由以上结果可以看出，具有式I结构的本发明化合物(如化合物I C-1)相较于度洛西汀具有更优良的药代动力学性质，其半衰期更长，在血浆中暴露量更高，生物利用度更好，适合开发成口服给药，具有良好的成药前景。
实施例47
通过小鼠ICS模型考察化合物Ic-1对肌纤维痛的治疗作用
实验方法
1、实验分组
实验分组为：溶剂对照组、10mg/kg度洛西汀组(阳性对照组)和10mg/kg化合物Ic-1组(实施例9制备化合物)
2、化合物配置
10mg/kg度洛西汀：称取17mg度洛西汀，使用生理盐水溶解并定容至8.5mL，充分溶解后口服灌胃给药，给药体积为5ml/kg。
10mg/kg Ic-1：称取17mg Ic-1，使用生理盐水溶解并定容至8.5mL，充分溶解后口服灌胃给药，给药体积为5ml/kg。
3、动物
取用雄性C57BL/6小鼠，实验开始时体重为18-22克，每笼分配4只小鼠，可自由采食和饮水。每个实验组12只小鼠，采用动物尾部标记法标记实验小鼠。
4、实验方法
4.1建立模型
第0天：下午4:30，将小鼠放入带有不锈钢网的有机玻璃盒里，然后有机玻璃盒放入冷库(温度4±2℃)中过夜。自由采食并用琼脂块代替水。
第1天：早上10:00，将小鼠转移到室温(温度24±2℃)环境下,放置30分钟，之后再转移到冷库中放置30分钟。重复上述步骤直到下午4:30，将小鼠放入冷库中过夜。
第2天：重复第1天的操作。
第3天：上午10:00将小鼠从冷库中转移出来。
4.2给药
化合物按照实验安排的时间口服给药，给药剂量为10mg/kg。
4.3机械痛觉超敏测试
造模后第四天，对动物进行给药前机械痛觉超敏测试，PWT值大于0.5g的动物将被剔除，不用于正式实验。造模后第五天，化合物给药后0.5小时、1小时、2小时，对动物进行机械痛觉超敏测试。
机械痛觉超敏测试方法如下：
将小鼠单独放置在有机玻璃盒中，盒子底部为网格以保证小鼠脚部可以测试。在测试前小鼠将适应15分钟。适应完成后，使用测试纤维在小鼠左后脚脚底中心部位测试。测试纤维包括8个测试强度：2.36(0.02g),2.44(0.04g),2.83(0.07g),3.22(0.16g),3.61(0.4g),3.84(0.6g),4.08(1g),4.17(1.4g)。测试时，将测试纤维垂直压向皮肤并施力使纤维弯曲6-8秒，每次测试间隔5秒。测试时，动物迅速缩脚被记为疼痛反应。测试纤维离开动物皮肤时动物缩脚也被记为疼痛反应。如果动物移动或走动，不记疼痛反应，应重复测试。测试时首先使用3.22(0.16g)，如 果动物有疼痛反应，下一次测试使用力度小一级的测试纤维；如果动物没有疼痛反应，下一次测试使用力度大一级的测试纤维(Chaplan et al.1994)。测试纤维的最大力度为4.17(1.4g)。
测试结果记录在如下的表4中，有疼痛反应记录X，没有疼痛反应记录O。
表4
2.36      
2.44      
2.83      
3.22 O    
3.61 O O O
3.84 X X X
4.08      
4.17      
机械痛觉过敏使用如下公式计算：
50％反应阈值(g)＝(10 (Xf+kδ))/10,000
Xf＝测试中使用的最终测试纤维值
k＝表值(Chaplan et al.1994,page 62)
δ＝平均差
5、数据收集和分析
Figure PCTCN2019101197-appb-000076
化合物Ic-1在小鼠ICS模型中的镇痛活性结果如表5和图4所示。
表5 化合物Ic-1和度洛西汀在小鼠ICS模型中给药后不同时间机械痛觉超敏测试结果(PWT)统计数据
Figure PCTCN2019101197-appb-000077
Figure PCTCN2019101197-appb-000078
从表5和图4中可以看出，本发明的化合物Ic-1在10mg/kg的给药剂量下表现出非常强效的镇痛效果，口服给药1小时和2小时都显示能抑制ICS模型引起的机械痛觉超敏。与阳性对照组相比，化合物Ic-1在0.5h、1h和2h三个测试时间下，镇痛效果全部优于度洛西汀。小鼠ICS模型是经典的评价药物治疗肌纤维痛的药效模型，因此本发明的化合物Ic-1对肌纤维疼痛具有优异的治疗效果。
实施例48
通过小鼠醋酸扭体痛模型考察化合物I C-1对内脏疼痛、炎症疼痛的治疗作用
实验方法
取ICR小鼠，雄性，22-25g，给药前禁食2h，不禁水。对所有ICR小鼠进行称重，并随机分组，每组动物数>10只。阴性对照组为生理盐水组(Vehicle，空白对照)，阳性对照组设置为给药剂量10mg/kg吲哚美辛(一种非甾体类抗炎药)，给药剂量10mg/kg山莨菪碱(一种解痉药，临床上具有镇痛活性)，给药剂量10mg/kg和20mg/kg的度洛西汀。测试化合物为I C-1(实施例9制备的化合物)，给药剂量设置为5mg/kg和10mg/kg。根据小鼠体重通过灌胃的方式给药。给药后1h腹腔注射1.5％醋酸溶液(0.1ml/10g)，并观察之后30min内各组小鼠出现内脏痛的次数，小鼠出现腹部内凹，躯干与后腿伸张，臀部高起记为一次，最终统计30min内出现上述现象的次数。给药后小鼠出现的内脏痛次数越少，说明化合物的镇痛药效越强。
实验结果
小鼠醋酸扭体痛模型测试如图5所示，从图5可以看出，本发明的化合物I C-1(5mg/kg和10mg/kg)单次灌胃给药可显著降低醋酸引起的小鼠扭体反应次数，与生理盐水组(Vehicle，空白对照)(49次)相比具有显著性差异。化合物I C-1在5mg/kg的给药剂量下，小鼠扭体反应次数为20次，低于生理盐对照组的49次的50％，提示化合物I C-1在该模型的半数有效剂量(ED 50)小于5mg/kg。10mg/kg剂量下的化合物I C-1镇痛效果(17次)要优于同剂量下的阳性药吲哚美辛(28次)、山莨菪碱(27次)和度 洛西汀(27次)，并且5mg/kg剂量下化合物I C-1的镇痛效果(20次)与20mg/kg的度洛西汀的镇痛效果相当(21次)。该实验表明，在小鼠醋酸扭体痛模型中，本发明的化合物I C-1的镇痛活性明显优于阳性对照药物。小鼠醋酸扭体痛模型是经典的评价药物治疗内脏疼痛和炎症疼痛的药效模型，因此本发明的化合物I C-1对内脏疼痛和炎症疼痛具有优异的治疗效果。
实施例49
通过大鼠SNL模型考察化合物I C-1对神经疼痛的治疗作用
实验方法
取SD大鼠进行手术，雄性，SPF级，质量150g-180g。手术过程执行无菌操作。使用戊巴比妥钠(50mg/kg,腹腔注射)麻醉动物。对动物腰部手术区域剃毛，使用碘伏和70％乙醇对皮肤消毒三遍。待皮肤干燥后开始手术。使用手术刀在动物腰部荐骨后部开一纵向切口，暴露左侧椎旁肌，使用撑开器分离肌肉组织以暴露脊椎骨。分离左侧脊神经L5和L6，使用6-0丝线结扎，缝合伤口。手术后将动物放置在电热毯上，皮下注射5mL生理盐水以防止脱水。等动物完全苏醒后(可自由活动)将动物放回笼中。
手术后，将动物放在实验环境中适应，15分钟/天，适应3天。给药前一天，对大鼠进行机械痛觉超敏基线测试，将没有表现出机械痛觉超敏的动物(缩脚阈值大于5g)的动物剔除后随机分成1组对照组和2组实验组。
称量动物体重，以给药剂量计，2组实验组分别通过灌胃给予100mg/kg加巴喷丁(加巴喷丁是目前临床上治疗神经痛的一线用药)和10mg/kg化合物I C-1(实施例9制备的化合物)，对照组为口服灌胃等体积的生理盐水。给药后1小时，进行机械痛觉超敏测试。将大鼠单独放置在有机玻璃盒中，盒子底部为网格以保证大鼠脚部可以测试。在测试前大鼠将适应15分钟。适应完成后，使用测试纤维在大鼠左后脚脚底中心部位测试。测试纤维包括8个测试强度：3.61(0.4g)，3.84(0.6g)，4.08(1g)，4.31(2g)，4.56(4g)，4.74(6g)，4.93(8g)，5.18(15g)。测试时，将测试纤维垂直压向皮肤并施力使纤维弯曲6-8秒，每次测试间隔5秒。测试时，动物迅速缩脚被记为疼痛反应。测试纤维离开动物皮肤时动物缩脚也被记为疼痛 反应。如果动物移动或走动，不记疼痛反应，应重复测试。测试时首先使用4.31(2g)，如果动物有疼痛反应，下一次测试使用力度小一级的测试纤维；如果动物没有疼痛反应，下一次测试使用力度大一级的测试纤维)。测试纤维的最大力度为5.18(15g)。
机械痛觉超敏在大鼠行为学测试中表述为缩脚阈值(PWT)，按照如下公式计算：
50％反应阈值(g)＝(10 (Xf+kδ))/10,000
Xf＝测试中使用的最终测试纤维值
k＝表值
δ＝平均差
使用Excel软件收集数据，使用Prism 6.01(Graph pad software,Inc.)软件分析数据。缩脚阈值(PWT)数值越大，说明化合物的镇痛药效越强。
实验结果
大鼠SNL模型中的镇痛活性结果如表6和图6所示。
表6.本发明的化合物I C-1和加巴喷丁在大鼠SNL模型中给药后1小时缩脚阈值(PWT)统计数据
化合物 剂量 PWT(g),
对照组   3.967±0.775
化合物I C-1 10mg/kg 7.869±2.846
加巴喷丁 100mg/kg 6.352±1.897
从表6和图6的结果可知，与生理盐水对照组相比，本发明的化合物I C-1在10mg/kg的给药剂量下表现出非常强效的镇痛效果，具有显著性差异。与阳性对照组相比，在给药后1小时本发明化合物I C-1的镇痛活性与100mg/kg的加巴喷丁镇痛效果相当。大鼠SNL模型是经典的评价药物治疗神经疼痛的药效模型，因此本发明的化合物I C-1对神经疼痛具有优异的治疗效果。
实施例50
通过小鼠福尔马林疼痛模型考察化合物I C-1对急性疼痛、炎症疼痛的治疗作 用实验方法
取C57BL/6小鼠(雄性，9周)100只，小鼠每10只一组，随机分为10组,用于2个化合物在小鼠福尔马林疼痛模型的镇痛活性测试：分别为度洛西汀组和化合物I C-1组(实施例9制备的化合物)。实验开始前，让小鼠适应实验环境72h，期间无需禁食禁水。采用腹腔注射方式给予受试药物，剂量设置分别为：
度洛西汀组：空白Vehicle(空白生理盐水对照)、1mg/kg、5mg/kg、10mg/kg和20mg/kg；
化合物I C-1组：空白Vehicle(空白生理盐水对照，同度洛西汀空白组)、0.1mg/kg、0.5mg/kg、1mg/kg、5mg/kg和10mg/kg。
给药后将小鼠置于透明、通气的有机玻璃圆筒内，1h后于各组小鼠左后足底以微量进样器注射4％福尔马林溶液20μl，以微型摄像机实时记录小鼠的足部疼痛反应。以舔左足的时间长度作为疼痛反应的指标，分别观察记录0-10min(I相)和10-60min(II相)两时段内的舔足时间，进行统计学分析，并计算3个化合物的半数有效剂量(ED 50)：ED 50指的是与空白对照组相比添足时间降低一半的药物剂量。ED 50数值越小，表示化合物的镇痛有效剂量越低，其镇痛效果越好。
实验结果
化合物Ic-1和度洛西汀在小鼠福尔马林模型中不同给药剂量下(10-60min)期添足时间统计结果如表7和图7所示：
表.7化合物Ic-1和度洛西汀在小鼠福尔马林模型中不同给药剂量下在II相(10-60min)期添足时间统计结果
Figure PCTCN2019101197-appb-000079
Figure PCTCN2019101197-appb-000080
从表7和图7中可以看出，本发明的化合物Ic-1在1mg/kg的给药剂量下，其II相(10-60min)添足时间相较于空白Vehicle已经降低超过50％，在II相疼痛的镇痛药效ED 50为2.22mg/kg，而度洛西汀在II相疼痛的ED 50为8.00mg/kg。在同样的给药剂量下，本发明的化合物Ic-1的镇痛活性均显著优于度洛西汀。由以上数据可知，本发明的化合物Ic-1在小鼠福尔马林疼痛模型中表现出极强的镇痛活性。小鼠福尔马林模型是经典的评价药物急性疼痛和炎症疼痛药效的模型，因此本发明的化合物Ic-1对急性疼痛和炎症疼痛具有优异的治疗效果。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (16)

  1. 一种化合物，或其药学上可接受的盐、或其前药的用途，其特征在于，用于(a)制备瞬时受体电位通道蛋白(TRP)抑制剂；(b)制备预防和/或治疗与瞬时受体电位通道蛋白(TRP)相关的疾病的药物；
    其中，所述化合物具有式I结构：
    Figure PCTCN2019101197-appb-100001
    式中：
    A为
    Figure PCTCN2019101197-appb-100002
    基团；其中，环B为取代或未取代的5-7元碳环、取代或未取代的5-7元杂环、取代或未取代的5-7元杂芳基、取代或未取代的C 6-C 12芳基；环D为取代或未取代的5-7元杂芳基、取代或未取代的C 6-C 12芳基；并且当A为取代或未取代的芳香结构时，A含有1-3个选自N、O和S的杂原子；
    其中，所述的杂环或杂芳基含有1-3个选自N、O和S的杂原子；
    R 1和R 2各自独立为氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基、取代或未取代的C 2-C 4酰基、取代或未取代的C 2-C 6酯基，或R 1、R 2和相连的N原子组成取代或未取代的C 3-C 7杂环烷基；其中，所述的杂环烷基含有1-2个N原子以及0-1个O或S原子；
    X为碳原子、氧原子、硫原子或氮原子；
    Y为碳原子或氮原子；
    X和Y中至少一个是为杂原子；
    R 3为氢、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基；
    n为1、2、3、4或5；
    “*”表示手性碳原子，所述手性碳原子绝对构型为S型；
    其中，所述的任一“取代”是指基团上的一个到四个(优选为1、2、3个)氢原子被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、羟基、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤 代烷氧基、苄基、五元或六元的芳基或杂芳基(优选C 6芳基或C 5杂芳基)。
  2. 如权利要求1所述的用途，其特征在于，所述的化合物包括选自下组的一种或多种特征：
    A为取代或未取代的C 6-C 12双环杂芳基、取代或未取代的5-6元杂环并苯基、取代或未取代的5-6元杂环并5-6元杂芳基、或取代或未取代的C 6-C 12苯并脂肪环基；和/或
    R 1和R 2各自独立为氢原子、C 1-C 3烷基、C 2-C 4酰基；或者R 1、R 2和相连的N原子组成羧基或C 2-C 4酯基取代的四氢吡咯基；和/或
    R 3为氢原子、卤素、取代或未取代的C 1-C 3烷基。
  3. 如权利要求1所述的用途，其特征在于，所述的化合物包括选自下组的一种或多种特征：
    A为喹啉基、异喹啉基、邻苯二甲酰亚胺基、苯并呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并噻唑基、喹喔啉基、咪唑并吡啶基、苯并咪唑酮基、茚满基、四氢萘基或二氢萘基；和/或
    R 1和R 2各自独立为氢原子、甲基、乙酰基，或R 1、R 2和N原子组成脯氨酸基或脯氨酸甲酯基；和/或
    R 3为氢原子、氯原子或甲基。
  4. 如权利要求1所述的用途，其特征在于，所述的化合物选自下组：
    Figure PCTCN2019101197-appb-100003
    Figure PCTCN2019101197-appb-100004
  5. 如权利要求1所述的用途，其特征在于，所述的瞬时受体电位通道蛋白(TRP)为TRPA1。
  6. 如权利要求1所述的用途，其特征在于，与瞬时受体电位通道蛋白(TRP)相关的疾病选自下组：疼痛、癫痫、炎症、呼吸障碍、瘙痒、尿路障碍或炎症性肠病。
  7. 如权利要求1所述的用途，其特征在于，所述的疼痛包括急性炎性疼痛、慢性炎性疼痛、内脏痛、神经源性疼痛、肌纤维痛、头痛、神经痛或癌症引起疼痛。
  8. 一种化合物，或其药学上可接受的盐、或其前药，其特征在于，所述化合物具有式I结构：
    Figure PCTCN2019101197-appb-100005
    式中：
    A为
    Figure PCTCN2019101197-appb-100006
    基团；其中，环B为取代或未取代的5-7元碳环、取代或未取代的5-7元杂环、取代或未取代的5-7元杂芳基、取代或未取代的C 6-C 12芳基；环D为取代或未取代的5-7元杂芳基、取代或未取代的C 6-C 12芳基；并且当A为取代或未取代的芳香结构时，A含有1-3个选自N、O和S的杂原子；
    其中，所述的杂环或杂芳基含有1-3个选自N、O和S的杂原子；
    R 1和R 2各自独立为氢、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基、取代或未取代的C 2-C 4酰基、取代或未取代的C 2-C 6酯基，或R 1、R 2和相连的N原子组成取代或未取代的C 3-C 7杂环烷基；其中，所述的杂环烷基含有1-2个N原子以及0-1个O或S原子；
    X为碳原子、氧原子、硫原子或氮原子；
    Y为碳原子或氮原子；
    X和Y中至少一个是为杂原子；
    R 3为氢、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 7环烷基；
    n为1、2、3、4或5；
    “*”表示手性碳原子，所述手性碳原子绝对构型为S型；
    其中，所述的任一“取代”是指基团上的一个到四个(优选为1、2、3个)氢原子被选自下组的取代基所取代：C 1-C 6烷基、C 3-C 7环烷基、C 1-C 3卤代烷基、卤素、硝基、氰基、羟基、C 1-C 4羧基、C 2-C 4酯基、C 2-C 4酰胺基、C 1-C 6烷氧基、C 1-C 6卤代烷氧基、苄基、五元或六元的芳基或杂芳基(优选C 6芳基或C 5杂芳基)。
  9. 如权利要求8所述的化合物，其特征在于，所述的化合物包括选自下组的一种或多种特征：
    A为取代或未取代的C 6-C 12双环杂芳基、取代或未取代的5-6元杂环并苯基、 取代或未取代的5-6元杂环并5-6元杂芳基、或取代或未取代的C 6-C 12苯并脂肪环基；和/或
    R 1和R 2各自独立为氢原子、C 1-C 3烷基、C 2-C 4酰基；或者R 1、R 2和相连的N原子组成羧基或C 2-C 4酯基取代的四氢吡咯基；和/或
    R 3为氢原子、卤素、取代或未取代的C 1-C 3烷基。
  10. 如权利要求8所述的化合物，其特征在于，所述的化合物包括选自下组的一种或多种特征：
    A为喹啉基、异喹啉基、邻苯二甲酰亚胺基、苯并呋喃基、苯并噻吩基、吲哚基、苯并噁唑基、苯并噻唑基、喹喔啉基、咪唑并吡啶基、苯并咪唑酮基、茚满基、四氢萘基或二氢萘基；和/或
    R 1和R 2各自独立为氢原子、甲基、乙酰基，或R 1、R 2和N原子组成脯氨酸基或脯氨酸甲酯基；和/或
    R 3为氢原子、氯原子或甲基。
  11. 如权利要求8所述的化合物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2019101197-appb-100007
    Figure PCTCN2019101197-appb-100008
  12. 一种药物组合物，其特征在于，所述的组合物包括如权利要求8所述的化合物，或其药学上可接受的盐，或其前药；和药学上可接受的载体。
  13. 一种制备如权利要求8所述的化合物，或其药学上可接受的盐，或其前药的方法，其特征在于，所述的方法包括步骤：在惰性溶剂中，将中间体II与R 1-NH-R 2化合物进行反应，形成所述化合物：
    Figure PCTCN2019101197-appb-100009
    其中，X、Y、A、R 1、R 2、R 3和“*”的定义如权利要求8所述。
  14. 一种中间体，其特征在于，所述的中间体如具有式II或式III结构：
    Figure PCTCN2019101197-appb-100010
    其中，X、Y、A、R 3和“*”的定义如权利要求8所述。
  15. 一种体外非治疗性和非诊断性的抑制瞬时受体电位通道蛋白活性的方法，其特征在于，包括步骤：将瞬时受体电位通道蛋白或表达所述蛋白的细胞与权利要求8所述的化合物，或其药学上可接受的盐、或其前药进行接触，从而抑制瞬时受体电位通道蛋白的活性。
  16. 一种抑制瞬时受体电位通道蛋白或预防和/或治疗与瞬时受体电位通道蛋白(TRP)相关的疾病的方法，其特征在于，给需要的对象施用如权利要求8所述的化合物，或其药学上可接受的盐，或其前药。
PCT/CN2019/101197 2018-08-17 2019-08-16 3-芳氧基-3-芳香基-丙胺类化合物及其用途 WO2020035070A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2021532507A JP7283669B2 (ja) 2018-08-17 2019-08-16 ３－アリールオキシ－３－アリール－プロピルアミン化合物およびその用途
EP19849974.1A EP3838900A4 (en) 2018-08-17 2019-08-16 3-ARYLOXY-3-ARYL-PROPYLAMINE COMPOUNDS AND RELATED USES
US17/268,763 US20220119375A1 (en) 2018-08-17 2019-08-16 3-aryloxy-3-aryl-propylamine compound and uses thereof
CN201980053661.1A CN112654616B (zh) 2018-08-17 2019-08-16 3-芳氧基-3-芳香基-丙胺类化合物及其用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810942562.6 2018-08-17
CN201810942562 2018-08-17

Publications (1)

Publication Number Publication Date
WO2020035070A1 true WO2020035070A1 (zh) 2020-02-20

Family

ID=69524687

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/101197 WO2020035070A1 (zh) 2018-08-17 2019-08-16 3-芳氧基-3-芳香基-丙胺类化合物及其用途

Country Status (5)

Country Link
US (1) US20220119375A1 (zh)
EP (1) EP3838900A4 (zh)
JP (1) JP7283669B2 (zh)
CN (1) CN112654616B (zh)
WO (1) WO2020035070A1 (zh)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020228789A1 (zh) * 2019-05-16 2020-11-19 上海璃道医药科技有限公司 3-芳氧基-3-五元杂芳基-丙胺类化合物及其晶型和用途
WO2021160134A1 (zh) * 2020-02-14 2021-08-19 漳州片仔癀药业股份有限公司 3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法及晶型
WO2023016249A1 (zh) * 2021-08-12 2023-02-16 上海璃道医药科技有限公司 3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法
US11603396B2 (en) 2019-05-22 2023-03-14 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11679120B2 (en) 2019-12-04 2023-06-20 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11845950B2 (en) 2018-06-06 2023-12-19 Massachusetts Institute Of Technology Circular RNA for translation in eukaryotic cells

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7272709B2 (ja) * 2018-08-17 2023-05-12 シャンハイ リード ファーマテック カンパニー リミテッド ３－アリールオキシル－３－５員ヘテロアリール－プロピルアミン化合物およびその使用
CN111943943A (zh) * 2019-05-16 2020-11-17 上海璃道医药科技有限公司 3-芳氧基-3-五元杂芳基-丙胺类化合物及其晶型和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094262A1 (en) * 2001-05-18 2002-11-28 Eli Lilly And Company Heteroaryloxy 3-substituted propanamines s serotonin and norepinephrine reuptake inhibitors
WO2010075353A1 (en) 2008-12-22 2010-07-01 Hydra Biosciences, Inc. Compositions useful for treating disorders related to trpa1
CN107625762A (zh) * 2016-07-25 2018-01-26 上海璃道医药科技有限公司 萘环类药物的新用途
CN107840845A (zh) * 2016-09-19 2018-03-27 上海璃道医药科技有限公司 胺类化合物的新用途
WO2018115064A1 (en) * 2016-12-20 2018-06-28 Laboratorios Del Dr. Esteve, S.A. New quinoline and isoquinoline derivatives for treating pain and pain related conditions

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7037932B2 (en) * 2001-05-18 2006-05-02 Eli Lilly And Company Heteroaryloxy 3-substituted propanamines as serotonin and norepinephrine reuptake inhibitors
CN101613347B (zh) 2008-06-23 2012-07-04 中国人民解放军军事医学科学院毒物药物研究所 胺类化合物及其医药用途
CN109758455A (zh) * 2014-09-25 2019-05-17 石药集团中奇制药技术（石家庄）有限公司 胺类化合物的光学异构体治疗疼痛的医药用途
CN105497019A (zh) 2014-09-25 2016-04-20 中国人民解放军军事医学科学院毒物药物研究所 胺类化合物治疗疼痛的医药用途
JP7272709B2 (ja) 2018-08-17 2023-05-12 シャンハイ リード ファーマテック カンパニー リミテッド ３－アリールオキシル－３－５員ヘテロアリール－プロピルアミン化合物およびその使用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094262A1 (en) * 2001-05-18 2002-11-28 Eli Lilly And Company Heteroaryloxy 3-substituted propanamines s serotonin and norepinephrine reuptake inhibitors
WO2010075353A1 (en) 2008-12-22 2010-07-01 Hydra Biosciences, Inc. Compositions useful for treating disorders related to trpa1
CN107625762A (zh) * 2016-07-25 2018-01-26 上海璃道医药科技有限公司 萘环类药物的新用途
CN107840845A (zh) * 2016-09-19 2018-03-27 上海璃道医药科技有限公司 胺类化合物的新用途
WO2018115064A1 (en) * 2016-12-20 2018-06-28 Laboratorios Del Dr. Esteve, S.A. New quinoline and isoquinoline derivatives for treating pain and pain related conditions

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BOOT, J.R.: "Benzothienyloxy phenylpropanamines, novel dual inhibitors of serotonin and norepinephrine reuptake", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, no. 21, 9 September 2004 (2004-09-09), pages 5395 - 5399, XP004580536, DOI: 10.1016/j.bmcl.2004.08.005 *
CASHMAN JOHN R.: "Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 17, no. 19, 20 August 2009 (2009-08-20), pages 6890 - 6897, XP026601536 *
See also references of EP3838900A4

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11845950B2 (en) 2018-06-06 2023-12-19 Massachusetts Institute Of Technology Circular RNA for translation in eukaryotic cells
US11981909B2 (en) 2018-06-06 2024-05-14 Massachusetts Institute Of Technology Circular RNA for translation in eukaryotic cells
WO2020228789A1 (zh) * 2019-05-16 2020-11-19 上海璃道医药科技有限公司 3-芳氧基-3-五元杂芳基-丙胺类化合物及其晶型和用途
JP2022532746A (ja) * 2019-05-16 2022-07-19 シャンハイ リード ファーマテック カンパニー リミテッド ３―アリールオキシル―３―５員ヘテロアリール―プロピルアミン化合物およびその結晶形態ならびに用途
JP7429998B2 (ja) 2019-05-16 2024-02-09 シャンハイ リード ファーマテック カンパニー リミテッド ３―アリールオキシル―３―５員ヘテロアリール―プロピルアミン化合物およびその結晶形態ならびに用途
US11603396B2 (en) 2019-05-22 2023-03-14 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11802144B2 (en) 2019-05-22 2023-10-31 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11679120B2 (en) 2019-12-04 2023-06-20 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11766449B2 (en) 2019-12-04 2023-09-26 Orna Therapeutics, Inc. Circular RNA compositions and methods
US11771715B2 (en) 2019-12-04 2023-10-03 Orna Therapeutics, Inc. Circular RNA compositions and methods
WO2021160134A1 (zh) * 2020-02-14 2021-08-19 漳州片仔癀药业股份有限公司 3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法及晶型
WO2023016249A1 (zh) * 2021-08-12 2023-02-16 上海璃道医药科技有限公司 3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法

Also Published As

Publication number Publication date
JP2021534249A (ja) 2021-12-09
EP3838900A1 (en) 2021-06-23
EP3838900A4 (en) 2021-10-20
CN112654616B (zh) 2024-03-12
US20220119375A1 (en) 2022-04-21
CN112654616A (zh) 2021-04-13
JP7283669B2 (ja) 2023-05-30

Similar Documents

Publication Publication Date Title
WO2020035070A1 (zh) 3-芳氧基-3-芳香基-丙胺类化合物及其用途
CN112566909B (zh) 3-芳氧基-3-五元杂芳基-丙胺类化合物及其用途
KR101991327B1 (ko) 오피오이드 수용체 리간드와 그 용도 및 제조방법
EP1448560B1 (en) 3-SUBSTITUTED OXINDOLE beta 3 AGONISTS
JP4599347B2 (ja) グルカゴンレセプターアンタゴニストとしての置換３−シアノチオフェンアセトアミド
KR20080027352A (ko) 스핑고신 키나제 저해제
CZ20032696A3 (cs) Thiohydantoiny a jejich použití při léčení cukrovky
SI9012429A (en) New chroman and thiochroman derivatives
TW201940486A (zh) 抑制瞬時受體電位a1離子通道
EP3971181A1 (en) 3-aryloxyl-3-five-membered heteroaryl propylamine compound, and crystal form and use thereof
US11834432B2 (en) Substituted amino six-membered nitric heterocyclic ring compound and preparation and use thereof
CA3140231C (en) 3-aryloxyl-3-five-membered heteroaryl-propylamine compound, and crystal form and use thereof
BR112021009921A2 (pt) composição farmacêutica que compreende inibidores de histona desacetilase 6
JP2021523934A (ja) ミトコンドリア脱共役剤として有用なアミノピラジンおよび関連化合物
JP2014514259A (ja) 疼痛および他の障害の処置のための化合物および方法
WO2021160134A1 (zh) 3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法及晶型
WO2022262657A1 (zh) N-取代苯基磺酰胺类化合物及其用途
JP2007262022A (ja) 新規２−チオフェンカルボキサミド誘導体
KR20140120903A (ko) 여포 자극 호르몬수용체의 아고니스트로서 중수소화 티아졸리디논 유사체
CN118234716A (zh) 艾地苯醌衍生物及其在治疗植物中的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19849974

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021532507

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019849974

Country of ref document: EP

Effective date: 20210317