WO2021073643A1 - Médicament pour le traitement de la stéatohépatite non alcoolique - Google Patents

Médicament pour le traitement de la stéatohépatite non alcoolique Download PDF

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Publication number
WO2021073643A1
WO2021073643A1 PCT/CN2020/121958 CN2020121958W WO2021073643A1 WO 2021073643 A1 WO2021073643 A1 WO 2021073643A1 CN 2020121958 W CN2020121958 W CN 2020121958W WO 2021073643 A1 WO2021073643 A1 WO 2021073643A1
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compound
ring
pharmaceutically acceptable
formula
acceptable salt
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PCT/CN2020/121958
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English (en)
Chinese (zh)
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田心
张喜全
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正大天晴药业集团股份有限公司
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Priority to CN202080071609.1A priority Critical patent/CN114555076B/zh
Publication of WO2021073643A1 publication Critical patent/WO2021073643A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members

Definitions

  • This application belongs to the field of medicine, and relates to a class of drugs for the treatment of non-alcoholic steatohepatitis, specifically, to a class of bicyclic compounds for the treatment of non-alcoholic steatohepatitis.
  • Non-alcoholic steatohepatitis also known as metabolic steatohepatitis, refers to a clinical syndrome with pathological changes similar to alcoholic hepatitis found in people without a history of excessive drinking.
  • the main features are Fatty degeneration of liver cells, ballooning and inflammation of liver lobules, etc., severe cases can progress to liver cirrhosis, and even liver cancer or liver failure.
  • the pathogenesis of non-alcoholic steatohepatitis is complex and is closely related to metabolic disorders such as obesity, type II diabetes, and dyslipidemia. Due to the complexity of the pathogenesis, the drugs currently under research mainly target a variety of possible different receptors or enzymes, such as PPAR ⁇ / ⁇ , FXR, CCR2/5, ASK1, and Caspase. Many drug molecules have entered the clinic. Such as selonsertib, resmetirom, elafibranor and cenicriviroc. However, there is no known correspondence between the inhibition, antagonism or agonism of these receptors or enzymes and the effective treatment of non-alcoholic steatohepatitis.
  • Caspase is a class of cysteine proteases, and many important proteins in cells are its substrates. The process of apoptotic cell death involves the absorption of fragments of cells decomposed by caspase enzymes by other cells, or they are eliminated by macrophages without causing inflammation.
  • the application provides a method for treating non-alcoholic steatohepatitis, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of the treatment.
  • the application also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-alcoholic steatohepatitis.
  • this application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of non-alcoholic steatohepatitis.
  • the application also provides a pharmaceutical composition for treating non-alcoholic steatohepatitis, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the “treatment of non-alcoholic steatohepatitis” includes one or more histopathological characteristics of the patient, for example, in terms of portal inflammation, hepatosteatosis, and ballooning degeneration. (ballooning degeneration), and/or lobular inflammation (lobular inflammation) provide improvement or stop progression.
  • Ring A is selected from a 5-membered heteroaryl group or a 6-membered heteroaryl group, the 5-membered heteroaryl group or 6-membered heteroaryl group is optionally substituted by R;
  • Ring B is selected from phenyl or C 3-6 cycloalkyl, said phenyl or C 3-6 cycloalkyl is optionally substituted by R;
  • R is selected from halogen, OH, NH 2 , or C 1-3 alkyl optionally substituted with 1, 2 or 3 R 1;
  • R 1 is selected from F, Cl, Br, I, OH, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 .
  • the heteroatoms of ring A are independently selected from O, S, or N.
  • the number of heteroatoms of ring A is selected from 1, 2, or 3.
  • the ring A is selected from oxazolyl, isoxazolyl, imidazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or pyridine. Azole.
  • the ring A is selected from
  • the ring B is selected from phenyl or cyclohexyl, and the phenyl or cyclohexyl is optionally substituted with R.
  • the R is selected from F, Cl, Br, I, OH, NH 2 , or Me or Et optionally substituted with 1, 2, or 3 R 1.
  • the above-mentioned R 1 is selected from F, Cl or NH 2 .
  • the R is selected from F, Cl, Br, I, OH, NH 2, or optionally substituted with 1, 2 or 3 F, Me or Et.
  • the R is selected from F, Cl, Br, I, OH, NH 2 or CF 3 .
  • the ring B is selected from:
  • the Selected from The ring B is optionally substituted by R.
  • the compound of formula (I) of the present application is selected from the compound represented by formula (II),
  • ring A and ring B are as defined above.
  • the compound of formula (I) of the present application is selected from the following compounds:
  • the application provides a method for treating non-alcoholic steatohepatitis, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of the treatment.
  • the compound of formula (I) can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted into the free base form of the compound of formula (I) in vivo.
  • the compound of formula (I) is in crystalline form.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by a variety of routes, including but not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, and intraperitoneal , Intramuscular, subcutaneous, or intravenous administration, preferably oral administration.
  • the amount of the compound of formula (I) or its pharmaceutically acceptable salt administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 100 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 80 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 50 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered three times a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered in a single dose or multiple doses.
  • the method of administration can be determined comprehensively according to the drug activity, side effects, patient tolerance, etc., and it is preferable to administer the compound of formula (I) or a pharmaceutically acceptable salt thereof in a continuous administration manner.
  • the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 28 days.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient alone as the sole active ingredient.
  • the application also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-alcoholic steatohepatitis.
  • the application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of non-alcoholic steatohepatitis.
  • the compound of formula (I) can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted into the free base form of the compound of formula (I) in vivo.
  • the compound of formula (I) is in crystalline form.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by a variety of routes, including but not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, and intraperitoneal , Intramuscular, subcutaneous, or intravenous administration, preferably oral administration.
  • the amount of the compound of formula (I) or its pharmaceutically acceptable salt administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 100 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 80 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 50 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered three times a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered in a single dose or multiple doses.
  • the method of administration can be determined comprehensively according to the drug activity, side effects, patient tolerance, etc., and it is preferable to administer the compound of formula (I) or a pharmaceutically acceptable salt thereof in a continuous administration manner.
  • the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 28 days.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient alone as the sole active ingredient.
  • the application also provides a pharmaceutical composition for treating non-alcoholic steatohepatitis, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the compound of formula (I) can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted into the free base form of the compound of formula (I) in vivo.
  • the compound of formula (I) is in crystalline form.
  • the amount of the compound of formula (I) or its pharmaceutically acceptable salt administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 2 mg to 100 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 80 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 50 mg.
  • the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., preferably tablets and capsules.
  • the tablets may be ordinary tablets, dispersible tablets, effervescent tablets, sustained-release tablets, controlled-release tablets or enteric-coated tablets, and capsules may be ordinary capsules, sustained-release capsules, controlled-release capsules or enteric-coated capsules.
  • the oral preparations can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art.
  • Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants and the like.
  • the aforementioned pharmaceutical composition may be administered in a single dose or multiple doses.
  • a pharmaceutical composition formulated in a single dose form for the treatment of non-alcoholic steatohepatitis contains 2 mg to 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the single dose form contains 5 mg to 80 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the single dose form contains 5 mg to 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the above-mentioned pharmaceutical composition can be administered one or more times a day. In some embodiments, the pharmaceutical composition described above is administered once a day. In some embodiments, the pharmaceutical composition described above is administered twice a day. In some embodiments, the pharmaceutical composition described above is administered three times a day.
  • the method of administration can be determined comprehensively according to drug activity, side effects, patient tolerance, etc., and it is preferable to administer the above-mentioned pharmaceutical composition in a continuous administration manner.
  • the administration cycle of the above-mentioned pharmaceutical composition is 28 days.
  • the crystalline form of the compound of formula (I) includes, but is not limited to, crystal I, crystal II, crystal IV, crystal V, crystal VII, crystal VIII, and crystal IX of the compound of formula (I) disclosed in the international patent application WO2019174589. .
  • the in vivo pharmacodynamic study in the DIO/CCl mouse model of this application shows that the compound of formula (I) or its pharmaceutically acceptable salt of this application has a good therapeutic effect on non-alcoholic steatohepatitis, NAS score, balloon Metamorphosis and steatosis have been improved.
  • the compound of formula (I) of the present application also improves blood biochemical indicators in liver injury.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reactions or other problems or complications of the disease are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present application, which is prepared from a compound with specific substituents discovered in the present application and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Certain specific compounds in this application contain basic and acidic functional groups, which can be converted into any base or acid addition salt.
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the pharmaceutically acceptable salt of the present application can be synthesized from a parent compound containing an acidic functional group or a basic functional group by conventional chemical methods.
  • such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
  • the organic solvent is preferably a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.
  • the compounds provided in this application also exist in prodrug forms.
  • the prodrugs of the compounds described herein can easily undergo chemical changes under physiological conditions to convert the claimed compounds.
  • prodrugs can be converted to the compounds of the present application through chemical or biochemical methods in the in vivo environment.
  • Certain compounds of this application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included in the scope of the present application.
  • wedge-shaped solid and dashed keys Represents the absolute configuration of a three-dimensional center, using wavy lines A solid or dashed key representing a wedge
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E and Z geometric isomers.
  • all tautomeric forms are included within the scope of this application.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms.
  • This application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of this application.
  • 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 you want to obtain an enantiomer of a compound of this application, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is removed to provide Pure desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), the molecule is formed with a suitable optically active acid or base to form a diastereomeric salt, and then the salt is obtained by the art
  • the diastereoisomers are resolved by well-known conventional methods, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). All changes in the isotopic composition of the compounds of this application, whether radioactive or not, are included in the scope of this application.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • Ketone substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • C mn refers to having mn carbon atoms in this part.
  • C 3-10 cycloalkyl means that the cycloalkyl has 3-10 carbon atoms.
  • the numerical range in this article refers to each integer in the given range.
  • C 1-10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 Carbon atoms, 9 carbon atoms, or 10 carbon atoms.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • substituents When a substituent can be connected to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • heterocycle or “heterocyclic group” means a stable monocyclic, bicyclic or tricyclic ring containing heteroatoms or heteroatoms, which may be saturated, partially unsaturated or unsaturated ( Aromatic), they contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring. Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the nitrogen atom may be substituted or unsubstituted (ie N or NR, where R is H or other substituents already defined herein).
  • the heterocyclic ring can be attached to any heteroatom or carbon atom pendant group to form a stable structure. If the resulting compound is stable, the heterocyclic ring described herein can be substituted at the carbon or nitrogen position.
  • the nitrogen atom in the heterocyclic ring is optionally quaternized.
  • a preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1.
  • aromatic heterocyclic group or “heteroaryl” means a stable 5-, 6, 7-membered monocyclic or bicyclic or 7, 8, 9 or 10-membered bicyclic heterocyclic aromatic ring, which contains carbon atoms And 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S.
  • the nitrogen atom may be substituted or unsubstituted (ie N or NR, where R is H or other substituents already defined herein).
  • Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S(O) p , p is 1 or 2). It is worth noting that the total number of S and O atoms in the aromatic heterocycle does not exceed 1.
  • Bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) connect two non-adjacent carbon atoms or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In bridged rings, substituents on the ring can also appear on the bridge.
  • hydrocarbyl or its subordinate concepts (such as alkyl, alkenyl, alkynyl, aryl, etc.) by itself or as part of another substituent means a linear, branched or cyclic hydrocarbon
  • the atomic group or a combination thereof can be fully saturated (e.g. alkyl), unitary or polyunsaturated (e.g. alkenyl, alkynyl, aryl), can be mono- or multi-substituted, and can be monovalent (e.g.
  • methyl Group divalent (such as methylene) or multivalent (such as methine), which can include divalent or multivalent atomic groups, with a specified number of carbon atoms (such as C 1 -C 12 representing 1 to 12 carbons, C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • “Hydrocarbon group” includes but is not limited to aliphatic hydrocarbon groups and aromatic hydrocarbon groups.
  • the aliphatic hydrocarbon groups include chain and cyclic hydrocarbon groups, specifically including but not limited to alkyl, alkenyl, and alkynyl groups.
  • the aromatic hydrocarbon groups include but are not limited to 6-12 Elementary aromatic hydrocarbon groups, such as phenyl, naphthyl and the like.
  • the term "hydrocarbyl” refers to linear or branched atomic groups or combinations thereof, which can be fully saturated, unitary or polyunsaturated, and can include divalent and multivalent atomic groups.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, ring Propylmethyl, and homologs or isomers of atomic groups such as n-pentyl, n-hexyl, n-heptyl, and n-octyl.
  • Unsaturated hydrocarbon groups have one or more double bonds or triple bonds, examples of which include but are not limited to vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl) , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • alkyl is used to denote a linear or branched saturated hydrocarbon group, which may be mono-substituted (such as -CH 2 F) or multi-substituted (such as -CF 3 ), and may be monovalent (such as Methyl), divalent (such as methylene) or multivalent (such as methine).
  • alkyl groups examples include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl , T-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the like.
  • cycloalkyl includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom is saturated, can be mono- or poly-substituted, and can be monovalent, divalent or multivalent. Examples of these cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2] dicyclooctyl, [4.4.0] dicyclodecyl, and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • treatment means administering the compound or formulation described in this application to prevent, ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • the term "effective amount” or “therapeutically effective amount” means non-toxic but capable of (i) treating or preventing a specific disease, condition or disorder, (ii) reducing, ameliorating or eliminating specific One or more symptoms of a disease, condition, or disorder, or (iii) the amount of the compound of the present application to prevent or delay the onset of one or more symptoms of a specific disease, condition, or disorder described herein.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • active ingredient refers to a chemical entity that can effectively treat the target disorder, disease or condition.
  • patient refers to a mammal, preferably a human. In some embodiments, the patient is a patient who has failed or lacks standard treatment.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent replacement manners, preferred implementation manners include but are not limited to the embodiments of the present application.
  • NMM stands for N-methylmorpholine
  • DMSO dimethyl sulfoxide
  • HOBt 1-hydroxybenzotriazole
  • EDCI 1-ethyl-( 3-Dimethylaminopropyl) carbodiimide hydrochloride
  • TEMPO tetramethylpiperidine nitroxide
  • T3P stands for propyl phosphoric anhydride
  • DIPEA stands for N,N-diisopropylethylamine.
  • the compound is artificially or
  • the software is named, and the commercially available compounds use the supplier catalog name.
  • LCMS m/z 652.3 [M+Na] + .
  • Example 2-17 Referring to the synthetic route of Example 1, the compound of Example 2-17 was prepared by replacing compound 1-b with a different intermediate acid.
  • Example 18 Referring to the synthetic route of Example 1, the compound of Example 18 was prepared by using intermediate 1-e instead of compound 1-a.
  • the purpose of this study is to study the improvement effect of the compound of the application on NASH in the DIO/CCl 4 mouse model.
  • the DIO+CCl 4 mouse model used in this study is an animal model that simulates the progression of human non-alcoholic fatty liver disease to the NASH process.
  • High-fat diet leads to accumulation and degeneration of fat in liver cells; CCl 4 (intraperitoneal injection, every time Twice a week) to simulate the "second blow" of liver injury.
  • This model is stable and reliable, and has a high similarity to the pathogenesis of human NASH. It has the main pathological characteristics of NASH, including steatosis, apoptosis, inflammation, etc., and also shows elevated plasma aminotransferase (ALT and AST) levels.
  • the model in this experiment includes two steps: high-fat feed and CCl 4 induction.
  • the injection time of CCl 4 should be at least 4 hours apart from the time point of the first administration of the day, and at least 2 hours apart from the time point of the second administration of the BID group.
  • the experiment was divided into 5 groups, namely healthy control group, model group, and test compound group (Example 1, 0.6, 2 and 6 mg/kg).
  • the healthy control group consisted of 9 normal mice. During the experiment, they were fed with ordinary diet without CCl 4 injection; 29 obese mice were used in the model group and the test compound group, the model group was 8 mice, and the test compound group was 7 mice in each group, after grouping, CCl 4 was injected intraperitoneally and different doses of drugs or solvents were given respectively.
  • the grouping and dosage design are shown in Table 3 below.
  • Example 1 the 0.6 mg/kg group was euthanized on Day 11 and Day 20 due to a large weight loss. The number of animals actually included in the statistics in this group was 5.
  • Liver tissues of each group of animals were collected and analyzed for NAS scores after HE staining.
  • NASH Non-alcoholic hepatic steatohepatitis
  • Inflammatory cell infiltration A large number of aggregated inflammatory cells can be seen around the portal area of the liver lobules, mainly neutrophils and macrophages.
  • liver degeneration of liver cells Regular fatty vacuoles can be seen in liver cells, with different sizes, and liver cell nuclei are located at the edge.
  • the inflammatory infiltration, steatosis and ballooning scores of the model group were significantly increased, and the NAS score was also significantly increased, indicating the success of the modeling.
  • the compound of Example 1 showed a dose-dependent improvement in the NAS score at the three doses of 0.6, 2 and 6 mg/kg.
  • the NAS score of the high-dose 6 mg/kg group was significantly reduced (p ⁇ 0.01).
  • the compound of Example 1 can improve ballooning and steatosis at a high dose of 6 mg/kg.
  • the compound of the present application can show a good effect in treating non-alcoholic steatohepatitis in animals.
  • experimental example 1 For the research purpose, experimental equipment and materials, and experimental methods of this experimental example, please refer to experimental example 1.
  • ALT aslanine aminotransferase
  • AST aspartate aminotransferase
  • TG triglycerides
  • TC total cholesterol
  • GLU blood sugar
  • GPO Glycerol-3-phosphate oxidase
  • ALT, AST, TG, TC and GLU in the model group were significantly higher.
  • Example 1 Compared with the model group, the compound of Example 1 can significantly reduce the levels of TG, GLU, ALT, AST and TC in the serum at 2 mg/kg. The specific results are shown in Table 8.

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Abstract

La présente invention concerne le domaine de la médecine, concerne des médicaments pour le traitement de la stéatohépatite non alcoolique, en particulier, des composés cycliques liés pour le traitement de la stéatohépatite non alcoolique, plus particulièrement, un composé tel que représenté par la formule (I) ou l'utilisation de sels pharmaceutiquement acceptables de ceux-ci dans la préparation d'un médicament pour le traitement de la stéatohépatite non alcoolique.
PCT/CN2020/121958 2019-10-18 2020-10-19 Médicament pour le traitement de la stéatohépatite non alcoolique WO2021073643A1 (fr)

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WO2018133870A1 (fr) * 2017-01-23 2018-07-26 正大天晴药业集团股份有限公司 Composé cyclique lié en tant qu'inhibiteur de caspase

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US20080194575A1 (en) * 2006-10-04 2008-08-14 Naiara Beraza Treatment for non-alcoholic-steatohepatitis
KR20080042286A (ko) * 2006-11-09 2008-05-15 주식회사 엘지생명과학 피리다지논 구조를 포함하는 캐스파제 저해제
WO2010120880A1 (fr) * 2009-04-14 2010-10-21 Vertex Pharmaceuticals Incorporated Traitement de maladies hépatiques avec un inhibiteur de caspase
WO2017136309A1 (fr) * 2016-02-01 2017-08-10 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'une stéatohépatite non alcoolique (shna)
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