WO2022007875A1 - Nouvelle utilisation d'un composé - Google Patents
Nouvelle utilisation d'un composé Download PDFInfo
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- WO2022007875A1 WO2022007875A1 PCT/CN2021/105137 CN2021105137W WO2022007875A1 WO 2022007875 A1 WO2022007875 A1 WO 2022007875A1 CN 2021105137 W CN2021105137 W CN 2021105137W WO 2022007875 A1 WO2022007875 A1 WO 2022007875A1
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- optionally substituted
- alkyl
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- 0 *c1cc(*)c(C2*C2)c(*)c1 Chemical compound *c1cc(*)c(C2*C2)c(*)c1 0.000 description 7
- FPTUCCXFFWYEOU-UHFFFAOYSA-N Cc(c(Cl)c1)ncc1Cl Chemical compound Cc(c(Cl)c1)ncc1Cl FPTUCCXFFWYEOU-UHFFFAOYSA-N 0.000 description 1
- YJSHWTREZKRDEI-UHFFFAOYSA-N Cc(c(Cl)cc(C(F)(F)F)c1)c1Cl Chemical compound Cc(c(Cl)cc(C(F)(F)F)c1)c1Cl YJSHWTREZKRDEI-UHFFFAOYSA-N 0.000 description 1
- RCTKUIOMKBEGTG-UHFFFAOYSA-N Cc(c(Cl)cc(Cl)c1)c1Cl Chemical compound Cc(c(Cl)cc(Cl)c1)c1Cl RCTKUIOMKBEGTG-UHFFFAOYSA-N 0.000 description 1
- LRQPEHJWTXCLQY-UHFFFAOYSA-N Cc(c(F)c1F)ccc1F Chemical compound Cc(c(F)c1F)ccc1F LRQPEHJWTXCLQY-UHFFFAOYSA-N 0.000 description 1
- YSEYOMUPVMGJPP-UHFFFAOYSA-N Cc(nccc1)c1Cl Chemical compound Cc(nccc1)c1Cl YSEYOMUPVMGJPP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
- C07D231/40—Acylated on said nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- 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
Definitions
- the invention belongs to the field of medicine, and specifically relates to a new use of a class of compounds.
- it relates to the compounds of formula I of the present application or their pharmaceutically acceptable salts, stereoisomers, active metabolites, prodrugs, crystals or solvates or their compositions in the treatment of diseases associated with mutations in the fish nicotine receptor the use of.
- Fish nicotine receptors are a class of calcium ligand-gated channels present in the sarcoplasmic reticulum or endoplasmic reticulum, which control the release of intracellular calcium ions and play a key role in the excitation-contraction coupling of muscles effect.
- fish nicotine receptors can be divided into three categories: RyR1, RyR2 and RyR3.
- RyR1 is mainly distributed in skeletal muscle
- RyR2 is mainly distributed in cardiac muscle
- RyR3 is mainly distributed in smooth muscle.
- RyR mutations affect the opening function of calcium ion channels, thereby affecting the content of calcium ions in the cytoplasm. Decreased calcium ion concentration in the cytoplasm can lead to, for example, muscle weakness, muscle weakness, and cardiac arrhythmias.
- RyR2 mutations cause a variety of muscle diseases, such as catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia (ARVD), and sudden cardiac death, See, eg, Jim W. Cheung et al., "Short-Coupled Polymorphic Ventricular Tachycardia At Rest Linked to a Novel Ryanodine Receptor (RyR2) Mutation: Leaky RyR2 Channels Under Non-Stress Conditions", Int J Cardiol, 2015 February 1;180: 228–236. Yingjie Liu et al., “CPVT-associated cardiac ryanodine receptor mutation G357S with reduced penetrance impairs Ca 2+ release termination and diminishes protein expression”, PLOS ONE, September 29, 2017.
- CPVT catecholaminergic polymorphic ventricular tachycardia
- ARVD arrhythmogenic right ventricular dysplasia
- sudden cardiac death See, eg, Jim W. Che
- the application provides a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate thereof, or a composition thereof, in the manufacture of a compound for the treatment of fish nicotine Use in medicine for somatic mutation-related diseases,
- Ring A and Ring B are each independently aromatic or heteroaromatic;
- L 1 is -N(R 4 )C(O)- or -N(R 4 )C(O)C(O)N(R 4 )-;
- R 1 is selected from -C(O)NR'R", -N(R')C(O)R 6 , optionally substituted alkenyl and optionally substituted aryl;
- Each R 0 is independently selected from hydrogen, halogen, -CN, and optionally substituted alkyl;
- R 4 is hydrogen or alkyl
- Each R 5 is independently selected from hydrogen, halogen, -CN, optionally substituted alkyl and optionally substituted alkoxy;
- each R is independently selected from hydrogen, halogen, and optionally substituted alkyl
- R' and R" are each independently selected from: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, and optionally substituted amino;
- R 6 is selected from optionally substituted alkoxy and optionally substituted alkyl
- x and y are each independently an integer selected from 1, 2, 3 and 4.
- the present application provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate thereof, or a composition thereof, for use in the treatment of fish nicotine infection.
- a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate thereof, or a composition thereof, for use in the treatment of fish nicotine infection.
- the present application provides a method for treating a disease associated with a mutation of the fish nitin receptor, comprising:
- a therapeutically effective amount of a compound of formula I described herein, or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate, or a combination thereof, is administered to an individual in need thereof.
- the present application provides a compound of formula I described in the present application, or a pharmaceutically acceptable salt, stereoisomer, active metabolite thereof, for use in the treatment of diseases associated with fish nicotine receptor mutations , prodrugs, crystals or solvates or combinations thereof.
- Figure 1 is a saturation binding experiment to analyze the maximum number of binding sites for fish nicotine receptor 1.
- Figure 2 is a calcium ion-dependent binding experiment of [ 3 H]onidine with RyR1-R4825C and RyR1-R4861C mutations.
- 3A-3B show the fluorescence changes induced in the determination of calcium ion concentration in the endoplasmic reticulum by the positive control caffeine and an exemplary compound of the present application.
- Cmn as used herein means that the moiety has an integer number of carbon atoms in the given range.
- C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
- membered refers to the number of skeletal atoms that make up the ring.
- “5-20 members” means that the number of skeleton atoms constituting the ring is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 .
- an ethyl group “optionally” substituted with one or more fluorine or chlorine means ethyl may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F, CHClCH 3 ), multiple substituted (e.g. CHFCH 2 F, CHClCHF 2, CH 2 CHF 2 , etc.) or completely substituted (CCl 2 CF 3, CF 2 CF 3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
- any variable eg, R
- its definition in each case is independent. So, for example, if a group is substituted with 2 Rs, each R has independent options.
- halo by themselves or as part of another substituent represent a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.
- hydroxy refers to the -OH group.
- amino refers to -NH 2.
- aminoacyl refers to -CO-NH 2.
- Optionally substituted aminoacyl means that the amino moiety of the aminoacyl group is substituted or unsubstituted, and when substituted, can form a mono- or disubstituted aminoacyl group.
- alkyl refers to a formula C n H 2n + 1 is a saturated hydrocarbon.
- the alkyl group can be straight or branched.
- C1-6 alkyl refers to an alkyl group (eg, methyl, ethyl, n-propyl, isopropyl) containing 1 to 6 (eg, 1, 2, 3, 4, 5, or 6) carbon atoms propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
- alkoxy refers to -O-alkyl, wherein alkyl is as defined above.
- cycloalkyl refers to a fully saturated non-aromatic ring composed of carbon and hydrogen atoms.
- the cycloalkyl group may be a monocyclic, fused polycyclic, bridged or spirocyclic structure, preferably containing 1 or 2 rings.
- Non-limiting examples of cycloalkyl include, but are not limited to, 3-20 membered cycloalkyl, 3-18 membered cycloalkyl, 3-15 membered cycloalkyl, 3-12 membered cycloalkyl, 3-10 membered cycloalkane cycloalkyl, 3-8 membered cycloalkyl, 3-7 membered cycloalkyl, 3-6 membered cycloalkyl, 3-5 membered cycloalkyl, etc., such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, spiro[3.3]heptyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, bicyclo[1.1.1]pentan-1- Base et al.
- alkenyl refers to a straight or branched chain hydrocarbon group having at least one site of unsaturation, i.e. a carbon-carbon double bond, such as C2-12 alkenyl, C2-10 alkenyl, C2-6 alkenyl, etc.
- alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
- ester group refers to a group having -C (O) 8 structures OR, wherein R 8 is as defined above, optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.
- R 8 is alkyl, haloalkyl, aryl, heteroaryl, alkaryl, alkylheteroaryl.
- R 8 is alkyl or haloalkyl.
- R 8 is alkyl, such as C 1-6 alkyl.
- Optionally substituted ester group refers to the group R 8 is a substituted or unsubstituted moiety is unsubstituted.
- aryl refers to an aromatic ring or an aromatic or partially aromatic ring system composed of carbon atoms and hydrogen atoms. It may be a single ring or may be polycyclic (2 or more rings such as bicyclic) fused together or covalently linked.
- aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetralin, and the like.
- Heteroaryl or “heteroaromatic ring” means containing at least one (eg 1 to 5, eg 1, 2, 3, 4 or 5) ring atoms selected from N, O and S, the remaining ring atoms is a monocyclic or fused polycyclic ring system having at least one aromatic ring.
- Heteroaryl groups can have 4-8 membered monocyclic rings (eg, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered monocyclic rings), or can have 6-14 ring atoms (eg, 6-membered rings, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring and 14-membered ring).
- 4-8 membered monocyclic rings eg, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered monocyclic rings
- 6-14 ring atoms eg, 6-membered rings, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring and
- heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, iso Quinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl and the like.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of sound medical judgment, suitable for use in contact with human and animal tissue without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
- the diastereoisomers were resolved and the pure enantiomers recovered.
- separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- solvate refers to a solvate formed by combining a compound of the present application with solvent molecules.
- the solvate is a monohydrate, eg, the solvent is water, and the compound of the present application forms a monohydrate with water.
- the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, including individual polymorphs thereof or mixtures of multiple polymorphs in any ratio.
- polymorph means that a compound of the present application exists in different crystal lattice forms.
- prodrug includes acid derivatives or alcohol derivatives, and the like, as known to practitioners in the art.
- the acid derivatives are, for example, esters prepared by the reaction of the parent acid with a suitable alcohol, or amides, acid anhydrides, or mixed acid anhydrides prepared by the reaction of the parent acid and a substituted or unsubstituted amine;
- the alcohol derivatives are, for example, selected from Alcohol esters, alcohol alkoxylates, alcohol ethers, carboxylic acids, carboxylic acid esters, phosphates and mixtures thereof, etc.
- Simple aliphatic or aromatic esters, amides and anhydrides and phosphates on hydroxyl groups resulting from acidic groups pendant on the compounds of the present invention are specific prodrugs.
- active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
- the term "individual” includes humans and animals, eg, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and birds, etc.).
- mammals eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and birds, etc.
- treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
- an effective amount or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
- the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
- RyR1-R4825C mutation and “RyR1-R4861C mutation” include human RyR1-R4825C mutation and RyR1-R4861C mutation as well as other animal species (eg, mammals (eg, primates, cows, horses, pigs, dogs, Mutations of corresponding sequences in cats, mice, rats, rabbits, goats, sheep and birds, etc.)), such as mutations of the corresponding sequences in rabbits rRyR1-R4824C mutation and rRyR1-R4860C mutation.
- mammals eg, primates, cows, horses, pigs, dogs, Mutations of corresponding sequences in cats, mice, rats, rabbits, goats, sheep and birds, etc.
- composition refers to a mixture comprising one or more compounds of the present application, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
- pharmaceutical composition refers to a mixture comprising one or more compounds of the present application, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
- the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
- pharmaceutically acceptable excipients refers to those excipients which are not significantly irritating to 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.
- the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, lozenges, ointments, emulsions, suspensions, solutions, syrups, pastes, suppositories, injections, inhalants, gels, microspheres and aerosols.
- suitable pharmaceutically acceptable excipients for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, lozenges, ointments, emulsions, suspensions, solutions, syrups, pastes, suppositories, injections, inhalants, gels, microspheres and aerosols.
- Typical routes for administering 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, transdermal, intravenous administration.
- the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
- the pharmaceutical composition is in oral form.
- the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, emulsions, suspensions, etc., for oral administration to patients.
- Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or icing core.
- Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
- compositions for oral administration can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules, if desired, with the addition of suitable auxiliaries Tablets or dragee cores are then obtained.
- suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulosic preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, Methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
- disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or alginates such as sodium alginate can be added.
- Dragee cores are suitably coated.
- concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, shellac solution and suitable organic solvents or solvent mixture.
- Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. These formulations can be manufactured using methods well known in the art.
- compositions of the present application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
- the daily dose administered is 0.01 mg/kg body weight to 300 mg/kg body weight, eg, 10 mg/kg body weight to 300 mg/kg body weight, 25 mg /kg body weight to 200 mg/kg body weight, administered in single or divided doses.
- the application provides a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate thereof, or a composition thereof, in the manufacture of a compound for the treatment of fish nicotine Use in medicine for somatic mutation-related diseases,
- Ring A and Ring B are each independently aromatic or heteroaromatic;
- L 1 is -N(R 4 )C(O)- or -N(R 4 )C(O)C(O)N(R 4 )-;
- R 1 is selected from -C(O)NR'R", -N(R')C(O)R 6 , optionally substituted alkenyl and optionally substituted aryl;
- Each R 0 is independently selected from hydrogen, halogen, -CN, and optionally substituted alkyl;
- R 4 is hydrogen or alkyl
- Each R 5 is independently selected from hydrogen, halogen, -CN, optionally substituted alkyl and optionally substituted alkoxy;
- each R is independently selected from hydrogen, halogen, and optionally substituted alkyl
- R' and R" are each independently selected from: hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, and optionally substituted amino;
- R 6 is selected from optionally substituted alkoxy and optionally substituted alkyl
- x and y are each independently an integer selected from 1, 2, 3 and 4.
- Ring A and Ring B are each independently a 6-20 membered aromatic ring or a 5-20 membered heteroaromatic ring.
- Ring A and Ring B are each independently a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring.
- Ring A and Ring B are each independently a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring.
- Ring A is a benzene ring or a pyrazole ring.
- Ring B is a benzene ring or a pyridine ring.
- heteroaromatic ring has 1 to 5 heteroatoms independently selected from N, O, and S.
- R 1 is selected from: -C(O)NR'R", -N(R')C(O)R 6 independently selected from CN, ester groups, and optionally substituted aminoacyl groups alkenyl optionally substituted with one or more substituents of , and aryl optionally substituted with halogen.
- R 1 is selected from: -C(O)NR'R", -N(R')C(O)R 6 independently selected from CN, ester, and optionally substituted with amino Alkenyl optionally substituted with one or more substituents of aminoacyl, and aryl optionally substituted with halogen.
- R 1 is selected from: -C(O)NR'R", -N(R')C(O)R 6 independently selected from CN, ester, and optionally substituted with amino C 2-6 alkenyl optionally substituted with one or more substituents of aminoacyl , and C 6-20 aryl optionally substituted with halogen.
- R 1 is selected from: -C(O)NR'R", -N(R')C(O)R 6 independently selected from CN, ester, and optionally substituted with amino C2-6 alkenyl optionally substituted with one or more substituents of aminoacyl , and C6-15 aryl optionally substituted with halogen.
- R 1 is selected from: -C(O)NR'R", -N(R')C(O)R 6 independently selected from CN, ester, and optionally substituted with amino C2-6 alkenyl optionally substituted with one or more substituents of aminoacyl , and C6-10 aryl optionally substituted with halogen.
- R 1 is selected from: -C(O)NR'R", -N(R')C(O)R 6 independently selected from CN, -CO 2 C 2 H 5 and - CONHNH 2 or more of a substituent group is optionally substituted C 2-6 alkenyl group, optionally substituted by halogen, and phenyl;
- R 1 is selected from: -C(O)NR'R", -N(R')C(O)R 6 independently selected from CN, -CO 2 C 2 H 5 and - One or more substituents of CONHNH 2 are optionally substituted vinyl, and 2,4-dichlorophenyl.
- each R 0 is each independently selected from hydrogen, halogen, -CN, and optionally substituted C 1-6 alkyl.
- each R 0 is each independently selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl.
- each R 0 is each independently selected from hydrogen, Cl, Br, -CN and methyl.
- R 1 is located ortho to L 1 .
- the building blocks selected from Wherein R 2 is selected from halo and -CN, R 3 is selected from halogen and optionally substituted alkyl.
- the building blocks selected from Wherein R 1 is selected an optionally substituted aryl group.
- R 1 is selected from C 6-20 aryl optionally substituted with halogen.
- R 1 is selected from C 6-15 aryl optionally substituted with halogen.
- R 1 is selected from C 6-10 aryl optionally substituted with halogen.
- R 1 is selected from phenyl optionally substituted with halogen.
- R 1 is selected from 2,4-dichlorophenyl.
- each R 5 is each independently selected from hydrogen, halogen, -CN, alkyl optionally substituted with halogen, and alkoxy optionally substituted with halogen.
- each R 5 is each independently selected from hydrogen, halogen, -CN, C 1-6 alkyl optionally substituted with halogen, and C 1-6 alkoxy optionally substituted with halogen.
- each R 5 is each independently selected from hydrogen, halogen, -CN, C 1-4 alkyl optionally substituted with halogen, and C 1-4 alkoxy optionally substituted with halogen.
- each R 5 is independently selected from hydrogen, Cl, Br, -CN, -CF 3 , and -OCH 2 CF 3.
- each R is independently selected from hydrogen, halogen, and alkyl optionally substituted with halogen.
- each R is independently selected from hydrogen, halogen, and C 1-6 alkyl optionally substituted with halogen.
- each R is independently selected from hydrogen, halogen, and C 1-4 alkyl optionally substituted with halogen.
- each R is independently selected from hydrogen, F, Cl, and CF 3.
- At least one R is not hydrogen.
- At least one R is selected from halogen.
- R 4 is hydrogen or C 1-6 alkyl.
- R 4 is hydrogen or C 1-4 alkyl.
- R 4 is hydrogen or C 1-2 alkyl.
- R 4 is hydrogen
- R' and R" are each independently selected from: hydrogen, alkyl optionally substituted with substituents selected from cycloalkyl, aryl, hydroxy, and ester, optionally substituted cycloalkyl , an alkenyl group optionally substituted by an ester group, an aryl group optionally substituted by an alkyl group, and an amino group optionally substituted by -C(O)C(O)OR 7 ; wherein R 7 is an alkyl group.
- R' and R" are each independently selected from: hydrogen, C 1 optionally substituted with a substituent selected from 3-20 membered cycloalkyl, C 6-20 aryl, hydroxy, and ester -6 alkyl, optionally substituted 3-20 membered cycloalkyl, C2-6 alkenyl optionally substituted by ester group, C6-20 aryl optionally substituted by C1-6 alkyl, and Amino optionally substituted by -C(O)C(O)OR 7 ; wherein R 7 is C 1-6 alkyl.
- R' and R" are each independently selected from: hydrogen, C 1 optionally substituted with a substituent selected from 3-10 membered cycloalkyl, C 6-15 aryl, hydroxy, and ester -6 alkyl, optionally substituted 3-10 membered cycloalkyl, C2-6 alkenyl optionally substituted by ester group, C6-15 aryl optionally substituted by C1-6 alkyl, and Amino optionally substituted by -C(O)C(O)OR 7 ; wherein R 7 is C 1-6 alkyl.
- R' and R" are each independently selected from: hydrogen, C 1 optionally substituted with substituents selected from 3-7 membered cycloalkyl, C 6-10 aryl, hydroxy, and ester -4 alkyl, optionally substituted 3-7 membered cycloalkyl, C2-4 alkenyl optionally substituted by ester group, C6-10 aryl optionally substituted by C1-4 alkyl, and Amino optionally substituted by -C(O)C(O)OR 7 ; wherein R 7 is C 1-4 alkyl.
- At least one of R' and R" is not hydrogen.
- one of R' and R" is hydrogen, and the other is selected from the group consisting of substituted with 3-7 membered cycloalkyl, C6-10 aryl, hydroxy, and ester optionally substituted C 1-4 alkyl, optionally substituted 3-7 membered cycloalkyl, C 2-4 alkenyl optionally substituted by ester group, C optionally substituted by C 1-4 alkyl 6-10 aryl, and amino optionally substituted by -C(O)C(O)OR 7 ; wherein R 7 is C 1-4 alkyl.
- R 6 is selected from: optionally substituted alkoxy, and optionally substituted alkyl with substituents selected from halogen and optionally substituted amino.
- R 6 is selected from: optionally substituted alkoxy, and alkyl optionally substituted with substituents selected from halogen and amino optionally substituted with alkyl.
- R 6 is selected from: optionally substituted C 1-6 alkoxy group, and a substituted selected from halogen and C 1-6 alkyl substituted optionally substituted amino group optionally substituted C 1 -6 alkyl.
- R 6 is selected from: optionally substituted C 1-4 alkoxy substituted and selected from F, Cl, and methyl optionally substituted amino group is optionally substituted C 1-4 alkyl.
- R 6 is selected from methoxy, ethoxy, -CH 2 Cl, -CCl 3 , -CF 3 and -CH 2 NHCH 3 .
- the compound of Formula I, or a pharmaceutically acceptable salt thereof is a compound of Formula Ia or Formula Ib, or a pharmaceutically acceptable salt thereof:
- Ring A is an aromatic ring, and Ring B is a heteroaromatic ring;
- Ring A is a 6-20 membered aromatic ring, a 6-15 membered aromatic ring, or a 6-10 membered aromatic ring;
- Ring B is a 5-20 membered heteroaromatic ring, a 5-15 membered heteroaromatic ring, or a 5-10 membered heteroaromatic ring;
- Ring A is a benzene ring
- Ring B is a pyridine ring
- R 1 is positioned ortho to -N(R 4 )C(O)-;
- R 4 is hydrogen
- each R is independently selected from hydrogen and halogen
- each R is independently selected from hydrogen and Cl;
- At least one R is not hydrogen
- At least one R is selected from halogen
- each R 5 is each independently selected from hydrogen, halogen, alkyl optionally substituted with halogen, and alkoxy optionally substituted with halogen;
- each R 5 is each independently selected from hydrogen, halogen, C 1-6 alkyl optionally substituted with halogen, and C 1-6 alkoxy optionally substituted with halogen;
- each R 5 is each independently selected from hydrogen, halogen, C 1-4 alkyl optionally substituted with halogen, and C 1-4 alkoxy optionally substituted with halogen;
- each R 5 is each independently selected from hydrogen, Cl, Br, -CF 3 and -OCH 2 CF 3 ;
- Ring A and Ring B are each independently selected from aromatic rings;
- Ring A and Ring B are each independently a 6-20 membered aromatic ring, a 6-15 membered aromatic ring, or a 6-10 membered aromatic ring;
- Ring A and Ring B are benzene rings
- each R 0 is independently selected from hydrogen, halo, and optionally substituted alkyl
- each R 0 is each independently selected from hydrogen, halogen, and optionally substituted C 1-6 alkyl;
- each R 0 is each independently selected from hydrogen, halogen, and optionally substituted C 1-4 alkyl;
- each R 0 is independently selected from hydrogen, Cl, and methyl.
- R 1 is positioned ortho to -N(R 4 )C(O)C(O)N(R 4 )-;
- R 1 is selected from -C(O)NR'R";
- R' and R" are each independently selected from: hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl;
- R' and R" are each independently selected from: hydrogen, optionally substituted C 1-6 alkyl, and optionally substituted 3-20 membered cycloalkyl;
- R' and R" are each independently selected from: hydrogen, optionally substituted C 1-6 alkyl, and optionally substituted 3-10 membered cycloalkyl;
- R' and R" are each independently selected from: hydrogen, optionally substituted C 1-4 alkyl, and optionally substituted 3-7 membered cycloalkyl;
- At least one of R' and R" is not hydrogen
- one of R' and R" is hydrogen, and the other is selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl;
- R 4 is hydrogen
- R 5 is -CN
- the compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal, or solvate thereof, is selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof, Stereoisomer, Active Metabolite, Prodrug, Crystal or Solvate:
- the application provides a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate thereof, or a composition thereof, for use in the treatment of fish nicotine receptors Use in mutation-related diseases.
- the present application provides a method for treating a disease associated with a mutation of the fish nitin receptor, comprising:
- a therapeutically effective amount of a compound of formula I described herein, or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate, or a combination thereof, is administered to an individual in need thereof.
- the present application provides a compound of formula I described in the present application, or a pharmaceutically acceptable salt, stereoisomer, active metabolite thereof, for use in the treatment of diseases associated with fish nicotine receptor mutations , prodrugs, crystals or solvates or combinations thereof.
- the fish nicotine receptor mutation is a fish nicotine receptor 1 mutation.
- the fish nicotine receptor 1 mutation includes, but is not limited to, the RyR1-R4825C mutation, the RyR1-R4861C mutation, the rRyR1-R4824C mutation, and the rRyR1-R4860C mutation.
- the disease is selected from the group consisting of muscle diseases; in some embodiments, the disease is selected from the group consisting of central axis space disease, polymicroaxial space disease, congenital disease with fibrous disproportion, Linear body myopathy, malignant hyperthermia, catecholamine-sensitive ventricular tachycardia, arrhythmic right ventricular dysplasia, and sudden cardiac death.
- the following known compounds 1-38 were prepared by commercially available or reported synthetic methods or synthetic routes, such as compound 1 (Product No.: N-11422-100MG) and Compound 2 (Product No.: N-12886-10MG) were both Purchased from chem service inc.
- Compound 3 was provided by "Shenyang Chemical Research Institute Co., Ltd.”.
- Compound 4 was purchased from dr.ehrenstorfer, Germany, product number: DRE-C11817600.
- Example 1 Construction of plasmids containing RyR1-R4825C and RyR1-R4861C mutations
- Cs11-pBluescript KS+SB2 was point mutated using NEB Q5 ultra-fidelity DNA polymerase, and the mutated fragment was confirmed by sequencing and then introduced into RyR1-pcDNA5/FRT/TO ((pcDNA5/FRT/TO) using Cla I and EcoR V Plasmids were purchased from ThermoFisher Scientific, Catalog Number K6500-01), and were used for cell transfection after being confirmed by sequencing.
- Flp-In T-REx HEK293-R-CEPIA1er cell line stably expressing RyR1-R4825C and RyR1-R4861C genes
- Flp-In T-REx HEK293 cell line was purchased from ThermoFisher Scientific (Catalog No: R780-07), Referring to the Jump-In system of Thermo Fisher Scientific company to introduce the gene expressing R-CEPIA1er protein, the red fluorescent protein R-CEPIA1er is specifically located in the endoplasmic reticulum and can be used to indicate the concentration of calcium ions in the endoplasmic reticulum).
- the Flp-In T-REx HEK293-R-CEPIA1er cells were digested with EDTA-trypsin digestion solution, diluted with DMEM complete medium to 5 ⁇ 10 5 /mL, and added to a 6-well cell culture plate, 1 ml per well . Set 37 °C, 5% CO 2 incubator 24h.
- DMEM complete medium containing 100 ⁇ g/ml hygromycin B was replaced every 3-4 days until positive clones were generated.
- Calcium ions regulate the opening of RyR in a concentration-dependent manner micromolar calcium ions can activate RyR, while below millimolar or higher calcium ions cannot activate RyR.
- Ionidine is an alkaloid compound derived from plants, which can specifically bind to the open state of RyR, so the activity of RyR channel can be studied by using radioactive 3 H-labeled ionidine ([ 3 H]-unedine).
- step 4) The solution in step 4) was centrifuged at 100,000 ⁇ g for 30 minutes at 4°C, the supernatant was discarded, the pellet was resuspended in microsome separation solution and centrifuged again, and the supernatant was discarded.
- Precipitate was resuspended in microsome separation solution and the concentration was determined by BCA method. After sub-packaging, liquid nitrogen was quick-frozen and placed at -80°C for later use.
- step 3 Add 100 ⁇ l of the binding mixture in step 1) and incubate at 37°C for 2 h.
- step 6) Place the PEI-treated cell strainer on a 96-well cell harvester and pre-filter twice with pre-chilled distilled water. Then the solution of step 5) was filtered, and washed three times with pre-cooled distilled water after filtering.
- Example 3 Determination of calcium ion concentration in the endoplasmic reticulum
- DMEM complete medium containing 6 ⁇ g/ml doxycycline was added to each well to induce the expression of RyR gene, and the final concentration of doxycycline was 2 ⁇ g/ml at this time. Incubate in a 37°C, 5% CO 2 incubator.
- HEPES-buffered Krebs solution 140 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 11 mM glucose, 5 mM HEPES, pH 7.4
- HEPES-buffered Krebs solution 140 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 11 mM glucose, 5 mM HEPES, pH 7.4
- test compound F/F0 test compound F/F0 Compound 6 0.60 Compound 7 0.61 Compound 8 0.84 Compound 9 0.87
- NT means not detected.
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Abstract
La présente invention concerne l'utilisation d'un composé de formule I ou d'un sel pharmacologiquement acceptable, un stéréoisomère, un métabolite actif, un promédicament, un cristal ou un solvate de celui-ci ou une composition de celui-ci dans la préparation d'un médicament pour le traitement de maladies associées à une mutation du récepteur de la ryanodine. La présente invention concerne en outre une méthode de traitement de maladies associées à une mutation du récepteur de la ryanodine, et le composé de formule I ou le sel pharmacologiquement acceptable de celui-ci utilisé pour traiter des maladies liées à une mutation du récepteur de la ryanodine.
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CN1829707A (zh) * | 2003-01-28 | 2006-09-06 | 杜邦公司 | 氰基邻氨基苯甲酰胺杀虫剂 |
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DATABASE REGISTRY 11 February 2009 (2009-02-11), ANONYMOUS : "1H-Pyrazole-5-carboxamide, 3-bromo-N-[2,4-dichloro-6- [(methylamino)carbonyl]phenyl]-1-(3,5-dichloro-2-pyridinyl)- (CA INDEX NAME) OTHER CA INDEX NAMES: CN - 3-Bromo-N-[2,4-dichloro-6-[(methylamino)carbonyl]phenyl]-1-(3,5-dichloro-2- pyridinyl)-1H-pyrazole-5-carboxamide", XP055886609, retrieved from STN Database accession no. 1104384-14-6 * |
MA RUIFANG; HAJI-GHASSEMI OMID; MA DAN; JIANG HENG; LIN LIANYUN; YAO LI; SAMURKAS ARTHUR; LI YUXIN; WANG YIWEN; CAO PENG; WU SHIAN: "Structural basis for diamide modulation of ryanodine receptor", NATURE CHEMICAL BIOLOGY, NATURE PUBLISHING GROUP US, NEW YORK, vol. 16, no. 11, 17 August 2020 (2020-08-17), New York, pages 1246 - 1254, XP037272559, ISSN: 1552-4450, DOI: 10.1038/s41589-020-0627-5 * |
MAO MING-ZHEN, LI YU-XIN, ZHOU YUN-YUN, ZHANG XIU-LAN, LIU QIAO-XIA, DI FENG-JUAN, SONG HAI-BIN, XIONG LI-XIA, LI YONG-QIANG, LI Z: "Synthesis and Insecticidal Evaluation of Novel N -Pyridylpyrazolecarboxamides Containing an Amino Acid Methyl Ester and Their Analogues", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 62, no. 7, 19 February 2014 (2014-02-19), US , pages 1536 - 1542, XP055886595, ISSN: 0021-8561, DOI: 10.1021/jf500003d * |
YAN TAO, LIU PENG-FEI,ZHANG JI-FENG,YU SHU-JING,XIONG LI-XIA,LI ZHENG-MING: "Design, Synthesis and Biological Activities of Novel Ortho-Dicarboxyamides", CHEMICAL JOURNAL OF CHINESE UNIVERSITIES, JILIN DAXUE, BEIJING, CN, vol. 33, no. 8, 31 August 2012 (2012-08-31), CN , pages 1745 - 1750, XP055886600, ISSN: 0251-0790, DOI: 10.3969/j.issn.0251-0790.2012.08.021 * |
ZHENG XUESONG, SHI LI-BO,RU LI-JUN,SU JIAN-YA: "Ryanodine Receptor and Insecticides Targeting at Ryanodine Receptor", XIANDAI NONGYAO = MODERN AGROCHEMICALS, XIAN DAI NONG YAO BIAN JI BU, CN, vol. 11, no. 3, 30 June 2012 (2012-06-30), CN , pages 1 - 6, XP055886602, ISSN: 1671-5284, DOI: 10.3969/j.issn.1671-5284.2012.03.001 * |
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