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WO2018130140A1 - Nouveau composé d'urée deutéré - Google Patents

Nouveau composé d'urée deutéré Download PDF

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Publication number
WO2018130140A1
WO2018130140A1 PCT/CN2018/071903 CN2018071903W WO2018130140A1 WO 2018130140 A1 WO2018130140 A1 WO 2018130140A1 CN 2018071903 W CN2018071903 W CN 2018071903W WO 2018130140 A1 WO2018130140 A1 WO 2018130140A1
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WO
WIPO (PCT)
Prior art keywords
compound
present application
reaction
formula
compounds
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Legal status (The legal status 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 status listed.)
Ceased
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PCT/CN2018/071903
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English (en)
Chinese (zh)
Inventor
张寅生
任景
高勇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Original Assignee
Chia Tai Tianqing Pharmaceutical Group Co Ltd
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
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Priority to CN201880006403.3A priority Critical patent/CN110139855B/zh
Publication of WO2018130140A1 publication Critical patent/WO2018130140A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members

Definitions

  • the present application is in the field of medicine, and in particular, the present application relates to novel deuterated urea compounds, a process for the preparation thereof, and pharmaceutical compositions containing these compounds.
  • the present application also relates to the use of these compounds and pharmaceutical compositions comprising these compounds in the manufacture of a medicament for the treatment of pain.
  • Opioids are alkaloids extracted from opioids (poppy) and derivatives in vitro and in vivo that interact with centrally-specific receptors to relieve pain and produce well-being. These drugs often have many serious side effects, such as addiction and respiratory depression. Since the 19th century, humans have been searching for safer and more effective analgesics. Although the natural products of morphine, codeine and semi-synthetic heroin, which were later discovered, have improved somewhat compared with raw opium, there are still many shortcomings.
  • Opioid receptors can be divided into ⁇ , ⁇ , ⁇ , and nociceptive subtypes, and subtype-selective agonists may avoid the side effects of morphine analogs.
  • the fully synthetic opioid receptor agonists methadone, fentanyl, and endogenous opioid peptides have been discovered, it is important to look for analgesics with fewer side effects.
  • PZM-21 This compound is effective in activating the Gi protein, has a good selectivity for the ⁇ OR receptor, and shows only a weak recruitment effect on ⁇ -arrestin. Unlike morphine and other drugs, PZM-21 showed significant analgesic effects in animals, but no side effects such as addiction and respiratory depression were found. Therefore, this compound is a very promising drug candidate in the field of analgesia, and the compound is currently in preclinical studies.
  • ADME absorption, distribution, metabolism, and/or excretion
  • PZM-21 has obvious analgesic effect and less side effects from the current research results, it is necessary to further discover new compounds suitable for drug formation with good curative effect, small side effects and better pharmacokinetic properties. .
  • the application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently Selected from H (hydrogen) or D ( ⁇ );
  • R 8 , R 9 and R 13 are each independently selected from CH 3 , CH 2 D, CHD 2 or CD 3 ;
  • the condition is that the compound of formula (I) contains at least one ruthenium atom.
  • the carbon atom substituted by R 13 may be in the R configuration or the S configuration.
  • R 1 is selected from H.
  • the compound of formula (I) contains from one to twenty ⁇ atoms, or the compound of formula (I) contains one to twenty ruthenium atoms, or the compound of formula (I) contains one to fifteen ruthenium atoms.
  • the compound of formula (I) contains one to fourteen germanium atoms, or the compound of formula (I) contains one to ten germanium atoms, or the compound of formula (I) contains one to nine germanium atoms, or the compound of formula (I) contains one to eight a ruthenium atom, or a compound of formula (I) containing two to eight ruthenium atoms, or a compound of formula (I) containing two to four ruthenium atoms, or a compound of formula (I) containing six to ten ruthenium atoms, or formula (I)
  • the compound contains three to four germanium atoms, or the compound of formula (I) contains one to two germanium atoms, or the compound of formula (I) contains six to eight germanium atoms.
  • the compound of formula (I) contains at least one and two 3, 4, 5, 6, 7, 8, 9, 9, 10, 11, 12, 14 Seventeen, eighteen, nineteen or twenty helium atoms.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 , R 14 , R 15 , R 16 , R 17 At least one, two, three, four, five, six or seven of R 18 and R 19 are deuterium atoms.
  • R 2 and R 3 are the same, R 4 and R 5 are the same, R 6 and R 7 are the same, R 8 and R 9 are the same, R 10 and R 11 are the same, and R 15 and R 16 are the same.
  • R 18 and R 19 are the same, and R 8 , R 9 and R 13 are each independently selected from CH 3 or CD 3 .
  • R 1 , R 4 and R 5 are H.
  • R 1 , R 4 , R 5 and R 17 are H.
  • R 1 , R 4 , R 5 , R 6 , R 7 and R 17 are H.
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 12 and R 17 are H.
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 12 and R 17 are H, and R 8 and R 9 are CH 3 .
  • R 8 and R 9 are the same and R 13 is CH 3 or CD 3 .
  • R 8 and R 9 are the same, and R 13 is different from R 8 and R 9 .
  • R 8 and R 9 are CD 3 and R 13 is CH 3 .
  • R 8 and R 9 are CH 3 and R 13 is CD 3 .
  • R 8 , R 9 , R 13 are the same. In some specific embodiments, R 8 , R 9 , R 13 are both CH 3 or CD 3 .
  • R 2 and R 3 are the same, R 8 and R 9 are the same, R 10 and R 11 are the same, R 15 and R 16 are the same, R 18 and R 19 are the same, and R 1 , R 4 are the same.
  • R 5 , R 6 , R 7 , R 12 and R 17 are H, and R 8 , R 9 and R 13 are each independently selected from CH 3 or CD 3 .
  • R 2 and R 3 are the same, R 8 and R 9 are the same, R 15 and R 16 are the same, and R 18 and R 19 are the same, while R 1 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 , R 12 and R 17 are H, and R 8 , R 9 and R 13 are each independently selected from CH 3 or CD 3 .
  • R 2 and R 3 are the same, R 8 and R 9 are the same, R 10 and R 11 are the same, R 18 and R 19 are the same, and R 1 , R 4 , R 5 , R 6 , R 7 , R 12 , R 15 , R 16 and R 17 are H, and R 8 , R 9 and R 13 are each independently selected from CH 3 or CD 3 .
  • R 8 and R 9 are the same, R 10 and R 11 are the same, R 15 and R 16 are the same, and R 18 and R 19 are the same, while R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 12 and R 17 are H, and R 8 , R 9 and R 13 are each independently selected from CH 3 or CD 3 .
  • R 8 and R 9 are CD 3 .
  • R 10 and R 11 are D.
  • R 2 and R 3 are D.
  • R 18 and R 19 are D.
  • R 14 is D.
  • R 15 and R 16 are D.
  • R 13 is CD 3
  • R 14 , R 15 , R 16 , R 18 and R 19 are D.
  • R 2 , R 3 , R 18 and R 19 are D.
  • R 8 and R 9 are CD 3 and R 18 and R 19 are D.
  • R 8 and R 9 are CD 3 and R 14 is D.
  • R 8 and R 9 are CD 3
  • R 2 , R 3 , R 10 and R 11 are D.
  • R 8 , R 13 and R 9 are CD 3
  • R 14 , R 15 , R 16 , R 18 and R 19 are D.
  • R 10 , R 11 , R 18 and R 19 are D.
  • R 10 , R 11 and R 14 are D.
  • R 13 is CD 3 , R 10 , R 11 , R 14 , R 15 , R 16 , R 18 and R 19 are D.
  • R 2 , R 3 and R 14 are D.
  • R 13 is CD 3
  • R 2 , R 3 , R 14 , R 15 , R 16 , R 18 and R 19 are D.
  • R 2 , R 3 , R 4 and R 5 are D.
  • R 6 and R 7 are D.
  • R 12 is D.
  • R 2 and R 3 are D
  • R 8 and R 9 are CD 3
  • R 10 and R 11 are D.
  • R 17 , R 18 and R 19 are D.
  • R 13 is CD 3
  • R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are D.
  • R 14 , R 15 , R 16 , R 18 and R 19 are D.
  • R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are D.
  • R 8 , R 13 and R 9 are CD 3 .
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 12 and R 17 are H, and R 8 and R 9 are CH 3 ; at the same time, R 2 and R 3 are D.
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 12 and R 17 are H, and R 8 and R 9 are CH 3 ; at the same time, R 10 and R 11 are D.
  • R 1, R 4, R 5, R 6, R 7, R 12 and R 17 is H, and R 8 and R 9 is CH 3; the same time, R 14 is D.
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 12 and R 17 are H, and R 8 and R 9 are CH 3 ; at the same time, R 18 and R 19 are D.
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 12 and R 17 are H, and R 8 and R 9 are CH 3 ; at the same time, R 14 , R 15 , R 16 , R 18 and R 19 are D and R 13 is CD 3 .
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 12 and R 17 are H, and R 8 and R 9 are CH 3 ; at the same time, R 2 and R 3 are D, R 18 and R 19 are D.
  • examples of compounds of formula (I) are as follows:
  • the present application is directed to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, of the present application.
  • the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
  • the present application relates to a method of treating pain in a mammal comprising administering to a mammal in need thereof, preferably a human, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof .
  • the present application relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of pain.
  • the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of pain.
  • the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of pain.
  • the compounds of formula (I) of the present application include specific compounds in one or more assays (eg, ⁇ OR agonistic activity (including selectivity), Gi/o agonistic activity, beta-arrestin recruitment assay, pharmacokinetic assay, liver Excellent properties are exhibited in the measurement of microbial metabolic stability and the like.
  • assays eg, ⁇ OR agonistic activity (including selectivity), Gi/o agonistic activity, beta-arrestin recruitment assay, pharmacokinetic assay, liver Excellent properties are exhibited in the measurement of microbial metabolic stability and the like.
  • assays eg, ⁇ OR agonistic activity (including selectivity), Gi/o agonistic activity, beta-arrestin recruitment assay, pharmacokinetic assay, liver Excellent properties are exhibited in the measurement of microbial metabolic stability and the like.
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the present application in which one or more symptoms of a particular disease, condition, or disorder are described herein.
  • the amount of a compound of the present application which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and severity thereof, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art It is determined by its own knowledge and the present disclosure.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • pharmaceutically acceptable excipient refers to those excipients which have no significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton transfer tautomers include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens.
  • Valence tautomers include recombination through some recombination of bonding electrons.
  • the deuterated atom of each of the specified deuterium atoms of the compound labeled in the present application may be at least 3500 times (52.5%), at least 4000 times (60%), at least 4500 times (67.5%), at least 5000 times. (75%), at least 5500 times (82.5%), at least 6000 times (90%), at least 6333.3 times (95%), at least 6466.7 times (97%), at least 6566.7 times (98.5%), At least 6600 times (99%), at least 6633.3 times (99.5%).
  • any atom not designated as hydrazine is present in its natural isotopic abundance.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the asymmetric carbon atom-containing compounds of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • the daily dose is from 0.01 to 200 mg/kg body weight.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
  • the compound of the formula (I) of the present application can be prepared by a person skilled in the art of organic synthesis (Nature 537 (2016): 185-190), which is prepared by the standard method in the art by the route 1, except that it is in the route.
  • the intermediate fragments involved are selected for the particular purpose of the synthesis, the definition of which is as defined above:
  • the deuterated or non-deuterated intermediate compound of formula II is subjected to a condensation reaction with a deuterated or non-deuterated intermediate compound of formula V under basic conditions to provide a compound of formula (I).
  • the synthesis method of the non-deuterated compound II is as follows: (s)-2-amino-3-phenyl-propionamide (commercially available) is obtained by a reductive amination reaction and a reduction reaction in this order.
  • the synthesis method of the compound of the formula II of the deuterated is: according to the deuteration site, the flexible selection of the first generation and then the reductive amination reaction, the reduction reaction, or the reductive amination reaction, the reduction reaction, or the deuteration, or directly through the deuterium
  • the reagent is prepared by a reductive amination reaction and/or a reduction reaction.
  • the deuterated or non-deuterated V compound is prepared by reacting a deuterated or non-deuterated compound of formula IV with p-nitrophenyl chloroformate.
  • the deuterated or non-deuterated compound IV can be prepared by methods conventional in the art, and those skilled in the art can flexibly select the deuterated reaction step according to the deuterated site.
  • a chiral R configuration or an S configuration V compound when the carbon atom substituted by R 13 is in the R configuration or the S configuration, a chiral R configuration or an S configuration V compound can be directly prepared from the compound of formula II, or The racemic compound of formula V is condensed with a compound of formula II and separated by a chiral preparative column.
  • DCM dichloromethane
  • MeOH is methanol
  • THF is tetrahydrofuran
  • LAH is lithium aluminum hydride
  • MW microwave
  • Trifluoroacetic anhydride (1.5 g, 7.41 mmol) was added to a microwave reaction flask, and heavy water (15 ml) was slowly added dropwise thereto in an ice water bath; Compound II-1 (0.8, 2.99 mmol) was added to the above reaction mixture.
  • the heavy aqueous solution was removed by rotary evaporation, and the same amount of trifluoroacetic anhydride and heavy water were added thereto, and exchanged again under the same reaction conditions.
  • the solvent was evaporated to dryness, and then acetone was added to be pulverized, and finally dried under reduced pressure to give Compound II-4 (0.654 g).
  • Example 5 Preparation of 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl)propane -2-yl-2-d)urea (compound (S)-5) and 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-( (R)-1-(thiophen-3-yl)propan-2-yl-2-d)urea (compound (R)-5)
  • Example 6 Preparation of 1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl-2) , 5-d 2 )propan-2-yl-1,1,2,3,3,3-d 6 )urea (compound (S)-6) and 1-((S)-2-(dimethylamino) --3-(4-hydroxyphenyl)propyl)-3-((R)-1-(thiophen-3-yl-2,5-d 2 )propan-2-yl-1,1,2, 3,3,3-d 6 )urea (compound (R)-6)
  • Phosphorus pentoxide 150 mg, 1.07 mmol was placed in a 35 ml microwave tube, and under ice bath, heavy water (22.0 g, 1.10 mol) was slowly added. The ice bath was removed and stirred at room temperature for 0.5 hours. To the solution was added 1-thiophen-3-yl-propan-2-one (1.50 g, 10.70 mol), MW, 150 ° C, and reacted for 2 hours. The same reaction was carried out in a total of three microwave tubes. The reaction mixture was combined and diluted with ethyl acetate. The mixture was evaporated and evaporated. Subsequent second and third deuteration exchanges were repeated and the first operation was repeated and purified by column chromatography to give intermediate d7-1-thiophen-3-yl-propan-2-one as a brown oil 3.15 g.
  • Examples 8-15 were isolated by high pressure preparation according to the synthesis procedures in Example 7 according to the intermediates II-2 ⁇ 3 ⁇ 4 and V-2 ⁇ 3 ⁇ 4.
  • 300 ⁇ L of the final incubation system containing 30 ⁇ L of human liver microsomes (protein concentration: 5 mg/mL, BD, USA), 30 ⁇ L of NADPH (10 mM) + MgCl 2 (5 mM), 3 ⁇ L of the substrate as the example compound (50% aqueous acetonitrile solution) Dissolved, 100 ⁇ M), 237 ⁇ L of PBS buffer in which the ratio of organic solvent (acetonitrile) was 0.5%.
  • Each tube was first prepared with a total volume of 270 ⁇ L of substrate and enzyme mixture. After pre-incubation at 37 °C for 5 min, add 30 ⁇ L of NADPH+MgCl 2 and remove 50 ⁇ L of diazepam with internal standard at 0 and 60 min. The reaction was stopped by ice acetonitrile (20 ng/mL) 300 ⁇ L.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
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  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau composé d'urée deutéré représenté par la formule (I), des sels pharmacologiquement acceptables de celui-ci, son procédé de préparation et une composition pharmaceutique contenant le composé. L'invention concerne également l'utilisation des composés et de la composition pharmaceutique contenant les composés dans la préparation de médicaments pour le traitement de la douleur.
PCT/CN2018/071903 2017-01-13 2018-01-09 Nouveau composé d'urée deutéré Ceased WO2018130140A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880006403.3A CN110139855B (zh) 2017-01-13 2018-01-09 新型的氘代脲类化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710024735 2017-01-13
CN201710024735.1 2017-01-13

Publications (1)

Publication Number Publication Date
WO2018130140A1 true WO2018130140A1 (fr) 2018-07-19

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017007695A1 (fr) * 2015-07-09 2017-01-12 The Regents Of The University Of California Modulateurs du récepteur opioïde de type mu

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017007695A1 (fr) * 2015-07-09 2017-01-12 The Regents Of The University Of California Modulateurs du récepteur opioïde de type mu

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KIEFFER BRIGITTE L: "Drug Discovery Designing the ideal opioid", NATURE, vol. 537, no. 7619, 17 August 2016 (2016-08-17), pages 170 - 171, XP055507976, Retrieved from the Internet <URL:doi:10.1038/nature19424> *
MANGLIK AASHISH: "Structure-based discovery of opioid analgesics with re- duced side effects", NATURE, vol. 537, no. 7619, 8 September 2016 (2016-09-08), pages 185 - 190, XP055507978, Retrieved from the Internet <URL:DOI:10.1038/nature19112> *
vol. 29, no. 11, 31 December 2010 (2010-12-31), pages 682 - 684 *

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CN110139855A (zh) 2019-08-16
CN110139855B (zh) 2021-11-19

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