CN111518020A - MAGL inhibitor and preparation method and application thereof - Google Patents

MAGL inhibitor and preparation method and application thereof Download PDF

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Publication number
CN111518020A
CN111518020A CN201910836454.5A CN201910836454A CN111518020A CN 111518020 A CN111518020 A CN 111518020A CN 201910836454 A CN201910836454 A CN 201910836454A CN 111518020 A CN111518020 A CN 111518020A
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Prior art keywords
aryl
pharmaceutically acceptable
compound
alkyl
arbitrary
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张贵民
王进欣
姚景春
赵桂芳
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Lunan Pharmaceutical Group Corp
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Lunan Pharmaceutical Group Corp
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Priority to CN202080061346.6A priority Critical patent/CN114401946A/en
Priority to JP2022513078A priority patent/JP2022546958A/en
Priority to BR112022004068A priority patent/BR112022004068A2/en
Priority to EP20861878.5A priority patent/EP4043436A4/en
Priority to KR1020227007788A priority patent/KR20220058553A/en
Priority to US17/640,785 priority patent/US20230090255A1/en
Priority to AU2020343737A priority patent/AU2020343737A1/en
Priority to MX2022002720A priority patent/MX2022002720A/en
Priority to CA3150147A priority patent/CA3150147A1/en
Priority to PCT/CN2020/104989 priority patent/WO2021042911A1/en
Publication of CN111518020A publication Critical patent/CN111518020A/en
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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 invention belongs to the field of medicines, and relates to a compound shown as a formula I and a pharmaceutically acceptable salt thereof, in particular to an MAGL inhibitor, a preparation method and an application thereof

Description

MAGL inhibitor and preparation method and application thereof
Technical Field
The invention relates to the field of medicines, and in particular relates to a MAGL inhibitor, and a preparation method and application thereof.
Background field of the invention
Monoacylglycerol lipases (MAGL) are a class of serine hydrolases that promote the breakdown of fat into glycerol and fatty acids, and are highly expressed in human invasive and primary tumor cells. High levels of MAGL can maintain high pathogenicity of tumor cells by increasing the levels of free fatty acids. The MAGL has become an important target for the development of anti-tumor drugs.
The invention content is as follows:
the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0002192313330000011
wherein R is H or C1-5Alkyl of (a), said C1-5Is selected from methyl, ethyl, propyl, isopropylPropyl, n-butyl, isobutyl, neopentyl, n-pentyl, isopentyl, neopentyl, cyclopentyl or substituted by halogen, hydroxy, carboxy, C1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C3-8Cycloalkoxy, aryl, heteroaryl substituted C1-5Alkyl groups of (a); the number of R is 0,1,2,3 or 4;
Ar1、Ar2are each independently selected from C5-18Aryl, heteroaryl, (C6-10 aryl) -C1-4 alkyl-, (C6-10 aryl) -C1-4 alkyl- (C6-10 aryl), (5-to 10-membered heteroaryl) -C1-4 alkyl- (C6-10 aryl), (C6-10 aryl) - (C6-10 aryl), (C6-10 aryl) -O- (C6-10 aryl), (C6-10 aryl) -O- (5-to 10-membered heteroaryl), (5-to 10-membered heteroaryl) - (5-to 10-membered heteroaryl), the substitution position being arbitrary;
X1、X2each independently selected from H, hydroxy, carboxy, halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic radical, C3-8Cycloalkoxy, aryl, heteroaryl, C substituted by hydroxy, carboxy, halogen, alkyl1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C3-8One or more of cycloalkoxy, aryl and heteroaryl, and the substituted position is arbitrary.
The compound of the formula I or the pharmaceutically acceptable salt thereof, wherein R is H, and the corresponding structural formula is shown in the specification
Figure BDA0002192313330000021
Wherein Ar is1、Ar2Are each independently selected from C5-18Aryl, heteroaryl, (C6-10 aryl) -C1-4 alkyl-, (C6-10 aryl) -C1-4 alkyl- (C6-10 aryl), (5-to 10-membered heteroaryl) -C1-4 alkyl- (C6-10 aryl), (C6-10 aryl) - (C6-10 aryl), (C6-10 aryl) -O- (C6-10 aryl), (C6-10 aryl) -O- (5-to 10-membered heteroaryl), (5-to 10-membered heteroaryl) - (5-to 10-membered heteroaryl), with arbitrary substitution positions;
X1、X2each independently selected from H, hydroxy, carboxy, halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic radical, C3-8Cycloalkoxy, aryl, heteroaryl, C substituted by hydroxy, carboxy, halogen, alkyl1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C3-8One or more of cycloalkoxy, aryl and heteroaryl, and the substituted position is arbitrary.
Specifically, Ar is1、Ar2Are each independently selected from C5-18Aryl, heteroaryl, (C6-10 aryl) -C1-4 alkyl-, (C6-10 aryl) -C1-4 alkyl- (C6-10 aryl), (5-to 10-membered heteroaryl) -C1-4 alkyl- (C6-10 aryl), (C6-10 aryl) - (C6-10 aryl), (C6-10 aryl) -O- (C6-10 aryl), (C6-10 aryl) -O- (5-to 10-membered heteroaryl), (5-to 10-membered heteroaryl) - (5-to 10-membered heteroaryl), the substitution position being arbitrary;
X1、X2each independently selected from H, hydroxy, carboxy, halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic radical, C3-8Cycloalkoxy, aryl, heteroaryl, C substituted by hydroxy, carboxy, halogen, alkyl1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C3-8One or more of cycloalkoxy, aryl and heteroaryl, and the substituted position is arbitrary.
In some embodiments, Ar1Is one or more of benzene, naphthalene, diphenyl ether and biphenyl, and the substitution position is arbitrary;
X1is one or more of H, methoxy, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary;
Ar2is benzene;
X2is one or more of H, methyl, dimethyl, methoxyl, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary.
In the detailed descriptionAr is described1In the meta position.
In some embodiments, the Ar is1Is one or more of benzofuranyl, benzimidazolyl, benzoxazolyl, indolyl, benzothienyl, quinolyl, isoquinolyl and purinyl, and the substitution position is arbitrary;
X1is one or more of H, methyl, methoxy, hydroxyl, fluorine, chlorine and bromine, and the position of the substituent is arbitrary;
Ar2is phenyl, and the position of the substituent is arbitrary;
X2is one or more of H, methyl, dimethyl, methoxyl, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary. In some embodiments, formula 1 above may be defined as formula III, as shown below
Figure BDA0002192313330000031
Wherein, said R is1Selected from hydroxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy; r2Selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy, phenyl, and aryl substituted with hydroxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy. R1、R2The number of (A) is 0 or 1 or 2 or 3 or 4; r1、 R2The manner of linkage to the parent nucleus is not limited to a single bond connection.
The invention provides a compound shown in a formula b,
Figure BDA0002192313330000032
the compound is used for synthesizing a compound of a formula I, wherein Ar is2、X2Is described by formula 1.
The invention provides a synthesis method of a compound shown as a formula I, which comprises the following specific steps:
Figure BDA0002192313330000033
salts of b or b with
Figure BDA0002192313330000041
Reacting to obtain I; ar is1、X1Is described by formula 1.
Salts of said b or b with
Figure BDA0002192313330000042
Reacting to obtain I; in the step, a condensing agent and alkali are added to facilitate the reaction, wherein the condensing agent is selected from HBTU, DMC, HOBT/EDCI, HATU/DIEPA, DCC, CDI and isopropyl chloroformate; the structural formulas are respectively as follows:
the salt of b or b is obtained by deprotection of a;
Figure BDA0002192313330000043
the base is an organic base such as N, N-Diisopropylethylamine (DIPEA), Diethylamine (DEA) or Triethylamine (TEA).
The salt of a or a is formed by
Figure BDA0002192313330000044
Or a salt thereof;
Figure BDA0002192313330000045
wherein sm can be prepared by the prior art or can be synthesized by a person skilled in the art on the basis of the prior art by a limited number of experiments without any inventive effort. In the reaction, a condensing agent and alkali are added to facilitate the reaction, wherein the condensing agent is selected from HBTU, DMC, HOBT/EDCI, HATU/DIEPA, DCC, CDI and isopropyl chloroformate.
In some embodiments, the following method may be adopted:
Figure BDA0002192313330000051
wherein, the reducing agent is preferably NaBH4、KBH4、NaBH4At least one of LiCl.
The solvent used in the above or below steps of the present invention is not specifically described, and is selected from solvents that are conventional in the art, and the principle of the solvent is to dissolve reactants but not participate in the reaction, extract the product or separate the corresponding product from impurities by crystallization, such as water, halogenated alkanes, alkyl amines, aliphatic hydrocarbons, esters, alcohols, aromatic hydrocarbons, ethers, heterocyclic solvents; specifically selected from, but not limited to, these solvents: methanol, ethanol, propanol, isopropanol, diethyl ether, ethyl acetate, acetic acid, cyclohexane, dichloromethane, chloroform, tetrahydrofuran, pyridine, diethylamine, triethylamine, dimethylformamide, toluene and mixtures of at least two thereof.
The numbers a, b, etc. used in the present invention are numbers used for describing the general formula conveniently, and they may be modified into other numbers such as 1,2,3, etc. in the specific embodiment, which are for convenience of description, and do not affect the structural formula and the fact of the reaction equation belonging to the general formula and the expression of the reaction equation of the general formula. The skilled person will be able to judge that the substituents of each intermediate in all the above synthetic routes depend on the structure of the target compound.
The chiral isomers or cis-trans isomers and mixtures of isomers in any ratio in the compounds covered by the general formula of the target compounds of the general formula I and the specific substances thereof are also included in the scope of the compounds covered by the general formula of the target compounds of the general formula I and the specific substances thereof.
The solvent used in the above or below steps of the present invention is not specifically described, and is selected from solvents that are conventional in the art, and the principle of the solvent is to dissolve reactants but not participate in the reaction, extract the product or separate the corresponding product from impurities by crystallization, such as water, halogenated alkanes, alkyl amines, aliphatic hydrocarbons, esters, alcohols, aromatic hydrocarbons, ethers, heterocyclic solvents; specifically selected from, but not limited to, these solvents: methanol, ethanol, propanol, isopropanol, diethyl ether, ethyl acetate, acetic acid, cyclohexane, dichloromethane, chloroform, tetrahydrofuran, pyridine, diethylamine, triethylamine, dimethylformamide, toluene and mixtures of at least two thereof.
In the above or below reactions of the present invention, when the reactant is in excess, the reaction may be terminated by quenching the reaction with the addition of a substance capable of reacting with the excess reactant. Quenching with water or saturated ammonium chloride can be used as in some examples.
In the above or below reactions of the present invention, the product is purified by a method selected from extraction, crystallization, solvent removal, and column chromatography; the operation is conventional in the art, and the skilled person can carry out the treatment according to specific situations.
The general formulae and general formula synthesis methods of the present invention may derive specific substances that are not limited to these, and the specific compounds obtainable by a person skilled in the art without any inventive effort, guided by the general formulae and general formula synthesis methods of the present invention, are within the scope of the present invention.
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
The invention provides a pharmaceutical composition, which comprises the compound, namely the compound covered by the general formula of the target compound I, a specific substance of the compound, or pharmaceutically acceptable salt of the compound, and one or more pharmaceutically acceptable pharmaceutic adjuvants.
The present application provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition includes, but is not limited to, oral dosage forms, parenteral dosage forms, topical dosage forms, and rectal dosage forms. The composition may be in the form of a liquid, solid, semi-solid, gel, or aerosol. In some embodiments, the pharmaceutical composition may be tablets, capsules, pills, powders, sustained release formulations, solutions and suspensions for oral administration, sterile solutions, suspensions or emulsions for parenteral injection, ointments or creams for topical use, or suppositories for rectal administration. In other embodiments, the pharmaceutical composition is in unit dosage form suitable for single administration of a precise dose
The invention provides all the compounds or pharmaceutically acceptable salts and pharmaceutical compositions thereof, and application thereof as monoacylglycerol esterase inhibitors; or for the manufacture of a medicament for the treatment of a disease or condition characterised by a pathology of a monoacylglycerol esterase metabolic pathway.
The present invention provides methods for inhibiting monoacylglycerol esterases with all of the above compounds or their pharmaceutically acceptable salts and pharmaceutical compositions thereof. The methods include methods of inhibiting monoacylglycerol esterases in vivo and in vitro. Also provided are methods of using all of the above compounds, or pharmaceutically acceptable salts and pharmaceutical compositions thereof, for treating monoacylglycerol esterase-mediated diseases or conditions.
Wherein the condition is selected from: metabolic disorders (e.g., obesity); renal diseases (e.g., acute inflammatory kidney injury and diabetic nephropathy); emesis or emesia (e.g., chemotherapy-induced emesis); nausea (e.g., refractory nausea or chemotherapy-induced nausea); eating disorders (e.g., anorexia or bulimia); neuropathy (e.g., diabetic neuropathy, pellagra neuropathy, alcoholic neuropathy, beriberi neuropathy); neurodegenerative disorders [ Multiple Sclerosis (MS), Parkinson's Disease (PD), Huntington's disease, dementia, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), epilepsy, frontotemporal dementia, sleep disorders, Creutzfeldt-Jakob disease (CJD) or prion diseases ]; schizophrenia; depression; bipolar disorder; shaking; movement disorders; tension disorder; spasticity; tourette's syndrome; withdrawal syndrome [ withdrawal syndrome, antidepressant withdrawal syndrome, antipsychotic withdrawal syndrome, benzodiazepine withdrawal syndrome, cannabis withdrawal, neonatal withdrawal, nicotine withdrawal or opioid withdrawal ]; traumatic brain injury; non-traumatic brain injury; spinal cord injury; seizures; a disorder associated with abnormal cell growth or proliferation [ e.g., a benign tumor or cancer, such as a benign skin tumor, brain tumor, papilloma, prostate tumor, brain tumor (glioblastoma, medulloblastoma, astrocytoma, ependymoma, oligodendroglioma, plexus tumor, neuroepithelioma, epiphyseal tumor, ependymoma, malignant meningioma, sarcoidosis, melanoma, schwannoma), melanoma, metastatic tumor, kidney cancer, bladder cancer, brain cancer, Glioblastoma (GBM), gastrointestinal cancer, leukemia, or blood cancer ]; inflammatory disorders [ e.g., appendicitis, bursitis, colitis, cystitis, dermatitis, phlebitis, rhinitis, tendonitis, tonsillitis, vasculitis, acne vulgaris, chronic prostatitis, glomerulonephritis, hypersensitivity, IBS, pelvic inflammatory disease, sarcoidosis, HIV encephalitis, rabies, brain abscess, neuroinflammation, Central Nervous System (CNS) inflammation ]; immune system disorders (e.g., transplant rejection or celiac disease); post-traumatic stress disorder (PTSD); acute stress disorder; panic disorder; substance-induced anxiety; obsessive Compulsive Disorder (OCD); agoraphobia; specific phobias; social phobia; anxiety disorders; attention Deficit Disorder (ADD); attention Deficit Hyperactivity Disorder (ADHD); pain [ e.g., acute pain; chronic pain; inflammatory pain; visceral pain; post-operative pain; migraine headache; low back pain; joint pain; abdominal pain; chest pain; post-mastectomy pain syndrome; menstrual pain; endometriosis pain; pain due to physical trauma; headache; sinus headache; tension headache, arachnoiditis, herpes virus pain, diabetic pain; pain resulting from a condition selected from: osteoarthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, labor, musculoskeletal diseases, skin diseases, toothache, heartburn, burn, sunburn, snake bite, venomous snake bite, spider bite, insect bite, neurogenic bladder, interstitial cystitis, Urinary Tract Infection (UTI), rhinitis, contact dermatitis/hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, Irritable Bowel Syndrome (IBS), cholecystitis, and pancreatitis; neuropathic pain (e.g., neuropathic low pain, complex regional pain syndrome, pillar trigeminal neuralgia, causalgia, toxic neuropathy, reflex sympathetic dystrophy, diabetic neuropathy, chemotherapy-induced chronic neuropathy, or sciatica pain); demyelinating diseases [ e.g. Multiple Sclerosis (MS), veryke's disease, CNS neuropathy, central pontine myelination, syphilitic myelopathy, leukoencephalopathy, leukodystrophy, guillain-barre syndrome, chronic inflammatory demyelinating polyneuropathy, anti-myelin-associated glycoprotein (MAG) peripheral neuropathy, charcot-marie-tooth-tree disease, peripheral neuropathy, myelopathy, optic neuropathy, progressive inflammatory neuropathy, optic neuritis, transverse myelitis ]; and cognitive impairment [ e.g., cognitive impairment associated with down's syndrome; cognitive impairment associated with alzheimer's disease; cognitive impairment associated with PD; mild Cognitive Impairment (MCI), dementia, post-chemotherapy cognitive impairment (PCCI), post-operative cognitive dysfunction (POCD) ].
Certain chemical terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter of the application. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It should also be noted that the use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the terms "include", "including" and other forms, such as "includes", "including" and "including", are used in a non-limiting sense.
Can be found in the reference (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4)THED. "Vols.A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR and UV/Vis spectroscopy, and pharmacological methods. Unless a specific definition is set forth, it is analyzed hereinThe terminology used in the description of chemistry, organic synthetic chemistry, and related medicines and pharmaceutical chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner known in the art or as described herein. The techniques and methods described above can generally be practiced according to conventional methods well known in the art, as described in various general and more specific documents referred to and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.
When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, CH2O is equivalent to OCH2。
The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes. The compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetrically substituted carbon atoms of the present application may be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents. The compounds of the present application also include tautomeric forms. Tautomeric forms result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton. The compounds of the present application also include all isotopic atoms, whether in the intermediate or final compound. Isotopic atoms include those having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. That is, the compounds of the present application include compounds in which part or all of hydrogen (H) is replaced with tritium (T) and/or deuterium (D); also includes part or all of12C quilt13C and/or14C substituted compound; and compounds substituted between other isotopes (e.g. N, O, P, S), e.g.14N and15N；18o and17O；31p and32P；35s and36s and the like. The compounds described herein may have one or more stereogenic centers, and each stereogenic center may exist in the R or S configuration or a combination thereof. Similarly, the compounds described herein may have one or more double bonds, and each double bond may exist in either the E (trans) or Z (cis) configuration, or a combination thereof. A particular stereoisomer, structural isomer (regioisomer), diastereoisomer, enantiomer or epimer is understood to include all possible isomers, such as stereoisomers, structural isomers, diastereomers, enantiomers or epimers and mixtures thereof. Thus, the compounds described herein include all configurationally different stereoisomers, structural isomers, diastereomers, enantiomers, or epimers, as well as the corresponding mixtures thereof. Techniques for converting or leaving as is a particular stereoisomer are well known in the art, as well as techniques for resolving mixtures of stereoisomers, and one skilled in the art will be able to select the appropriate method for a particular situation. See, e.g., Fumisset al (eds.), VOGEL' S ENCYCOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5. THED., Longman Scientific and Technical Ltd., Essex,1991, 809-816; and Heller, Acc.chem.Res. 1990,23, 128.
The terms "optionally/any" or "optionally/optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
Certain pharmaceutical terms
As used herein, the term "treating" and other similar synonyms include alleviating, alleviating or ameliorating a symptom of a disease or disorder, inhibiting a disease or disorder, e.g., arresting the development of a disease or disorder, alleviating a disease or disorder, ameliorating a disease or disorder, relieving a symptom caused by a disease or disorder, or halting a symptom of a disease or disorder, preventing another symptom, ameliorating or preventing an underlying metabolic cause that causes the symptom, and further, the term includes the purpose of prevention. The term also includes obtaining a therapeutic effect and/or a prophylactic effect. The therapeutic effect refers to curing or ameliorating the underlying disease being treated. In addition, a cure or amelioration of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, e.g., an improvement in the condition of the patient is observed, although the patient may still be affected by the underlying disease. For prophylactic effect, the composition can be administered to a patient at risk of developing a particular disease, or to a patient presenting with one or more physiological symptoms of the disease, even if a diagnosis of the disease has not yet been made.
The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one active agent (e.g., a compound of the present application) that is sufficient to alleviate, to some extent, one or more of the symptoms of the disease or disorder being treated upon administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is clinically necessary to provide a significant relief from the condition. An effective amount suitable in any individual case can be determined using techniques such as a dose escalation assay.
The terms "administering," "administration," "administering," and the like as used herein refer to a method capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, the pharmacological Basis of Therapeutics, current ed.; pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.
The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no long-term deleterious effect on the general health of the subject being treated.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
The term "pharmaceutical composition" as used herein refers to a mixture of a compound of the present application in admixture with at least one pharmaceutically acceptable material. The pharmaceutically acceptable material includes, but is not limited to, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and/or excipients.
The term "carrier" as used herein refers to a relatively non-toxic substance that facilitates the introduction of the compounds of the present application into a cell or tissue.
The term "pharmaceutically acceptable salt" as used herein refers to salts that retain the biological potency of the free acid and free base of the specified compound, and that are biologically or otherwise not adversely affected. The compounds of the present application also include pharmaceutically acceptable salts. Pharmaceutically acceptable salts refer to the form in which the base group in the parent compound is converted to a salt. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (amino) groups. Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound by reacting a basic group in the parent compound with 1-4 equivalents of an acid in a solvent system. Suitable salts are listed in Remingtong's Pharmaceutical sciences, 17thed., MackPublishing Company, Easton, Pa.,1985, p.1418 and Journal of pharmaceutical science,66,2 (1977).
Unless otherwise indicated, salts in this application refer to acid salts formed with organic/inorganic acids, as well as basic salts formed with organic/inorganic bases. In addition, when the basic functional group of the compound of formula (la) is pyridine or imidazole (but not limited to pyridine or imidazole) and the acidic functional group is carboxylic acid (but not limited to carboxylic acid), zwitterions (inner salts) are formed and are included in the salts herein.
The specific implementation mode is as follows:
the specific compound representatives of the invention can be synthesized by the general formula synthesis method disclosed by the invention. The present invention will be further described with reference to specific embodiments, but the present invention is not limited thereto. Under the guidance of the general formula, the general formula synthesis method and the specific implementation mode of the invention, other specific compounds which can be obtained by a person skilled in the art without creative efforts are all within the scope of the invention.
Example 1
Figure BDA0002192313330000111
Preparation of synthesis intermediate a of (1):
N-Boc-4 piperidinecarboxylic acid (458.6mg, 2mmol, 1eq) was dissolved in 15ml DCM, DIPEA (0.7ml, 4mmol, 2eq) was added, HATU (912mg, 2.4mmol, 1.2eq) was added and stirred at room temperature for 10 min. Aniline (0.365ml, 4mmol, 2eq) was added, stirred at room temperature for 12h, washed twice with water, washed twice with 0.1M dilute HCl, and the solvent was distilled off under reduced pressure to give intermediate a without purification.
Preparation of intermediate b:
intermediate a was dissolved in 10ml ethyl acetate, 2ml HCl/EA solution was added thereto, and the mixture was stirred at room temperature for 24 hours to precipitate a white solid, which was filtered with suction and washed with ethyl acetate to obtain 347.5mg (72.4%) of intermediate b as a white solid.
Preparation of MAGLZ-II-01:
intermediate b (120mg, 0.5mmol, 1.5eq) was dissolved in 10ml dmf, TEA (0.23ml, 1.65mmol, 5eq) was added, stirring was carried out at room temperature for 30min, HATU (152mg, 0.4mmol, 1.2eq) was added, 4-phenoxybenzoic acid (71.4mg, 0.33mmol, 1eq) was added, stirring was carried out at room temperature for 2h to complete the reaction, a saturated sodium chloride solution was added to the reaction solution, extraction was carried out 3 times with ethyl acetate, the organic phases were combined, the saturated sodium chloride solution was washed 3 times, dried over anhydrous sodium sulfate, and purification was carried out by column chromatography (petroleum ether/ethyl acetate: 1) to give the target compound as a pale yellow solid, 102.4mg (76.8%).
1HNMR(CDCl3) (ppm):7.80-7.88(m,1H),7.47-7.54(m,2H),7.29-7.39(m,5H),6.96-7.19(m,6H),2.79-3.05(m,2H), 2.45-2.58 (m,1H),1.65-2.06(m, 6H). MS results are comparable to theoretical values.
Examples 2-22 were prepared on the basis of a general synthesis procedure, similar to example 1, with the MS results for each target product being comparable to the theoretical values and the NMR results being as follows:
Figure BDA0002192313330000121
Figure BDA0002192313330000131
Figure BDA0002192313330000141
Figure BDA0002192313330000151
Figure BDA0002192313330000161
Figure BDA0002192313330000171
example 22-description of the synthesis of the target product of example 30 is based on the following structural formula:
Figure RE-GDA0002253158440000012
wherein, R is1Selected from hydroxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy; r2Selected from hydroxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy, phenyl, and aryl substituted with hydroxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy. R1、R2The number of (A) is 0 or 1 or 2 or 3 or 4; r1、R2Linking to parent nucleusThe manner is not limited to a single bond.
Figure BDA0002192313330000173
Figure BDA0002192313330000181
Figure BDA0002192313330000191
Example 34: MAGL enzyme assay
A reagent kit for screening the MAGL inhibitor of Cayman is adopted, according to the instruction, ethanol solution of 4-nitrophenylacetic acid is used as a substrate of MAGL, the final concentration of the substrate is 236UM.96 pore plates, 150 microliters of 1Xassay buffer, 10 microliters of recombinant human MAGL protein and 10 microliters of MAGL inhibitor (six points between 1nM and 1000 nM) with different concentrations are added into each pore, JZL195 (positive control inhibitor) is used as a positive control pore, after incubation for 5min at room temperature, 10 microliters of MAGL substrate is added into each pore, 86 pores are vibrated for 10 seconds, placed for 10min at room temperature, and the light absorption value of 410nM is detected. Also, 100% inhibition control wells (three duplicate wells were set with 150. mu.l of 1 Xassaay buffer, 10. mu.l of MAGL, and 10. mu.l of DMSO per well in a 96-well plate) and background wells (three duplicate wells were set with 160. mu.l of 1 Xassaay buffer and 10. mu.l of DMSO per well). IC50 curves fitted to each inhibitor were then calculated using graphpad prism 5.0, the specific values are shown in table 2.
Table 2 activity data
Figure BDA0002192313330000192
Figure BDA0002192313330000201
Figure BDA0002192313330000211
Example 35 tissue distribution assay for MAGL inhibitors
Detection reagent: MAGLZ-II-11, MAGLZ-II-16, MAGLZ-II-17;
test subjects: a mouse;
administration dose: 16mg/kg (formulation concentration: 8 mg/ml);
the administration mode comprises the following steps: subcutaneous injection;
sampling time: samples were taken 1,2, 5 hours after dosing;
and (3) detecting tissues: brain, heart, liver, spleen, lung, kidney, pancreas, blood;
the experimental results show that:
all 3 subjects were distributed in the brain examined, with the highest MAGLZ-II-16, 17-fold and the lowest MAGLZ-II-11 in the brain (Table 3).
TABLE 3 tissue distribution map
Figure BDA0002192313330000212
Figure BDA0002192313330000221
Example 36 Effect of MAGL on reserpine induced Depression in mice
1) Basic information
The species are as follows: ICR mice
Microorganism grade: SPF stage
Number and sex of animals purchased: male: 75, females: 75 are provided with
Animal numbers and sex were used: male: 75, females: 75 are provided with
Weight: 13 to 18g at the time of reception
2) Grouping animals
Group design: each batch of animals had 50 animals for a total of 3 batches; each batch of animals was randomly divided into 5 groups by weight: the low, medium and high dose test article groups, the blank control group and the model group, one test article per batch.
3) Test method
3.1 subcutaneous injections were given once daily at doses of 4, 8, 16mg/kg for 6 days. After 2h of the last administration, each animal except the placebo group was injected subcutaneously with reserpine at 4mg/kg, and then indexes of arousal, finger contact, fear, head touch, autonomic activity, erectness, eyelid closure, etc. were measured 2h later.
TABLE 4
Figure BDA0002192313330000222
Figure BDA0002192313330000231
Figure BDA0002192313330000241
Figure BDA0002192313330000251
4) Statistical analysis
Data statistics and analysis were performed by computer using software SPSS version 17.0 and office 2016, and data statistics was performed using Kruskal-Wallis test. If the Kruskal-Wallis test results are significant (P.ltoreq.0.05), then the Mann-Whitney U nonparametric test method is further used for multiple comparison test.
5) Results
5.1)MAGLZ-Ⅱ-11：
Non-parametric inspection
The indexes of Kruskal-Wallis test have statistical difference (P is less than 0.05);
comparison of differences between groups
Mann-Whitney U test
Compared with the solvent control group, the model group has statistical difference (P is less than 0.05), which indicates that the molding result is good; the low and medium dose groups were not statistically different (P > 0.05) from the model group; compared with the model control group, the high-dose group and the model control group show statistical differences (P is less than 0.01, P is less than 0.05) in autonomous activity and uprightness, and the index change trend is consistent with that of the vehicle control group.
5.2) MAGLZ-II-17: the indexes of Kruskal-Wallis test have statistical difference (P is less than 0.05); Mann-Whitney U test
Compared with the solvent control group, the model group has statistical difference (P is less than 0.05), which indicates that the molding result is good;
the low dose was not statistically different from the model group (P > 0.05);
the eyelids of the medium dose group have no statistical difference (P is less than 0.05) compared with the model group, but the average value is smaller than that of the model group, and other indexes have no statistical difference (P is more than 0.05);
the eyelids of the high-dose group have no statistical difference (P is less than 0.01) compared with the model group, but the average value is smaller than that of the model group, and other indexes have no statistical difference (P is more than 0.05);
5.3) MAGLZ-II-16: the indexes of Kruskal-Wallis test have statistical difference (P is less than 0.05); Mann-Whitney U test
Compared with the solvent control group, the model group has statistical difference (P is less than 0.05), which indicates that the molding result is good;
the low dose was not statistically different from the model group (P > 0.05);
compared with the model group, the head contact of the medium-dose group has statistical difference (P is less than 0.05), the average value is larger than that of the model group, the trend change is the same as that of the solvent control group, and other indexes have no statistical difference (P is more than 0.05);
compared with the model group, the head contact and the autonomic activity of the high-dose group have no statistical difference (P is less than 0.05), the average value is larger than that of the model group, the trend change is the same as that of the vehicle control group, and other indexes have no statistical difference (P is more than 0.05);
6) conclusion
6.1) under the test condition, MAGLZ-II-11 has certain influence on depression caused by reserpine.
6.2) under the test condition, MAGLZ-II-16 has certain influence on depression caused by reserpine.
6.3) under the test conditions, MAGLZ-II-17 may have the effect of strengthening the influence on the reserpine to cause depression.
Example 37
1 materials and methods
1.1 Experimental animals
Male IC R mice weighing 18-22 g. Animals were kept in normal 12h light, 12h dark schedule. The ambient temperature and relative humidity were maintained at 22 + -1 deg.C and 55 + -5%, respectively.
1.2 Experimental methods
1.2.1 animal grouping and administration methods
7 groups of experimental mice, 10 mice per group, were set as a control group (saline group), a positive control group (fluoxetine hydrochloride capsule, 5mg/kg), 5 MAGLZ-II series of treatment groups for drug administration: respectively MAGLZ-II-06, MAGLZ-II-07, MAGLZ-II-11, MAGLZ-II-17, MAGLZ-II-18, at a concentration of 5 mg/kg.
All drugs were administered by gavage at a dose of 20mL/kg body weight, 1 time/day, for 10 days. Animal behavioral testing was initiated 1h after the last dose.
1.2.2 forced swimming test of mice
Forced swimming experiments in mice were performed according to the method established by Portoll (Portal D. Behavioural despain in mice: aprimar screening test for antiperesation [ J ]. Arch. int. Pharmacolodyn.1977, 229). Mice were forced individually to swim in an open cylindrical container (diameter 10cm, height 25cm) with water temperature 25 ± 1 ℃ and water depth 19cm, and the total time each animal remained immobile over the course of 6 minutes was recorded as the immobility time (in seconds). Each mouse was judged to be immobile when stopped struggling and remained suspended in the water, making only the necessary movements to keep the head above the water surface. A reduction in immobility time indicates an antidepressant action.
1.2.3 mouse Tail suspension test
The Tail Suspension Test (TST) was performed according to the method established by Porsolt et al (Porsolt R D, Le Pichia M, Jalframe. Depression: a new animal model sensitive to anti-reactive reagents [ J ] Nature,1977,266(5604): 730-. Mice were suspended separately from the tail at a distance of 10mm from the tail and 5cm from the head to the bottom of a box (250 mm. times.250 mm. times.300 mm) using tail suspension clips. Noise was tested in a dark room with minimal background, each mouse was suspended for 6 minutes and immobility time was recorded at the last 4 minute interval. The criteria for the decision were that the mice stopped struggling and were completely motionless.
1.2.4 data processing
All data are provided with
Figure BDA0002192313330000272
Showing that the comparison among groups adopts one-way analysis of variance.
2 results
2.1 Effect of MAGLZ-II series Compounds on forced swimming behavior in mice
The experiment of the effect of the MAGLZ-II series compounds on the forced swimming behavior of the mice shows that the positive control drugs of fluoxetine hydrochloride and the MAGLZ-II series compounds can obviously shorten the accumulative immobility time (P is less than 0.05) of the forced swimming of the mice (Table 1).
TABLE 1 Effect of MAGLZ-II series Compounds on forced swimming behavior in mice
Figure BDA0002192313330000271
Note: compared with the control group, the compound of the formula,*P＜0.05，**P＜0.01。
2.2 Effect of MAGLZ-II series Compounds on Tail suspension behavior in mice
Compared with the control group, the MAGLZ-II series compound groups can obviously shorten the cumulative immobility time (P is less than 0.05) of tail suspension mice (Table 2).
TABLE 2 Effect of MAGLZ-II series Compounds on mouse Tail suspension behavior
Figure BDA0002192313330000281
Note: compared with the control group, the compound of the formula,*P＜0.05，**P＜0.01。
discussion of 3
Forced swimming of mice and tail suspension of mice are the more common and classical animal models of depression. The states of mouse despair, behavior distortion and the like reflected by the model are the remarkable characteristics of in vitro simulated depression, and the model is a commonly used screening model of antidepressant drugs because the antidepressant drugs are sensitive and convenient to operate. The study further evaluated and verified the antidepressant activity of the MAGLZ-II series compounds using these two classical animal models of depression. The results show that the MAGLZ-II series compounds can obviously shorten the accumulation immobility time of forced swimming and tail suspension of mice, and show that the MAGLZ-II series compounds have definite antidepressant effect.

Claims (21)

1. A compound of formula I:
Figure FDA0002192313320000011
wherein R is H or C1-5Alkyl of (a), said C1-5The alkyl of (A) is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, neo-butyl, n-pentyl, isopentyl, neopentyl, cyclopentyl or substituted by halogen, hydroxy, carboxy, C1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C3-8Cycloalkoxy, aryl, heteroaryl substituted C1-5Alkyl groups of (a); the number of R is 0,1,2,3 or 4;
Ar1、Ar2are each independently selected from C5-18Aryl, heteroaryl, (C6-10 aryl) -C1-4 alkyl-, (C6-10 aryl) -C1-4 alkyl- (C6-10 aryl), (5-to 10-membered heteroaryl) -C1-4 alkyl- (C6-10 aryl), (C6-10 aryl) - (C6-10 aryl), (C6-10 aryl) -O- (C6-10 aryl), (C6-10 aryl) -O- (5-to 10-membered heteroaryl), (5-to 10-membered heteroaryl) - (5-to 10-membered heteroaryl), the substitution position being arbitrary;
X1、X2each independently selected from H, hydroxy, carboxy, halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic radical, C3-8Cycloalkoxy, aryl, heteroaryl, C substituted by hydroxy, carboxy, halogen, alkyl1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C3-8One or more of cycloalkoxy, aryl and heteroaryl, and the substituent positions are arbitrary.
2. A compound of formula I as claimed in claim 1, wherein R is H, or a pharmaceutically acceptable salt thereof, corresponding to formula
Figure FDA0002192313320000012
Wherein Ar is1、Ar2Are each independently selected from C5-18Aryl, heteroaryl, (C6-10 aryl) -C1-4 alkyl-, (C6-10 aryl) -C1-4 alkyl- (C6-10 aryl), (5-to 10-membered heteroaryl) -C1-4 alkyl- (C6-10 aryl), (C6-10 aryl) - (C6-10 aryl), (C6-10 aryl) -O- (C6-10 aryl), (C6-10 aryl) -O- (5-to 10-membered heteroaryl), (5-to 10-membered heteroaryl) - (5-to 10-membered heteroaryl), the substitution position being arbitrary;
X1、X2each independently selected from H, hydroxy, carboxy, halogen, C1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic radical, C3-8Cycloalkoxy, aryl, heteroaryl, C substituted by hydroxy, carboxy, halogen, alkyl1-3Alkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl radical, C3-8Heterocyclic group, C3-8One or more of cycloalkoxy, aryl and heteroaryl, and the substituent positions are arbitrary.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
Ar1is one or more of phenyl, naphthyl, diphenyl ether group and biphenyl group, and the substitution position is arbitrary;
X1is one or more of H, methoxy, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary;
Ar2is phenyl, and the position of the substituent is arbitrary;
X2is a mixture of H, methyl, dimethyl,one or more of methoxyl, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary.
4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Ar is1In the meta position.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
ar is1Is one or more of benzofuranyl, benzimidazolyl, benzoxazolyl, benzothienyl, indolyl, quinolyl, isoquinolyl and purinyl, and the substitution position is arbitrary;
X1is one or more of H, methyl, methoxy, hydroxyl, fluorine, chlorine and bromine, and the position of the substituent is arbitrary;
Ar2is phenyl, and the position of the substituent is arbitrary;
X2is one or more of H, methyl, dimethyl, methoxyl, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary.
6. The compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the specific structural formula is selected from,
Figure FDA0002192313320000021
Figure FDA0002192313320000031
Figure FDA0002192313320000041
Figure FDA0002192313320000051
7. a compound according to claim 1 which is
Figure FDA0002192313320000061
Or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 which is
Figure FDA0002192313320000062
Or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1 which is
Figure FDA0002192313320000063
Or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1 which is
Figure FDA0002192313320000064
Or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 1 which is of formula III
Figure FDA0002192313320000071
Or a pharmaceutically acceptable salt thereof; wherein, R is1Selected from hydroxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy; r2Selected from the group consisting of hydroxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy, phenyl, and aryl substituted with hydroxy, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, methoxy. R1、R2The number of (A) is 0 or 1 or 2 or 3 or 4; r1、R2The manner of linkage to the parent nucleus is not limited to a single bond connection.
12. A process for the synthesis ofThe compound of the formula I is shown as a formula b,
Figure FDA0002192313320000072
said X2、Ar2As described in claim 1.
13. A method for synthesizing a compound shown as a formula I comprises the following specific steps:
Figure FDA0002192313320000073
salts of b or b with
Figure FDA0002192313320000074
Reacting to obtain I; said X1、X2、Ar1、Ar2Is one or more of benzene, naphthalene, diphenyl ether and biphenyl, and the substitution position is arbitrary; x1Is one or more of H, methoxy, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary.
14. The method of synthesis of claim 13, wherein the salt of b or b with
Figure FDA0002192313320000075
Reacting to obtain I; in the reaction, a condensing agent and alkali are added to facilitate the reaction, wherein the condensing agent is selected from HBTU, DMC, HOBT/EDCI, HATU/DIEPA, DCC, CDI and isopropyl chloroformate.
15. The method of claim 13, wherein the salt of b or b is obtained by deprotecting a;
Figure FDA0002192313320000081
16. the method of synthesis according to claim 13, wherein the salt of a or a is formed by reaction of sm with
Figure FDA0002192313320000082
Or a salt thereof;
Figure FDA0002192313320000083
17. a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of any one of claims 1 to 11 and a pharmaceutically acceptable carrier.
18. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 11, for use in the manufacture of a medicament for the treatment of a disease or disorder mediated by MAGL.
19. The use according to claim 18, wherein said condition is selected from the group consisting of: metabolic disorders, renal diseases, emesis or vomiting or nausea, eating disorders, neuropathy, schizophrenia, depression, bipolar disorder, tremor, movement disorders, withdrawal syndrome, traumatic brain injury, non-traumatic brain injury, spinal cord injury, seizures, conditions associated with abnormal cell growth or proliferation [ e.g., benign tumors or cancer, inflammatory conditions, immune system conditions, acute stress disorders, substance-induced anxiety, obsessive-compulsive disorders, anxiety disorders; attention deficit disorder, attention deficit hyperactivity disorder, pain; demyelinating disease, and cognitive impairment.
20. A method of inhibiting MAGL comprising contacting the MAGL with a compound or pharmaceutically acceptable salt of any one of claims 1 to 11.
21. A method of treating a disease or disorder mediated by MAGL in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1 to 11.
CN201910836454.5A 2019-02-01 2019-09-05 MAGL inhibitor and preparation method and application thereof Pending CN111518020A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112341396A (en) * 2020-11-04 2021-02-09 四川大学华西医院 Novel monoacylglycerol esterase inhibitor and preparation method and application thereof
WO2022135462A1 (en) * 2020-12-22 2022-06-30 鲁南制药集团股份有限公司 Medicinal use of magl inhibitor
WO2022135461A1 (en) * 2020-12-22 2022-06-30 鲁南制药集团股份有限公司 Use of magl inhibitor in preparation of medicament for preventing or treating fatty liver diseases

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112341396A (en) * 2020-11-04 2021-02-09 四川大学华西医院 Novel monoacylglycerol esterase inhibitor and preparation method and application thereof
CN112341396B (en) * 2020-11-04 2022-07-26 四川大学华西医院 Novel monoacylglycerol esterase inhibitor and preparation method and application thereof
WO2022135462A1 (en) * 2020-12-22 2022-06-30 鲁南制药集团股份有限公司 Medicinal use of magl inhibitor
WO2022135461A1 (en) * 2020-12-22 2022-06-30 鲁南制药集团股份有限公司 Use of magl inhibitor in preparation of medicament for preventing or treating fatty liver diseases

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