CN113912584B - Use of pyrazole derivatives - Google Patents

Use of pyrazole derivatives Download PDF

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CN113912584B
CN113912584B CN202110771594.6A CN202110771594A CN113912584B CN 113912584 B CN113912584 B CN 113912584B CN 202110771594 A CN202110771594 A CN 202110771594A CN 113912584 B CN113912584 B CN 113912584B
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use according
optionally substituted
alkyl
halogen
ring
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CN113912584A (en
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尉迟之光
马瑞芳
马丹
姜恒
张君
李正名
李玉新
周莎
毛明珍
菲利普·范·佩特格姆
奥米德·哈吉-加塞米
村山尚
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Shun Paradise University
University of British Columbia
Tianjin University
Nankai University
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Shun Paradise University
University of British Columbia
Tianjin University
Nankai University
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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
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • 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
    • 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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    • 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
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Abstract

The present application relates to the use of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate thereof or a composition thereof for the manufacture of a medicament for the treatment of a disease associated with a mutation in the ryanodine receptor, to a method for the treatment of a disease associated with a mutation in the ryanodine receptor, and to a compound of formula I or a pharmaceutically acceptable salt thereof for the use of the same for the treatment of a disease associated with a mutation in the ryanodine receptor.

Description

Use of pyrazole derivatives
Cross Reference to Related Applications
The present application claims priority and equity to chinese patent application number 202010652572.3 filed on 7/8/2020 to the chinese national intellectual property agency, the disclosure of which is incorporated herein by reference in its entirety.
Technical Field
The application belongs to the field of medicines, and particularly relates to a new application of a compound. In particular to the use of the compounds of formula I or pharmaceutically acceptable salts, stereoisomers, active metabolites, prodrugs, crystals or solvates thereof or compositions thereof in the treatment of diseases associated with mutation of the ryanodine receptor.
Background
The ryanodine receptor (RyR) is a class of calcium ion ligand-gated channels present in the sarcoplasmic or endoplasmic reticulum that control the release of intracellular calcium ions and play a key role in the excitatory contraction coupling of muscle. According to the different distribution positions of the ryanodine receptor, the ryanodine receptor can be divided into three types: ryR1, ryR2 and RyR3.RyR1 is mainly distributed in skeletal muscle, ryR2 is mainly distributed in cardiac muscle, and RyR3 is mainly distributed in smooth muscle. The RyR mutation affects the open function of the calcium ion channel, thereby affecting the content of calcium ions in the cytoplasm. The decrease in the concentration of calcium ions in the cytoplasm may lead to, for example, muscle weakness, arrhythmia, and the like.
It has been reported that ryanodine receptor mutations such as RyR1 mutations can lead to various muscle diseases such as central axises (Central core disease, CCD), malignant hyperthermia (MALIGNANT HYPER, MH), multiple microscopic axises (Multiminicore Disease, mmD), congenital diseases accompanied by a fiber-type proportional imbalance (Congenital myopathy with fiber type disproportion, CFTD), linear body myopathies (nemaline rod myopathy, NM) and some other congenital muscle diseases, see, e.g., shiwen Wu et al ,"Central core disease is due to RYR1 mutations in more than 90％of patients",Brain(2006),129,1470–1480;Muriel Herasse et al ,"Abnormal Distribution of Calcium-Handling Proteins:A Novel Distinctive Marker in Core Myopathies",J Neuropathol Exp Neurol,Volume 66,Number 1,January 2007); and Takashi Murayama et al ,"Efficient High-Throughput Screening by Endoplasmic Reticulum Ca2+ Measurement to Identify Inhibitors of Ryanodine Receptor Ca2+-Release Channels",Mol Pharmacol 94:722–730,July 2018., and RyR2 mutations can lead to various muscle diseases such as catecholamine-sensitive ventricular tachycardia (Catecholaminergic polymorphic ventricular tachycardia, CPVT), arrhythmic right ventricular dysplasia (arrhythmogenic right ventricular dysplasia, ARVD) and sudden cardiac death, see, e.g., 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 Ca2+ release termination and diminishes protein expression",PLOS ONE,September 29,2017.
Disclosure of Invention
In one aspect, the present application provides the use of 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 medicament for the treatment of a disease associated with a mutation in the ryanodine receptor,
Wherein:
ring a and ring B are each independently an aromatic or heteroaromatic ring;
L 1 is-N (R 4) C (O) -or-N (R 4)C(O)C(O)N(R4) -;
R 1 is selected from the group consisting of-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 the group consisting of 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; and
X and y are each independently selected from integers of 1, 2, 3 and 4.
In another aspect, the application provides the use of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate thereof, or a composition thereof, for the treatment of a disease associated with a mutation in the ryanodine receptor.
In yet another aspect, the application provides a method for treating a disease associated with a mutation in the ryanodine receptor comprising:
Administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate thereof, or a composition thereof, as described herein.
In a further aspect, 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, according to the application for use in the treatment of a disease associated with a mutation in the ryanodine receptor.
Drawings
FIG. 1 is a saturation binding assay to analyze the maximum number of binding sites for ryanodine receptor 1.
FIG. 2 is an experiment of the binding of calcium-dependent [ 3 H ] ryanodine to RyR1-R4825C and RyR1-R4861C mutations.
Fig. 3A-3B show fluorescence changes caused in the determination of calcium ion concentration in the endoplasmic reticulum by positive control caffeine and exemplary compounds of the present application.
Detailed Description
Definition of the definition
The following definitions and methods are provided to better define the present application and to guide those of ordinary skill in the art in the practice of the present application. Unless otherwise indicated, terms are to be construed according to conventional usage by those of ordinary skill in the relevant art. All patent documents, academic papers, and other publications cited herein are incorporated by reference in their entirety.
The word "comprise" and its english variants such as comprises or comprising should be understood in an open, non-exclusive sense, i.e. "including but not limited to".
The expression C m-n as used herein means that the moiety has an integer number of carbon atoms within the given range. For example, "C 1-6" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
The term "member" refers to the number of backbone atoms that make up the ring. For example, "5-20 membered" means that the number of skeleton atoms constituting a ring is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, an ethyl group that is "optionally" substituted with one or more fluorine or chlorine groups means that the ethyl group may be unsubstituted (CH 2CH3), monosubstituted (e.g., CH 2CH2F、CHClCH3), polysubstituted (e.g., CHFCH 2F、CHClCHF2、CH2CHF2, etc.), or fully substituted (CCl 2CF3、CF2CF3). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if one group is substituted with 2R's, then each R has an independent option.
The term "halo", "halo" or "halogen" by itself or as part of another substituent means a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom.
The term "hydroxy" refers to an-OH group.
The term "amino" refers to-NH 2. The term "aminoacyl" refers to-CO-NH 2. "optionally substituted aminoacyl" refers to an aminoacyl that is substituted or unsubstituted in the amino portion of the aminoacyl, and when substituted, can form a monosubstituted or disubstituted aminoacyl.
The term "alkyl" refers to a saturated hydrocarbon group of the formula C nH2n+1. The alkyl group may be linear or branched. For example, the term "C 1-6 alkyl" refers to an alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.) containing from 1 to 6 (e.g., 1,2, 3, 4, 5, or 6) carbon atoms.
The term "alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined above.
The term "cycloalkyl" refers to a fully saturated non-aromatic ring consisting of carbon and hydrogen atoms. The cycloalkyl group may be a monocyclic, fused polycyclic, bridged or spiro ring structure, preferably containing 1 or 2 rings. Non-limiting examples of cycloalkyl groups 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 cycloalkyl, 3-8 membered cycloalkyl, 3-7 membered cycloalkyl, 3-6 membered cycloalkyl, 3-5 membered cycloalkyl, and the like, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro [3.3] heptyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2 ] octyl, adamantyl, bicyclo [1.1.1] pent-1-yl, and the like.
The term "alkenyl" refers to a straight or branched hydrocarbon group having at least one unsaturated site, i.e., a carbon-carbon double bond, such as C 2-12 alkenyl, C 2-10 alkenyl, C 2-6 alkenyl, and the like, with specific examples of alkenyl groups including, but not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
The term "ester" refers to a group having the structure-C (O) OR 8, wherein R 8 is optionally substituted alkyl, optionally substituted aryl OR optionally substituted heteroaryl as defined above. In some embodiments, R 8 is alkyl, haloalkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl. In some embodiments, R 8 is alkyl or haloalkyl. In some embodiments, R 8 is alkyl, e.g., C 1-6 alkyl. "optionally substituted ester" means that the R 8 moiety in the group is substituted or unsubstituted.
The term "aryl" or "aromatic ring" refers to an aromatic ring or an aromatic or partially aromatic ring system composed of carbon and hydrogen atoms. It may be a single ring or may be multiple rings (e.g., more than 2 rings such as bicyclic rings) that are fused together or covalently linked. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, and 1,2,3, 4-tetrahydronaphthalene, and the like.
"Heteroaryl" or "heteroaromatic ring" refers to a monocyclic or fused polycyclic ring system containing at least one (e.g., 1 to 5, such as 1,2, 3,4, or 5) ring atoms selected from N, O and S, the remaining ring atoms being C, and having at least one aromatic ring. Heteroaryl groups may have a 4-8 membered monocyclic ring (e.g., 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, or 8-membered monocyclic ring), or have a fused polycyclic ring containing 6-14 ring atoms (e.g., 6-membered ring, 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). Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.
In the present description of the invention,Meaning the connection location.
The term "optionally substituted" as used herein means that the group may be optionally substituted with one or more (e.g., 1 to 4, 1 to 3, or 1 to 2) substituents independently selected from alkyl, alkenyl, halo, haloalkyl, haloalkenyl, alkoxy, alkylthio, cyano, nitro, hydroxy, mercapto, -C (=s) OH, -C (=s) O-alkyl, -C (=s) -H, -C (=s) -alkyl, aryl, aryloxy, aralkyl, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkenyl, cycloalkenyloxy, cycloalkenylalkyl, alicyclic oxy, alicyclic alkyl, aromatic heterocyclic group, aromatic heterocyclic alkyl, hydroxyamino, alkoxyamino 、-OC(O)-R14、-N(R14)2、-C(O)R14、-C(O)OR14、-C(O)N(R14)2、-N(R14)C(O)OR16、-N(R14)C(O)R16、-N(R14)(S(O)tR16)( wherein t is 1 or 2), -S (O) tOR16 (wherein t is 1 or 2), -S (O) 32 (wherein t is 0, 1 or 2), and-S (O) tN(R14)2 (wherein t is 1 or 2), wherein each R25 is independently selected from cycloalkyl, alicyclic, heterocyclic, or each of which is an alkyl, alicyclic, heterocyclic, alicyclic, or heterocyclic, or each of which is an aryl, alicyclic, heterocyclic, or an alicyclic, heterocyclic. For example, the substituents are independently selected from alkyl, halogen, and hydroxy.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
The compounds of the 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, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Or when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), forms a diastereomeric salt with an appropriate optically active acid or base, and then undergoes diastereomeric resolution by conventional methods well known in the art, followed by recovery of the pure enantiomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as tritium (3 H), iodine-125 (125 I) or C-14 (14 C). For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "solvate" refers to a solvent formed by combining a compound of the present application with a solvent molecule. In some embodiments, such a solvate is a monohydrate, for example, the solvent is water, and the compound of the application forms a monohydrate with water.
Furthermore, the present application includes all possible crystalline forms or polymorphs of the compounds of the present application, including individual polymorphs thereof or mixtures of polymorphs in any proportion. The term "polymorph" means that the compounds of the application exist in different lattice forms.
The term "prodrug" as used herein includes acid derivatives or alcohol derivatives and the like, which are well known to practitioners in the art. Wherein the acid derivative is, for example, an ester prepared by the reaction of a parent acid with a suitable alcohol, or an amide prepared by the reaction of a parent acid with a substituted or unsubstituted amine, or an anhydride, or a mixed anhydride, or the like; the alcohol derivative is selected from, for example, alcohol esters, alcohol alkoxylates, alcohol ethers, carboxylic acids, carboxylic acid esters, phosphorylates, mixtures thereof, and the like. Simple aliphatic or aromatic esters, amides and anhydrides, and phosphides on hydroxyl groups resulting from acidic groups pendant on the compounds of the invention are specific prodrugs.
The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
In the present invention, the term "individual" includes humans and animals, for example, mammals (e.g., primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.).
The term "treatment" means administration of a compound or formulation of the application to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) To arrest a disease or condition, i.e., to arrest its progression;
(ii) The disease or condition is alleviated, even if the disease or condition subsides.
For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
The terms "RyR1-R4825C mutation" and "RyR1-R4861C mutation" include mutations of corresponding sequences in humans, ryR1-R4825C mutation and RyR1-R4861C mutation, as well as in other animal species (e.g., mammals (e.g., primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.), such as mutations rRyR-R4824C mutation and rRyR-R4860C mutation of corresponding sequences in rabbits.
The term "composition" or "pharmaceutical composition" refers to a mixture comprising one or more compounds of the application, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the application to an organism.
The term "pharmaceutically acceptable excipients" refers to those excipients which have no significant stimulating effect on the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person 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 compositions of the application may be prepared by combining the compounds of the application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, lozenges, pastes, emulsions, suspensions, solutions, syrups, pastes, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
Typical routes of administration of the compounds of the application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, transdermal, intravenous administration.
The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.
In some embodiments of the application, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing 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, troches, dragees, capsules, liquids, gels, slurries, emulsions, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The pharmaceutical compositions of the application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In some embodiments, all methods of administering the compounds of formula I described herein are administered at a daily dosage of from 0.01mg/kg body weight to 300mg/kg body weight, for example from 10mg/kg body weight to 300mg/kg body weight, from 25mg/kg body weight to 200mg/kg body weight, either as a single dose or as separate doses.
In one aspect, the present application provides the use of 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 medicament for the treatment of a disease associated with a mutation in the ryanodine receptor,
Wherein:
ring a and ring B are each independently an aromatic or heteroaromatic ring;
L 1 is-N (R 4) C (O) -or-N (R 4)C(O)C(O)N(R4) -;
R 1 is selected from the group consisting of-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 the group consisting of 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; and
X and y are each independently selected from integers of 1, 2, 3 and 4.
In some embodiments, ring a and ring B are each independently a 6-20 membered aromatic ring or a 5-20 membered heteroaromatic ring.
In some embodiments, ring a and ring B are each independently a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring.
In some embodiments, ring a and ring B are each independently a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring.
In some embodiments, ring a is a benzene ring or a pyrazole ring.
In some embodiments, ring B is a benzene ring or a pyridine ring.
In some embodiments, wherein the heteroaromatic ring has 1 to 5 heteroatoms independently selected from N, O and S.
In some embodiments, R 1 is selected from: -C (O) NR 'R ", -N (R') C (O) R 6, alkenyl optionally substituted with one or more substituents independently selected from CN, ester group and optionally substituted aminoacyl, and aryl optionally substituted with halogen.
In some embodiments, R 1 is selected from: -C (O) NR 'R ", -N (R') C (O) R 6, alkenyl optionally substituted with one or more substituents independently selected from CN, ester group and aminoacyl optionally substituted with amino group, and aryl optionally substituted with halogen.
In some embodiments, R 1 is selected from: -C (O) NR 'R ", -N (R') C (O) R 6, C 2-6 alkenyl optionally substituted with one or more substituents independently selected from CN, ester group and aminoacyl optionally substituted with amino group, and C 6-20 aryl optionally substituted with halogen.
In some embodiments, R 1 is selected from: -C (O) NR 'R ", -N (R') C (O) R 6, C 2-6 alkenyl optionally substituted with one or more substituents independently selected from CN, ester group and aminoacyl optionally substituted with amino group, and C 6-15 aryl optionally substituted with halogen.
In some embodiments, R 1 is selected from: -C (O) NR 'R ", -N (R') C (O) R 6, C 2-6 alkenyl optionally substituted with one or more substituents independently selected from CN, ester group and aminoacyl optionally substituted with amino group, and C 6-10 aryl optionally substituted with halogen.
In some embodiments, R 1 is selected from: -C (O) NR 'R ", -N (R') C (O) R 6, C 2-6 alkenyl optionally substituted with one or more substituents independently selected from CN, -CO 2C2H5 and-CONHNH 2, and phenyl optionally substituted with halogen;
In some embodiments, R 1 is selected from: -C (O) NR ' R ', -N (R ') C (O) R 6, vinyl optionally substituted with one or more substituents independently selected from CN, -CO 2C2H5 and-CONHNH 2, and 2, 4-dichlorophenyl.
In some embodiments, each R 0 is independently selected from hydrogen, halogen, -CN, and optionally substituted C 1-6 alkyl.
In some embodiments, each R 0 is independently selected from hydrogen, halogen, -CN, and optionally substituted C 1-4 alkyl.
In some embodiments, each R 0 is independently selected from hydrogen, cl, br, -CN, and methyl.
In some embodiments, R 1 is located ortho to L 1.
In some embodiments, the building blockSelected from/>
In some embodiments, the building blockSelected from/> Wherein R 2 is selected from halogen and-CN and R 3 is selected from halogen and optionally substituted alkyl.
In some embodiments, the building blockSelected from/>Wherein R 2 is selected from halogen and-CN and R 3 is selected from halogen and optionally substituted C 1-6 alkyl.
In some embodiments, the building blockSelected from/>Wherein R 2 is selected from halogen and-CN, and R 3 is selected from halogen, C 1-4 alkyl.
In some embodiments, the building blockSelected from/>Wherein R 2 is selected from Cl, br and-CN; r 3 is selected from Cl, br or methyl.
In some embodiments, the building blockSelected from/>
In some embodiments, the building blockSelected from/>Wherein R 1 is selected from optionally substituted aryl. In some embodiments, R 1 is selected from C 6-20 aryl optionally substituted with halo. In some embodiments, R 1 is selected from C 6-15 aryl optionally substituted with halo. In some embodiments, R 1 is selected from C 6-10 aryl optionally substituted with halo. In some embodiments, R 1 is selected from phenyl optionally substituted with halo. In some embodiments, R 1 is selected from 2, 4-dichlorophenyl.
In some embodiments, the building blockSelected from/>
In some embodiments, the building blockSelected from/>
In some embodiments, each R 5 is independently selected from the group consisting of hydrogen, halogen, -CN, alkyl optionally substituted with halogen, and alkoxy optionally substituted with halogen.
In some embodiments, each R 5 is independently selected from hydrogen, halogen, -CN, C 1-6 alkyl optionally substituted with halogen, and C 1-6 alkoxy optionally substituted with halogen.
In some embodiments, each R 5 is independently selected from hydrogen, halogen, -CN, C 1-4 alkyl optionally substituted with halogen, and C 1-4 alkoxy optionally substituted with halogen.
In some embodiments, each R 5 is independently selected from the group consisting of hydrogen, cl, br, -CN, -CF 3, and-OCH 2CF3.
In some embodiments, the building blockSelected from/>
In some embodiments, the building blockSelected from/>
In some embodiments, the building blockSelected from/>
In some embodiments, each R is independently selected from hydrogen, halogen, and alkyl optionally substituted with halogen.
In some embodiments, each R is independently selected from hydrogen, halogen, and C 1-6 alkyl optionally substituted with halogen.
In some embodiments, each R is independently selected from hydrogen, halogen, and C 1-4 alkyl optionally substituted with halogen.
In some embodiments, each R is independently selected from hydrogen, F, cl, and CF 3.
In some embodiments, at least one R is not hydrogen.
In some embodiments, at least one R is selected from halogen.
In some embodiments, R 4 is hydrogen or C 1-6 alkyl.
In some embodiments, R 4 is hydrogen or C 1-4 alkyl.
In some embodiments, R 4 is hydrogen or C 1-2 alkyl.
In some embodiments, R 4 is hydrogen.
In some embodiments, R' and R "are each independently selected from: hydrogen, alkyl optionally substituted with a substituent selected from cycloalkyl, aryl, hydroxy, and ester, optionally substituted cycloalkyl, alkenyl optionally substituted with an ester, aryl optionally substituted with alkyl, and amino optionally substituted with-C (O) OR 7; wherein R 7 is alkyl.
In some embodiments, R' and R "are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted with a substituent selected from 3-20 membered cycloalkyl, C 6-20 aryl, hydroxy and ester, optionally substituted 3-20 membered cycloalkyl, C 2-6 alkenyl optionally substituted with ester, C 6-20 aryl optionally substituted with C 1-6 alkyl, and amino optionally substituted with-C (O) OR 7; wherein R 7 is C 1-6 alkyl.
In some embodiments, R' and R "are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of 3-10 membered cycloalkyl, C 6-15 aryl, hydroxy, and ester, optionally substituted 3-10 membered cycloalkyl, C 2-6 alkenyl optionally substituted with an ester, C 6-15 aryl optionally substituted with C 1-6 alkyl, and amino optionally substituted with-C (O) OR 7; wherein R 7 is C 1-6 alkyl.
In some embodiments, R' and R "are each independently selected from: hydrogen, C 1-4 alkyl optionally substituted with a substituent selected from 3-7 membered cycloalkyl, C 6-10 aryl, hydroxy and ester, optionally substituted 3-7 membered cycloalkyl, C 2-4 alkenyl optionally substituted with ester, C 6-10 aryl optionally substituted with C 1-4 alkyl, and amino optionally substituted with-C (O) OR 7; wherein R 7 is C 1-4 alkyl.
In some embodiments, at least one of R' and R "is not hydrogen.
In some embodiments, one of R' and R "is hydrogen and the other is selected from the following groups: c 1-4 alkyl optionally substituted with a substituent selected from the group consisting of 3-7 membered cycloalkyl, C 6-10 aryl, hydroxy and ester, optionally substituted 3-7 membered cycloalkyl, C 2-4 alkenyl optionally substituted with an ester, C 6-10 aryl optionally substituted with C 1-4 alkyl, and amino optionally substituted with-C (O) OR 7; wherein R 7 is C 1-4 alkyl.
In some embodiments, one of R' and R "is hydrogen and the other is selected from: methyl, ethyl, isopropyl, cyclopropyl, 1-cyclopropylethyl, phenyl, 2-methylphenyl, benzyl 、-CH(CO2CH3)CH2OH、-C(CO2CH3)＝CH、-NHC(O)C(O)OCH2CH3、-NHC(O)C(O)OCH(CH3)2、, and-NHC (O) C (O) OC (CH 3)3).
In some embodiments, R 6 is selected from: optionally substituted alkoxy, and alkyl optionally substituted with a substituent selected from halogen and optionally substituted amino.
In some embodiments, R 6 is selected from: optionally substituted alkoxy, and alkyl optionally substituted with a substituent selected from halogen and amino optionally substituted with alkyl.
In some embodiments, R 6 is selected from: optionally substituted C 1-6 alkoxy, and C 1-6 alkyl optionally substituted with a substituent selected from halogen and amino optionally substituted with C 1-6 alkyl.
In some embodiments, R 6 is selected from: optionally substituted C 1-4 alkoxy, and C 1-4 alkyl optionally substituted with a substituent selected from F, cl and amino optionally substituted with methyl.
In some embodiments, R 6 is selected from methoxy, ethoxy, -CH 2Cl、-CCl3、-CF3, and-CH 2NHCH3.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is a compound of formula Ia or formula Ib:
In formula Ia, wherein:
ring a is an aromatic ring and ring B is a heteroaromatic ring;
in some embodiments, ring A is a 6-20 membered aromatic ring, a 6-15 membered aromatic ring, or a 6-10 membered aromatic ring;
In some embodiments, ring B is a 5-20 membered heteroaryl ring, a 5-15 membered heteroaryl ring, or a 5-10 membered heteroaryl ring;
in some embodiments, ring a is a phenyl ring;
In some embodiments, ring B is a pyridine ring;
In some embodiments, R 1 is located ortho to-N (R 4) C (O) -;
In some embodiments, R 4 is hydrogen;
In some embodiments, the building block Selected from/>
In some embodiments, the building blockSelected from/>
In some embodiments, the building blockSelected from/>
In some embodiments, each R is independently selected from hydrogen and halogen;
In some embodiments, each R is independently selected from hydrogen and Cl;
in some embodiments, at least one R is not hydrogen;
in some embodiments, at least one R is selected from halogen;
In some embodiments, each R 5 is independently selected from the group consisting of hydrogen, halogen, alkyl optionally substituted with halogen, and alkoxy optionally substituted with halogen;
In some embodiments, each R 5 is independently selected from hydrogen, halogen, C 1-6 alkyl optionally substituted with halogen, and C 1-6 alkoxy optionally substituted with halogen;
In some embodiments, each R 5 is independently selected from hydrogen, halogen, C 1-4 alkyl optionally substituted with halogen, and C 1-4 alkoxy optionally substituted with halogen;
In some embodiments, each R 5 is independently selected from hydrogen, cl, br, -CF 3, and-OCH 2CF3;
Other groups in formula Ia are as defined for R 1、R0, x, y, R' and R "in formula I;
In formula Ib, wherein:
ring a and ring B are each independently selected from aromatic rings;
In some embodiments, 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;
In some embodiments, ring a and ring B are benzene rings;
In some embodiments, each R 0 is independently selected from hydrogen, halogen, and optionally substituted alkyl;
In some embodiments, each R 0 is independently selected from hydrogen, halogen, and optionally substituted C 1-6 alkyl;
in some embodiments, each R 0 is independently selected from hydrogen, halogen, and optionally substituted C 1-4 alkyl;
in some embodiments, each R 0 is independently selected from hydrogen, cl, and methyl.
In some embodiments, R 1 is ortho to-N (R 4)C(O)C(O)N(R4) -;
in some embodiments, R 1 is selected from-C (O) NR' R ";
In some embodiments, R' and R "are each independently selected from: hydrogen, optionally substituted alkyl, and optionally substituted cycloalkyl;
In some embodiments, R' and R "are each independently selected from: hydrogen, optionally substituted C 1-6 alkyl, and optionally substituted 3-20 membered cycloalkyl;
In some embodiments, R' and R "are each independently selected from: hydrogen, optionally substituted C 1-6 alkyl, and optionally substituted 3-10 membered cycloalkyl;
In some embodiments, R' and R "are each independently selected from: hydrogen, optionally substituted C 1-4 alkyl, and optionally substituted 3-7 membered cycloalkyl;
In some embodiments, at least one of R' and R "is not hydrogen;
In some embodiments, one of R' and R "is hydrogen and the other is selected from the following groups: methyl, ethyl, isopropyl and cyclopropyl;
In some embodiments, R 4 is hydrogen;
In some embodiments, R 5 is —cn;
In some embodiments, the building block Selected from/>
In some embodiments, the building blockSelected from/>
In some embodiments, the building blockSelected from/>
In some embodiments, 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:
/>
/>
In another aspect, the application provides the use of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate thereof, or a composition thereof, for the treatment of a disease associated with a mutation in the ryanodine receptor.
In yet another aspect, the application provides a method for treating a disease associated with a mutation in the ryanodine receptor comprising:
Administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, active metabolite, prodrug, crystal or solvate thereof, or a composition thereof, as described herein.
In a further aspect, 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, according to the application for use in the treatment of a disease associated with a mutation in the ryanodine receptor.
In some embodiments of any of the above aspects, the mutation of the ryanodine receptor is a mutation of ryanodine receptor 1. In some embodiments of any of the above aspects, the ryanodine receptor 1 mutation includes, but is not limited to, a RyR1-R4825C mutation, a RyR1-R4861C mutation, a rRyR-R4824C mutation, and a rRyR-R4860C mutation.
In some embodiments of any of the above aspects, the disease is selected from muscle diseases; in some embodiments, the disease is selected from central axises, polymicro axises, congenital diseases with fibrotic scaling disorders, linear body myopathies, malignant hyperthermia, catecholamine sensitive ventricular tachycardia, arrhythmic right ventricular dysplasia, and sudden cardiac death.
Detailed Description
The following describes the embodiments of the present application in further detail with reference to examples. The following examples are for illustrative purposes only and are not intended to limit the scope of the application.
Preparation example 1
The following known compounds 1-38, such as compound 1 (cat# N-11422-100 MG) and compound 2 (cat# N-12886-10 MG), were prepared by synthetic methods or synthetic routes reported in the commercial or reference literature, and were each purchased from CHEM SERVICE INC. Compound 3 is provided by "Shenyang chemical industry Co., ltd. Compound 4 was purchased from dr. DRE-C11817600.
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Example 1: construction of plasmids containing RyR1-R4825C and RyR1-R4861C mutations
Since the RyR1 sequence contains 15114 bases, it is difficult to directly mutate RyR1, so that 14296-15099 bases of RyR1 are firstly introduced into a vector pBluescript KS+SB2 by using cleavage sites ClaI and EcoRV, and the constructed vector is named Cs11-pBluescript KS+SB2. (the homology of human RyR1 with rabbit RyR1 is as high as 97%, and the human RyR1 disease is usually studied by using rabbit RyR 1. Human RyR1-R4825 corresponds to rabbit RyR1-R4824, human RyR1-R4861 corresponds to rabbit RyR1-R4860. Human RyR1 uses amino acid sequence NP-000531.2, and rabbit RyR1 uses amino acid sequence NP-001095188.1).
Primers RyR1-R4825C-F (5'-CAAGACGCTGTGCACCATCCTC-3'), ryR1-R4825C-R (5'-GAGGATGGTGCACAGCGTCTTG-3') and RyR1-R4861C-F (5'-CAACTTCTTCTGCAAGTTCTAC-3'), ryR1-R4861C-R (5'-GTAGAACTTGCAGAAGAAGTTG-3') were designed according to the mutation sites. The NEB Q5 super fidelity DNA polymerase was used TO point mutate Cs11-pBluescript KS+SB2, and the mutated fragment was sequenced and confirmed and then introduced into RyR1-pcDNA5/FRT/TO ((pcDNA 5/FRT/TO plasmid available from ThermoFisher Scientific, catalog Number K6500-01) using ClaI and EcoR V for cell transfection.
Construction of Flp-In T-REx HEK293-R-CEPIA er cell lines stably expressing RyR1-R4825C and RyR1-R4861C genes (Flp-In T-REx HEK293 cell line was purchased from ThermoFisher Scientific company (Catalog No: R780-07), and a gene expressing R-CEPIA er protein was introduced by referring to the thermal FISHER SCIENTIFIC company Jump-In system, and red fluorescent protein R-CEPIA1er was specifically located In the endoplasmic reticulum, and was used to indicate the concentration of calcium ions In the endoplasmic reticulum).
1) Flp-In T-REx HEK293-R-CEPIA er cells were digested with EDTA-pancreatin digest and diluted to 5X 10 5/mL with DMEM complete medium and added to 6 well cell culture plates at 1mL per well. Culturing in a 5% CO 2 incubator at 37deg.C for 24 hr.
2) RyR1-WT-pcDNA5/FRT/TO (WT, wild type), ryR1-R4825C-pcDNA5/FRT/TO and RyR1-R4861C-pcDNA5/FRT/TO were transferred TO HEK293-R-CEPIA1er cells (Lipofectamine 3000, invitrogen) in a 1:1 ratio with pOG44 (recombinase expression plasmid, expression of Flp recombinase under the control of the human CMV promoter) respectively, and incubated in a 5% CO 2 incubator at 37℃for 24h.
3) Transfected cells were digested with EDTA-pancreatin digestions, cells from each 6-well plate were transferred to two 10cm cell culture plates, 8ml of culture medium was added to each plate, incubated for 4-6h at 37℃in a 5% CO 2 incubator, and hygromycin B was added at a final concentration of 100. Mu.g/ml for screening positive clones.
4) DMEM complete medium containing 100 μg/ml hygromycin B was changed every 3-4 days until positive clones were generated.
Example 2: experiment of binding of fish Nidine
Calcium ion regulates RyR opening with concentration dependence: micro-molar calcium ions can activate RyR, while below millimoles or higher calcium ions cannot activate RyR. Since ryanodine is a plant-derived alkaloid compound that can specifically bind to the open state of RyR, activity of RyR channels can be studied using ryanodine labeled with radioactivity 3 H ([ 3 H ] -ryanodine).
Extraction of microsomes
1) Preparing microsome separating liquid before experiment: 5ml of a 60% sucrose solution, 3ml of a 0.2M MOPS solution (pH 7.4), 0.3ml of a protease inhibitor complex (available from Bimake company, catalog No. B14002) were diluted to 30ml for use.
2) The cell lines which successfully express RyR1-R4825C, ryR1-R4861C and the wild RyR genes are inoculated into a culture dish and cultured until 70-80% fusion, and doxycycline is added to a final concentration of 2 mug/ml to induce RyR gene expression.
3) The cells were incubated in a 5% CO 2 incubator at 37℃for 48h, scraped and centrifuged at 500 Xg for 5min at room temperature, and the supernatant was discarded. The pellet was resuspended in PBS, centrifuged, the supernatant discarded, and the pellet was the harvested cells.
4) Cells were resuspended using microsomal isolation and lysed using nitrogen chamber depressurization, and the cell suspension was centrifuged at 1000 Xg for 5 minutes at 4℃and the supernatant collected. The pellet was resuspended and centrifuged again and the supernatants of both times combined.
5) In step 4) the solution was centrifuged at 100,000Xg for 30 minutes at 4℃and the supernatant was discarded, the pellet was resuspended in microsomal separation and centrifuged again and the supernatant discarded.
6) The precipitate was resuspended in microsomal separation solution and assayed for concentration using BCA method, and the pellet was frozen in liquid nitrogen after packaging and placed at-80 ℃ for use.
(II) [ 3 H ] -ryanodine binding
1) Preparing [ 3 H ] -ryanodine binding mixed solution: 0.17M NaCl,20mM MOPS (pH 7.2), 2mM DTT, protease inhibitor, 1mM AMPPCP, 1. Mu.M calmodulin (Calmodulin), 5nM [ 3 H ] -ryanodine, 0.5mg/ml microsomes (WT or mutant), distilled water was added to a total volume of 180. Mu.l.
2) 20 Μl of calcium ion-EGTA solutions of different calcium ion concentrations were added to each 1.5ml centrifuge tube.
3) Mu.l of the binding mixture from step 1) was added and incubated at 37℃for 2h.
4) Type B glass filters were immersed in a 2% pei solution at room temperature for 5 minutes.
5) The solutions in each centrifuge tube were transferred to two wells adjacent to a 96-well plate, with 90 μl each.
6) PEI treated cell filters were placed on 96-well cell collectors and pre-filtered twice with pre-chilled distilled water. The solution of step 5) was then filtered and washed three times with pre-chilled distilled water.
7) The filters were dried on a hot plate at 120℃for 15 minutes and then calculated for RyR-bound [ 3 H ] -ryanodine using a microplate isotope reader. For the determination of the maximum binding capacity of [ 3 H ] -RyR to RyR, the calcium ion concentration was fixed at 0.1mM, and mixtures containing different concentrations of [ 3 H ] -RyR were prepared.
8) The results showed a decrease in [ 3 H ] -ryanodine in combination with the two mutations RyR1-R4825C and RyR1-R4861C compared to the wild type (see FIGS. 1 and 2), indicating that these two mutations reduce the activity of the RyR channel.
Example 3: determination of calcium ion concentration in endoplasmic reticulum
1) Cells successfully expressing RyR1-R4825C, ryR1-R4861C and wild-type RyR genes described above were digested with EDTA-pancreatin digests, diluted to 2X 10 5 cells/mL with DMEM complete medium, and added to 96-well cell ELISA plates at 100. Mu.L per well at a cell density of 2X 10 4 cells/well. Culturing at 37deg.C in 5% CO 2 incubator. 24h after inoculation, 50. Mu.l of DMEM complete medium containing 6. Mu.g/ml doxycycline was added to each well to induce RyR gene expression, at which point the final doxycycline concentration was 2. Mu.g/ml. Culturing at 37deg.C in 5% CO 2 incubator.
2) After incubation for 24-28h, the medium was aspirated, 81. Mu.l of HEPES buffered Krebs solution (140mM NaCl,5mM KCl,2mM CaCl 2,1mM MgCl2, 11mM glucose, 5mM HEPES, pH 7.4) pre-warmed at 37℃was added to each well, and the cells were placed in a Flexstation III instrument and left at 37℃for 15 min to stabilize the cell state.
3) The fluorescence values of R-CEPIA er at 560nm excitation wavelength and 610nm emission wavelength were recorded at a frequency of 10 s/time for 300 seconds, and test compounds (caffeine as positive control) were added at different concentrations at 100s in a ratio of drug to cell culture broth of 1:1.5.
4) The ratio (F/F0) of the average value (F0) of the initial 100s fluorescence signal to the average value (F) of the final 100s fluorescence signal is the fluorescence change caused by the compound. Fig. 3A-3B show changes in fluorescence caused by exemplary compounds of the present application.
5) The results of the experiment while measuring the final concentration of 50mM, in which each of the other compounds caused a change F/F0 in the fluorescence value of RyR1-R4861C cells, are shown in Table 1 below.
6) The half-effective concentration of the drug was calculated using GRAPHPAD PRISM 8.0.2 software (Concentration for 50%of maximal effect,EC 50),EC50 results are shown in table 2 below.
TABLE 1
Test compounds F/F0 Test compounds F/F0
Compound 6 0.60 Compound 7 0.61
Compound 8 0.84 Compound 9 0.87
Compound 10 0.60 Compound 11 0.44
Compound 12 0.53 Compound 13 0.34
Compound 14 0.35 Compound 15 0.42
Compound 16 0.54 Compound 17 0.34
Compound 18 0.69 Compound 19 0.77
Compound 20 0.81 Compound 21 0.36
Compound 22 0.38 Compound 23 0.69
Compound 24 0.47 Compound 25 0.33
Compound 26 0.32 Compound 27 0.67
Compound 28 0.80 Compound 29 0.88
Compound 30 0.72 Compound 31 0.38
Compound 32 0.40 Compound 33 0.89
Compound 34 0.88 Compound 35 0.88
Compound 36 0.90 Compound 37 0.88
Compound 38 0.86
TABLE 2
NT indicates undetected.
These results indicate that the compounds of formula I of the present application can specifically act on rRyR1 to regulate RyR development, thereby promoting calcium ion release from endoplasmic reticulum to cytoplasm, regulating calcium ion concentration in cytoplasm, and can be used for muscle diseases caused by rRyR1 mutation, such as central axises caused by RyR1-R4825C and RyR1-R4861C mutation in human body, etc.
While the invention has been described in detail with respect to the general description and specific embodiments thereof, it will be apparent to those skilled in the art that various modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.

Claims (86)

1. The use of a compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, or a composition thereof, in the manufacture of a medicament for the treatment of a disease associated with mutation of the ryanodine receptor,
Wherein:
Ring a and ring B are each independently a 6-20 membered aromatic ring or a 5-20 membered heteroaromatic ring;
L 1 is-N (R 4) C (O) -or-N (R 4)C(O)C(O)N(R4) -;
R 1 is selected from: -C (O) NR 'R",-N(R')C(O)R6, C 2-6 alkenyl optionally substituted with one OR more substituents independently selected from CN, -C (O) OR 8 and aminoacyl optionally substituted with amino, and C 6-20 aryl optionally substituted with halogen;
Each R 0 is independently selected from hydrogen, halogen, -CN, and C 1-6 alkyl;
R 4 is hydrogen or C 1-6 alkyl;
Each R 5 is 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 is independently selected from hydrogen, halogen, and C 1-6 alkyl optionally substituted with halogen;
R ' and R " are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of 3-20 membered cycloalkyl, C 6-20 aryl, hydroxy and-C (O) OR 8, 3-20 membered cycloalkyl, C 2-6 alkenyl optionally substituted with-C (O) OR 8, C 6-20 aryl optionally substituted with C 1-6 alkyl, and amino optionally substituted with-C (O) OR 7; wherein R 7 is C 1-6 alkyl;
R 6 is selected from: a C 1-6 alkoxy group, a C 1-6 alkyl group optionally substituted with a substituent selected from halogen and amino optionally substituted with a C 1-6 alkyl group;
r 8 is C 1-6 alkyl; and
X and y are each independently selected from integers of 1, 2, 3 and 4;
Wherein the heteroaromatic ring has 1 to 5 heteroatoms independently selected from N, O and S;
Wherein the ryanodine receptor mutation is selected from the group consisting of a RyR1-R4825C mutation and a RyR1-R4861C mutation.
2. The use according to claim 1, wherein:
Ring a and ring B are each independently a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring.
3. The use according to claim 1, wherein:
Ring a and ring B are each independently a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring.
4. The use according to claim 1, wherein:
Ring a is a benzene ring or a pyrazole ring.
5. The use according to claim 1, wherein:
Ring B is a benzene ring or a pyridine ring.
6. The use according to any one of claims 1 to 5, wherein:
R 1 is selected from: -C (O) NR 'R",-N(R')C(O)R6, C 2-6 alkenyl optionally substituted with one OR more substituents independently selected from CN, -C (O) OR 8 and aminoacyl optionally substituted with amino, and C 6-15 aryl optionally substituted with halogen; wherein R 8 is C 1-6 alkyl.
7. The use according to any one of claims 1 to 5, wherein: r 1 is selected from: -C (O) NR 'R",-N(R')C(O)R6, C 2-6 alkenyl optionally substituted with one OR more substituents independently selected from CN, -C (O) OR 8 and aminoacyl optionally substituted with amino, and C 6-10 aryl optionally substituted with halogen; wherein R 8 is C 1-6 alkyl.
8. The use according to any one of claims 1 to 5, wherein: r 1 is selected from: -C (O) NR 'R",-N(R')C(O)R6, C 2-6 alkenyl optionally substituted with one or more substituents independently selected from CN, -CO 2C2H5 and-CONHNH 2, and phenyl optionally substituted with halogen.
9. The use according to any one of claims 1 to 5, wherein: r 1 is selected from: -C (O) NR 'R",-N(R')C(O)R6, vinyl optionally substituted with one or more substituents independently selected from CN, -CO 2C2H5 and-CONHNH 2, and 2, 4-dichlorophenyl.
10. The use according to any one of claims 1 to 5, wherein:
Each R 0 is independently selected from hydrogen, halogen, -CN, and C 1-4 alkyl.
11. The use according to any one of claims 1 to 5, wherein: each R 0 is independently selected from the group consisting of hydrogen, cl, br, -CN and methyl.
12. The use according to any one of claims 1 to 5, wherein:
r 1 is located in the ortho-position to L 1.
13. The use according to any one of claims 1 to 5, wherein:
Structural unit Selected from/>
14. The use according to any one of claims 1 to 5, wherein:
Structural unit Selected from/>Wherein R 2 is selected from halogen and-CN and R 3 is selected from halogen and C 1-6 alkyl.
15. The use according to any one of claims 1 to 5, wherein:
Structural unit Selected from/>Wherein R 2 is selected from halogen and-CN and R 3 is selected from halogen and C 1-6 alkyl.
16. The use according to any one of claims 1 to 5, wherein:
Structural unit Selected from/>Wherein R 2 is selected from halogen and-CN, and R 3 is selected from halogen, C 1-4 alkyl.
17. The use according to any one of claims 1 to 5, wherein:
Structural unit Selected from/>Wherein R 2 is selected from Cl, br and-CN; r 3 is selected from Cl, br or methyl.
18. The use according to any one of claims 1 to 5, wherein:
Structural unit Selected from/>
19. The use according to any one of claims 1 to 5, wherein:
Structural unit Selected from/>Wherein: r 1 is selected from C 6-20 aryl optionally substituted with halogen.
20. The use of claim 19, wherein: r 1 is selected from C 6-15 aryl optionally substituted with halogen.
21. The use of claim 19, wherein: r 1 is selected from C 6-10 aryl optionally substituted with halogen.
22. The use according to any one of claims 1 to 5, wherein:
R 1 is selected from phenyl optionally substituted with halogen.
23. The use according to any one of claims 1 to 5, wherein:
R 1 is selected from 2, 4-dichlorophenyl.
24. The use according to any one of claims 1 to 5, wherein:
Structural unit Selected from/>
25. The use according to any one of claims 1 to 5, wherein: structural unitSelected from the group consisting of
26. The use according to any one of claims 1 to 5, wherein:
Each R 5 is independently selected from hydrogen, halogen, -CN, C 1-4 alkyl optionally substituted with halogen, and C 1-4 alkoxy optionally substituted with halogen.
27. The use according to any one of claims 1 to 5, wherein: each R 5 is independently selected from the group consisting of hydrogen, cl, br, -CN, -CF 3, and-OCH 2CF3.
28. The use according to any one of claims 1 to 5, wherein:
Structural unit Selected from/>And/>
29. The use according to any one of claims 1 to 5, wherein: structural unitSelected from the group consisting of
30. The use according to any one of claims 1 to 5, wherein: structural unitSelected from the group consisting of
31. The use according to any one of claims 1 to 5, wherein:
each R is independently selected from hydrogen, halogen, and C 1-4 alkyl optionally substituted with halogen.
32. The use according to any one of claims 1 to 5, wherein:
Each R is independently selected from hydrogen, F, cl, and CF 3.
33. The use according to any one of claims 1 to 5, wherein:
At least one R is not hydrogen.
34. The use according to any one of claims 1 to 5, wherein:
At least one R is selected from halogen.
35. The use according to any one of claims 1 to 5, wherein:
R 4 is hydrogen or C 1-4 alkyl.
36. The use according to any one of claims 1 to 5, wherein: r 4 is hydrogen or C 1-2 alkyl.
37. The use according to any one of claims 1 to 5, wherein: r 4 is hydrogen.
38. The use according to any one of claims 1 to 5, wherein:
R ' and R " are each independently selected from: hydrogen, C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of 3-10 membered cycloalkyl, C 6-15 aryl, hydroxy and-C (O) OR 8, 3-10 membered cycloalkyl, C 2-6 alkenyl optionally substituted with-C (O) OR 8, C 6-15 aryl optionally substituted with C 1-6 alkyl, and amino optionally substituted with-C (O) OR 7; wherein R 7 is C 1-6 alkyl and R 8 is C 1-6 alkyl.
39. The use according to any one of claims 1 to 5, wherein:
R ' and R " are each independently selected from: hydrogen, C 1-4 alkyl optionally substituted with a substituent selected from the group consisting of 3-7 membered cycloalkyl, C 6-10 aryl, hydroxy and-C (O) OR 8, 3-7 membered cycloalkyl, C 2-4 alkenyl optionally substituted with-C (O) OR 8, C 6-10 aryl optionally substituted with C 1-4 alkyl, and amino optionally substituted with-C (O) OR 7; wherein R 7 is C 1-4 alkyl and R 8 is C 1-4 alkyl.
40. The use according to any one of claims 1 to 5, wherein:
at least one of R ' and R " is not hydrogen.
41. The use according to any one of claims 1 to 5, wherein:
One of R ' and R " is hydrogen and the other is selected from the following groups: c 1-4 alkyl optionally substituted with a substituent selected from the group consisting of 3-7 membered cycloalkyl, C 6-10 aryl, hydroxy and-C (O) OR 8, 3-7 membered cycloalkyl, C 2-4 alkenyl optionally substituted with-C (O) OR 8, C 6-10 aryl optionally substituted with C 1-4 alkyl, and amino optionally substituted with-C (O) OR 7; wherein R 7 is C 1-4 alkyl and R 8 is C 1-4 alkyl.
42. The use according to any one of claims 1 to 5, wherein:
One of R ' and R " is hydrogen and the other is selected from: methyl, ethyl, isopropyl, cyclopropyl, 1-cyclopropylethyl, phenyl, 2-methylphenyl, benzyl 、-CH(CO2CH3)CH2OH、-C(CO2CH3)＝CH、-NHC(O)C(O)OCH2CH3、-NHC(O)C(O)OCH(CH3)2、, and-NHC (O) C (O) OC (CH 3)3).
43. The use according to any one of claims 1 to 5, wherein:
R 6 is selected from: c 1-4 alkoxy, C 1-4 alkyl optionally substituted with a substituent selected from F, cl and amino optionally substituted with methyl.
44. The use according to any one of claims 1 to 5, wherein: r 6 is selected from methoxy, ethoxy, -CH 2Cl、-CCl3、-CF3, and-CH 2NHCH3.
45. The use of claim 1, wherein the compound of formula I is a compound of formula Ia:
In formula Ia:
Ring A is a 6-20 membered aromatic ring.
46. The use according to claim 45, wherein ring A is a 6-15 membered aromatic ring.
47. The use according to claim 45, wherein ring A is a 6-10 membered aromatic ring.
48. The use according to claim 45, wherein ring B is a 5-20 membered heteroaromatic ring.
49. The use according to claim 45, wherein ring B is a 5-15 membered heteroaromatic ring.
50. The use according to claim 45, wherein ring B is a 5-10 membered heteroaromatic ring.
51. The use according to claim 45, wherein
Ring A is a benzene ring.
52. The use according to claim 45, wherein
Ring B is a pyridine ring.
53. The method of claim 45, wherein R 1 is located ortho to-N (R 4) C (O) -.
54. The use according to claim 45, wherein R 4 is hydrogen.
55. The use according to claim 45, wherein
Structural unitSelected from/>
56. The use according to claim 45, wherein
Structural unitSelected from/>
57. The use according to claim 45, wherein
Structural unitSelected from/>
58. The use according to claim 45, wherein
Each R is independently selected from hydrogen and halogen.
59. The use according to claim 45, wherein
Each R is independently selected from hydrogen and Cl.
60. The use according to claim 45, wherein
At least one R is not hydrogen.
61. The use according to claim 45, wherein
At least one R is selected from halogen.
62. The use according to claim 45, wherein
Each R 5 is independently selected from hydrogen, halogen, C 1-6 alkyl optionally substituted with halogen, and C 1-6 alkoxy optionally substituted with halogen.
63. The use according to claim 45, wherein
Each R 5 is independently selected from hydrogen, halogen, C 1-4 alkyl optionally substituted with halogen, and C 1-4 alkoxy optionally substituted with halogen.
64. The use according to claim 45, wherein
Each R 5 is independently selected from hydrogen, cl, br, -CF 3, and-OCH 2CF3.
65. The use of claim 1, wherein the compound of formula I is a compound of formula Ib:
In formula Ib:
Ring a and ring B are each independently a 6-20 membered aromatic ring.
66. The use according to claim 65 wherein ring A and ring B are each independently a 6-15 membered aromatic ring.
67. The use according to claim 65 wherein ring A and ring B are each independently a 6-10 membered aromatic ring.
68. The use according to claim 65 wherein ring A and ring B are benzene rings.
69. The use of claim 65, wherein each R 0 is independently selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl.
70. The use of claim 65, wherein each R 0 is independently selected from the group consisting of hydrogen, halogen, and C 1-4 alkyl.
71. The use of claim 65, wherein each R 0 is independently selected from the group consisting of hydrogen, cl, and methyl.
72. The method of claim 65, wherein R 1 is located ortho to-N (R 4)C(O)C(O)N(R4) -.
73. The use according to claim 65 wherein R 1 is selected from-C (O) NR 'R".
74. The use of claim 65, wherein R ' and R " are each independently selected from: hydrogen, C 1-6 alkyl, and 3-20 membered cycloalkyl.
75. The use of claim 65, wherein R ' and R " are each independently selected from: hydrogen, C 1-6 alkyl, and 3-to 10-membered cycloalkyl.
76. The use of claim 65, wherein R ' and R " are each independently selected from: hydrogen, C 1-4 alkyl, and 3-7 membered cycloalkyl.
77. The use of claim 65, wherein at least one of R ' and R " is not hydrogen.
78. The use as claimed in claim 65, wherein one of R ' and R " is hydrogen and the other is selected from the group consisting of: methyl, ethyl, isopropyl and cyclopropyl.
79. The use according to claim 65, wherein R 4 is hydrogen.
80. The use according to claim 65, wherein R 5 is-CN.
81. The method of claim 65, wherein the structural unitSelected from/>
82. The method of claim 65, wherein the structural unitSelected from/>
83. The method of claim 65, wherein the structural unitSelected from/>
84. The use of claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof is selected from the following compounds or pharmaceutically acceptable salts or stereoisomers thereof:
/>
85. the use according to claim 1, wherein:
The disease is selected from muscle diseases.
86. The use according to claim 1, wherein:
the disease is selected from central axises, multiple microscopic axises, congenital diseases with fiber-like proportional imbalance, linear body myopathies, malignant hyperthermia, catecholamine sensitive ventricular tachycardia, arrhythmic right ventricular dysplasia, and sudden cardiac death.
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Citations (3)

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CN1829707A (en) * 2003-01-28 2006-09-06 杜邦公司 Cyano anthranilamide insecticides
CN104271562A (en) * 2012-05-07 2015-01-07 株式会社经农 Diaminoaryl derivatives substituted by carbamate and pesticidal composition containing same
CN104488943A (en) * 2014-10-23 2015-04-08 东莞市瑞德丰生物科技有限公司 Insecticidal composition

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Publication number Priority date Publication date Assignee Title
CN1829707A (en) * 2003-01-28 2006-09-06 杜邦公司 Cyano anthranilamide insecticides
CN104271562A (en) * 2012-05-07 2015-01-07 株式会社经农 Diaminoaryl derivatives substituted by carbamate and pesticidal composition containing same
CN104488943A (en) * 2014-10-23 2015-04-08 东莞市瑞德丰生物科技有限公司 Insecticidal composition

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