阅读说明：本技术 Magl抑制剂及其制备方法、用途 (MAGL inhibitor and preparation method and application thereof ) 是由 齐长鹏 李�杰 李欣 于 2019-09-10 设计创作，主要内容包括：本发明涉及一种式I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；及其用于制备治疗MAGL介导的疾病及病症药物的用途。(The present invention relates to a compound of formula I 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 preparation of a medicament for the treatment of MAGL-mediated diseases and disorders.)

1. A compound of formula I:

wherein R is selected from C1-4 alkyl, C1-4 alkoxy; the number of R is 1 or 2 or 3 or 4; the R position is any reasonable position.

2. A compound of formula I according to claim 1, wherein R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclobutyl, methoxy, ethoxy, propoxy, isopropoxy; the number of R is 1, 2 or 3; the R position is any reasonable position.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising an optical isomer of the corresponding compound.

4. A process for the synthesis of a compound of formula I according to claim 1, which is obtained by reaction of 19 with 22:

5. the synthetic method of claim 4 wherein 22 is a mixture of 20 andthe reaction is carried out to obtain:

6. the method of claim 5, wherein 19 is obtained by reduction of 4, 4' -difluorobenzophenone (17) followed by deprotection:

7. a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

8. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 3, for use in the manufacture of a medicament for the treatment of a disease or disorder mediated by MAGL.

9. The use according to claim 8, wherein said condition is selected from the group consisting of: metabolic disorders; renal disease; vomiting or vomiting-gushing; nausea; eating disorders; neuropathy; neurodegenerative disorders; schizophrenia; depression; bipolar disorder; shaking; movement disorders; tension disorder; spasticity; tourette's syndrome; withdrawal syndrome; traumatic brain injury; non-traumatic brain injury; spinal cord injury; seizures; one or more of a disorder associated with abnormal cell growth or proliferation or an inflammatory disorder.

10. The use according to claim 9, wherein the 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, benign tumors or cancers, inflammatory disorders, immune system disorders, acute stress disorders, substance-induced anxiety, obsessive-compulsive disorders, anxiety disorders; attention deficit disorder, attention deficit hyperactivity disorder, pain, demyelinating disease, cognitive impairment.

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 fats 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 research and 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:wherein R is selected from C1-4 alkyl, C1-4 alkoxy; the number of R is 1 or 2 or 3 or 4; the R position is any reasonable position.

In some embodiments, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neo-butyl, methoxy, ethoxy, propoxy, isopropoxy; the number of R is 1, 2 or 3; the R position is any reasonable position.

In some embodiments, the number of R is 1 or 2.

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.

The invention provides a pharmaceutical composition, which comprises the compound, namely the compound covered by the general formula of the target compound shown in the formula I, a specific substance of the compound, or pharmaceutically acceptable salt of the compound, and one or more pharmaceutically acceptable pharmaceutical excipients.

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 disease ]; 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, e.g., 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, chronic neuropathy caused by chemotherapeutic agents, 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" and other forms, such as "includes," "including," and "containing," 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, the terms used herein in the pertinent description of analytical chemistry, organic synthetic chemistry, and pharmaceutical chemistry are 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.

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. The compounds of the present application containing asymmetrically substituted carbon atoms 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 some or all of the hydrogens (H) are 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 intact a particular stereoisomer, as well as techniques for resolving mixtures of stereoisomers, are well known in the art and those skilled in the art will be able to select appropriate methods for a particular situation. See, e.g., Fumiss et al (eds.), VOGEL' S ENCYCOPEEDIAOF PRACTICAL ORGANIC CHEMISTRY 5. TH ED., 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, alleviating a symptom caused by a disease or disorder, or halting a symptom of a disease or disorder, preventing other symptoms, ameliorating or preventing an underlying metabolic cause causing 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 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, basic groups such as amine (amino) groupsInorganic or organic acid salts of (a). Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound by reacting a basic group in the parent compound with 1-3 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, a salt in this application refers to an acid salt formed with an organic/inorganic acid.

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.

Example 1 synthesis of intermediate 19 b:

4, 4' -Difluorobenzophenone (17b) (218.2mg,1mmol) was dissolved in 15mL of absolute ethanol and NaBH was added₄(151.3mg,4mmol), stirred at room temperature for 2 h. After the TLC detection reaction is completed, 10% diluted hydrochloric acid is added to quench the reaction, and ethanol is removed by spinning. Then adding a suitable amount of water, CH₂Cl₂Extraction was carried out three times and the organic phases were combined. The organic phase was washed three times with saturated brine, anhydrous Na₂SO₄Drying and rotary evaporation to remove the solvent gave intermediate 18b without further purification.

Intermediate 18b was dissolved in anhydrous 15mL of anhydrous CH₂Cl₂Adding PBr slowly and dropwise₃(0.38mL,4mmol) and stirred at room temperature for 10min, after completion of the TLC check reaction, 10mL of saturated sodium bicarbonate was added and stirred for 15 min. CH for reaction solution₂Cl₂Extraction was carried out three times. The organic phases are combined, washed three times with water and then Na₂SO₄Drying and rotary evaporation of the solvent gave 214.6mg of intermediate 19b as a yellow oil in 75.8% yield without further purification.

Example 2 synthesis of intermediate 22 d:

the starting material N-Boc-4-piperidinecarboxylic acid (20) (229.3mg, 1mmol) was dissolved in 10mL CH₂Cl₂Adding DIPEA (0.35mL, 2mmol) and HATU (456mg, 1.2mmol), stirring at room temperature for 10min, adding 3, 5-dimethylaniline (0.25mL, 2mmol), stirring at room temperature for 6h, washing with water for three times, washing with 10% diluted hydrochloric acid for three times, and washing with anhydrous Na₂SO₄Drying, rotary steaming to remove CH₂Cl₂Intermediate 21d was obtained without further purification.

Intermediate 21d was dissolved in 10mL EtOAc, 4M HCl/EtOAc solution (2mL) was added and stirred at room temperature for 12h whereupon a white solid precipitated which was filtered off with suction and the filter cake washed with EtOAc to afford intermediate 22d as a white solid 224.2mg, 83.4% yield.

Example 3 synthesis of MAGLZ-I-08:

hydrochloride intermediate 22d (200.0mg, 1mmol) was dissolved in 10mL DMF, NaH (72mg, 3mmol) was added, and after stirring at room temperature for 1h, bromide 19b (247.1mg, 1mmol) was added, and the reaction was stirred at room temperature for 2 h. After the reaction, 20mL of water was added to the reaction mixture to quench the reaction, the reaction was extracted with EtOAc three times, the organic phases were combined, washed with saturated brine three times, and dried over anhydrous sodium sulfate. Column chromatography separation and purification (petroleum ether: ethyl acetate ═ 4:1) gave 121.4 mg of MAGLZ-I-08 as a yellow solid in 27.9% yield.

Characterization data for MAGLZ-I-08:¹H NMR(300MHz,CDCl₃)δ(ppm):7.29-7.34(m,4H), 7.14-7.16(m,1H),7.02-7.07(m,1H),6.90-7.02(m,4H),6.73-6.77(m,1H),4.27(s,1H), 3.49(s,6H),3.06-3.12(m,1H),2.89-2.96(m,2H),1.82-1.96(m,6H)；[M+H]⁺435.22。

example 4 synthesis of intermediate 22 e:

the starting material N-Boc-4-piperidinecarboxylic acid (20) (229.3mg, 1mmol) was dissolved in 10mL CH₂Cl₂Adding DIPEA (0.35mL, 2mmol) and HATU (456mg, 1.2mmol), stirring at room temperature for 10min, adding 3-methoxyaniline (0.225mL, 2mmol), stirring at room temperature for 6h, washing with water for three times, washing with 10% diluted hydrochloric acid for three times, and washing with anhydrous Na₂SO₄Drying, rotary steaming to remove CH₂Cl₂Intermediate 21e was obtained without further purification.

Intermediate 21e was dissolved in 10mL EtOAc, 4M HCl/EtOAc solution (2mL) was added and stirred at room temperature for 12h whereupon a white solid precipitated which was filtered off with suction and the filter cake was washed with EtOAc to afford intermediate 22e as a white solid 173.0mg with 64.0% yield.

Example 5 synthesis of intermediate 22 f:

following the reaction procedure of example 4, where the 3-methoxyaniline was replaced with equimolar 3-nitroaniline, 22f was obtained.

Example 6: synthesis of MAGLZ-I-11:

hydrochloride intermediate 22e (270.8mg, 1mmol) was dissolved in 10mL DMF and NaH (72mg, 3mmol) was added, followed by stirring at room temperature for 1h, followed by addition of bromide 19b (247.1mg, 1mmol) and stirring at room temperature for 2h for reaction. After the reaction, 20mL of water was added to the reaction mixture to quench the reaction, the reaction was extracted with EtOAc three times, the organic phases were combined, washed with saturated brine three times, and dried over anhydrous sodium sulfate. Column chromatography separation and purification (petroleum ether: ethyl acetate ═ 4:1) gave 113.1mg of MAGLZ-I-11 as a yellow solid in 25.9% yield.

Characterization data for MAGLZ-I-11:

¹H NMR(300MHz,DMSO-d₆)δ(ppm):9.79(s,1H),7.39-7.48(m,4H),7.28-7.33(m,1H), 7.07-7.20(m,6H),6.56-6.62(m,1H),4.39(s,1H),3.71(s,3H),2.79-2.85(m,2H),2.27-2.33 (m,1H),1.69-1.87(m,6H)；[M+H]⁺437.20。

example 7: 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 samples with different concentrations (six points between 1nM and 1000 nM) 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). The IC50 curves for each inhibitor were then fit using graphad prism 5.0 calculations with 4.07. mu.M, 2.46. mu.M and ND IC50 for MAGLZ-I-08, MAGLZ-I-11, MAGLZ-I-12, respectively.