阅读说明：本技术 Magl抑制剂及制备方法和用途 (MAGL inhibitor and preparation method and application thereof ) 是由 张贵民 王进欣 高雷 李涛 于 2020-01-19 设计创作，主要内容包括：本发明属于药物领域,涉及一种化合物及其药学上可接受的盐；其制备方法；用于制备其的中间体；及含有这样的化合物或盐的组合物；及其用于治疗MAGL介导的疾病及病症(包括例如疼痛、炎症性病症、创伤性脑损伤、抑郁症、焦虑症、阿尔茨海默病、代谢紊乱、中风或癌症)的用途。(The invention belongs to the field of medicines, and relates to a compound and pharmaceutically acceptable salts thereof; a process for the preparation thereof; intermediates for the preparation thereof; and compositions containing such compounds or salts; and their use for the treatment of MAGL mediated diseases and disorders including, for example, pain, inflammatory disorders, traumatic brain injury, depression, anxiety, alzheimer's disease, metabolic disorders, stroke, or cancer.)

1. A compound of formula I:

wherein, X₁Is one of H, F and Cl;

r is one of methyl, tert-butyl, cyclohexyl and benzene;

X₂is one or more of H, methyl, dimethyl, methoxyl, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof,r is methyl, tert-butyl or cyclohexyl, X₂Is H.

3. The compound or pharmaceutically acceptable salt of claim 1, wherein R is benzene and X is₂Is one or more of H, methoxy, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary.

4. The compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein the specific structural formula is selected from

5. A compound according to claim 1 which isOr a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 which isOr a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 which isOr a pharmaceutically acceptable salt thereof.

8. A method for synthesizing a compound shown as a formula I comprises the following specific steps:salts of b or b withReacting to obtain I; ar is₁Is 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.

9. The method of synthesis according to claim 8, wherein the salt of b or b is reacted withAnd reacting to obtain I.

10. The method of claim 8, wherein the salt of b or b is obtained by deprotecting a;

11. the method of synthesis according to claim 8, wherein the salt of a or a is formed by reaction of sm withOr a salt thereof;

12. a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

13. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 7, for use in the manufacture of a medicament for the treatment of a disease or disorder mediated by MAGL.

14. The use of claim 13, wherein the disorder is selected from: 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.

15. A method of inhibiting MAGL comprising contacting the MAGL with a compound or pharmaceutically acceptable salt of any one of claims 1 to 7.

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 Lipase (MAGL), also known as monoglyceride, is a serine hydrolase that promotes the breakdown of fats into glycerol and fatty acids, is one of the members of the α/β hydrolase superfamily, is a serine hydrolase that is highly expressed in human invasive tumor cells and primary tumor cells. MAGL is widely expressed in adipose tissue, muscle, kidney, ovary, testis, and liver. In lipid metabolism tissues, MAGL can cooperate with hormone sensitive lipolytic enzymes to break down stored triacylglycerols into fatty acids and glycerol, providing energy to the body. In the central nervous system, MAGL hydrolyzes 2-arachidonic acid glycerol (2-AG) to arachidonic acid and glycerol, regulating the endocannabinoid system.

The invention content is as follows:

the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

wherein X1 is one of H, F and Cl;

r is one of methyl, tert-butyl, cyclohexyl and benzene;

x2 is one or more of H, methoxy, hydroxyl, fluorine and chlorine.

In some embodiments, R is methyl, t-butyl or cyclohexyl, X₂Is H.

In some embodiments, when R is benzene, X₂Is one or more of H, methoxy, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary.

The invention provides a synthesis method of a compound shown as a formula I, which comprises the following specific steps:

a and b are reacted to form I, wherein X₁Is one of H, F and Cl;

r is one of methyl, tert-butyl, cyclohexyl and benzene;

X₂is one or more of H, methoxy, hydroxyl, fluorine and chlorine.

In some embodiments, R is methyl, t-butyl or cyclohexyl, X₂Is H.

In some embodiments, when R is benzene, X₂Is one or more of H, methoxy, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary.

Wherein b is represented byReacting to obtain the compound; the R is one of methyl, tert-butyl, cyclohexyl and benzene;

X₂is one or more of H, methoxy, hydroxyl, fluorine and chlorine.

In some embodiments, R is methyl, t-butyl or cyclohexyl, X₂Is H.

In some embodiments, when R is benzene, X₂Is one or more of H, methoxy, hydroxyl, fluorine and chlorine, and the position of the substituent is arbitrary.

A is prepared fromReacting to obtain the compound; wherein, X is₁Is one of H, F and Cl.

Specifically, in some embodiments, the synthesis of I is performed using the following route:

the solvent used in the above or below steps of the present invention is not specifically illustrated, and is selected in the conventional art, and the solvent is selected in the principle of dissolving the reactants but not participating in the reaction, extracting the product or crystallizing the corresponding product therein to separate impurities, 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 expression of the structural formula and the reaction equation of the structural formula belonging to the general formula and 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 illustrated, and is selected in the conventional art, and the solvent is selected in the principle of dissolving the reactants but not participating in the reaction, extracting the product or crystallizing the corresponding product therein to separate impurities, 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 disorder 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](ii) a 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 ]](ii) a Traumatic brain injury; non-traumatic brain injury; spinal cord injury; seizures; disorders associated with abnormal cell growth or proliferation [ e.g., benign tumors or cancers, e.g., benign skin tumors, brain tumors, papillomas, prostate tumors, brain tumors (glioblastoma, medulloblastoma, astrocytoma, ependymoma, oligodendroglioma, plexus tumors, neuroepithelioma, epiphyseal tumors, ependymoma, malignant meningioma, sarcoidosis, melanoma, schwannoma), melanoma, metastatic tumors, kidney cancer, bladder cancer, brain cancer, Glioblastoma (GBM), gastrointestinal cancer, leukemia or blood cancer](ii) a 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 (CN)S) inflammation](ii) a 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, trigeminal neuralgia, causalgia, toxic neuropathy, reflex sympathetic dystrophy, diabetic neuropathy, chronic neuropathy caused by chemotherapeutic agents, or sciatica pain)](ii) a Demyelinating diseases [ e.g. Multiple Sclerosis (MS), Devycke'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-disease, peripheral neuropathy, myelopathy, optic neuropathy, progressive inflammatory neuropathy, optic neuritis, transverse myelitis](ii) a 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)]. 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, 17^thed., Mack Publishing 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. And other specific compounds that can be obtained by those skilled in the art without inventive effort, guided by the general formula, the general synthetic methods, and the specific embodiments of this invention, are within the scope of this invention.