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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the invention belongs to the field of medicinal chemistry, and relates to an alkoxybenzopentagon (hexagonal) heterocyclic amine compound and a pharmaceutical use thereof, in particular to an alkoxybenzopentagon (hexagonal) heterocyclic amine compound or a pharmaceutical thereof Acceptable salts and their use in the preparation of sphingomyelin synthase inhibitors and in the preparation of prophylactic or therapeutic atherosclerosis, type II diabetes, fatty liver and obesity and their metabolic syndrome, and inflammatory diseases including enteritis Use in medicine.
• Atherosclerosis is one of the main pathological basis of many cardiovascular and cerebrovascular diseases. Therefore, research on anti-atherosclerotic drugs has become a hot spot in the field of drug research and development. Studies have also shown that atherosclerosis is characterized by the appearance of yellow matter containing cholesterol, fat, etc. in the intima of the large and middle arteries, leading to thrombosis, blood supply disorders, etc.; although its molecular pathology has not yet been fully elucidated, it is recognized in the industry.
• dyslipidemia is the most important inducer of atherosclerosis, and the formation of atheroma and arteriosclerosis is closely related to the abnormal expression of lipid components.
• dyslipidemia refers to abnormal lipid metabolism or transport, resulting in higher than normal plasma lipids and increased blood viscosity.
• the main manifestations are low-density lipoprotein (LDL) and very low-density lipoprotein (very low).
• Low-density lipoprotein (VLDL) levels and high-density lipoprotein (HDL) levels decrease. Therefore, lowering LDL and/or raising HDL can play a role in regulating blood lipids, and blood lipid regulating drugs have become clinically the main drugs for anti-atherosclerosis.
• statins can reduce the level of LDL cholesterol in plasma by inhibiting the key enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG Co-A reductase) in the process of cholesterol biosynthesis.
• HMG Co-A reductase 3-hydroxy-3-methylglutaryl coenzyme A reductase
• sphingomyelin synthase inhibitors PPAR agonists
• infusion of apolipoproteins liver X receptor activators and phospholipid transfer proteins.
• PLTP phospholipid transfer proteins
• SM sphingomyelin
• its metabolic enzymes mediate a series of cellular processes while causing lipoprotein changes, suggesting that it plays an important role in the development of atherosclerosis .
• sphingomyelin can induce atherosclerosis through a variety of pathways: (1) inhibition of triglyceride (TG) lipolysis (Park TS, Panek RL, et al. Atherosclerosis. 2006, 189 (2): 264- 72.); (2) delaying the clearance of lipoprotein residues that cause AS (Schlitt A, Hojjati MR, et al. J Lipid Res. 2005, 46(2): 196-200.); (3) affecting HDL mediation Guided reverse cholesterol transport, causing cholesterol clearance disorder (Sano O, Kobayashi A, et al. J Lipid Res. 2007, 48 (11): 2377-84; Marmillot P, Patel S, et al. Metabolism.
• TG triglyceride
• ceramide and SM synthesis or decomposition related products are regulators of cell proliferation, activation, and apoptosis, affecting the growth and stability of atherosclerotic plaque (Park, T .-S.; Panek, RL; et al. Circulation. 2004, 110, 3465-3471.).
• SM-rich LDL has strong cohesion and adhesion, which makes it easier for macrophages to accumulate in the arterial wall to form foam cells and promote AS (Fan Y, Shi S, et al. Arterioscler Thromb Vasc Biol, 2010 , 30:2114-20.).
• SMS sphingomyelin synthase
• PC ceramide and lecithin
• Sr sphingomyelin synthase-associated protein
• SMS1 and SMS2 regulate the related functions, in which SMS1 is mainly distributed in the Golgi and is responsible for 60%-80% of SM synthesis, while SMS2 is mainly distributed on the cell membrane and responsible for 20%-40% of SM synthesis in vivo.
• SMSr has no enzyme catalytic function.
• Yano et al. found that SMS1 knockout in mice dysregulated mitochondrial function, thereby increasing active oxides and impairing insulin secretion (M. Yano, K., et al. J Biol Chem.
• SMS1 white adipose tissue
• WAT white adipose tissue
• knockout of SMS1 Will affect reproduction etc.
• Complete knockout of SMS1 can cause adverse reactions such as hearing loss (Lu MH, et al. J Physiol. 2012; 590: 4029–4044). Therefore, SMS1 may not be a very ideal target for drug action.
• the knockout of SMS2 is different from the SMS1 knockout. Not only is there no serious physiological damage, but it is also beneficial for prevention of atherosclerosis, improvement of insulin resistance, etc. (Li Z, Zhang H, et al. Mol. Cell. Biol. 2011, 31(20): 4205-4218).
• SMS directly regulates SM levels
• overexpression of SMS is a common phenomenon in atherosclerotic lesions and one of the key indicators of atherosclerotic lesions (Xian-cheng Jiang; Furcy Paultre; et al Arterioscler. Thromb. Vasc Biol. 2000, 20, 2614-2618; Zhiqiang Li; Tiruneh K. et al. Biochimica et Biophysica Acta, 2007, 1771, 1186-1194.).
• SMS2 deficiency can prevent obesity and insulin resistance induced by high-fat diet, while in the liver of SMS2 knockout mice, it is difficult to observe large mature fat plaques, indicating that SMS2 is involved in the liver.
• the formation of fatty plaques can induce the development of obesity and type 2 diabetes (Susumu Mitsutake, Kota Zama, et al. Journal of Biological Chemistry. 2011, 286 (32), 28544-28555).
• a decrease in SM in plasma caused by SMS2 deficiency can improve insulin sensitivity in animal tissues and throughout the body (Li Z, Zhang H, et al. Mol. Cell. Biol. 2011, 31(20): 4205-4218).
• Gene knockout SMS2 can increase glucose uptake by insulin-targeted tissues such as bones and muscles in mice, thereby lowering blood glucose levels (Sugimoto, Masayuki, et al. Biochimica et Biophysica Acta 1861 2016, 688-702).
• Sphingomyelin (d18:1/16) was found to accumulate in diabetic patients and glomeruli, and was also confirmed in mice on a high-fat diet compared to the blank group; in vitro, in the cell experiment, additional SM (d18) : 1 / 16) can mention ATP levels and reduce AMPK; inhibitor sphingomyelin synthase activity can reverse this phenomenon, which means SM (d18: 1 / 16) as a regulatory factor, can regulate diabetic nephropathy and obesity The ratio of ATP to AMP in the medium; inhibition of sphingomyelin synthase can reduce the high ratio of ATP to AMP in diabetic nephropathy and obesity (S. Miyamoto et al. EBio Medicine 2016, (7) 121-134). Sphingomyelinase small molecule inhibitors may be used to prevent and treat metabolic syndromes such as type 2 diabetes, obesity and fatty liver.
• SMS2 knockout can significantly improve inflammation and insulin resistance in other high-fat-fed mice and other metabolic syndromes (Susumu Mitsutake, Kota Zama, et al. Journal of Biological Chemistry. 2011, 286 (32), 28544-28555).
• SMS2 dextran sulfate sodium
• DSS dextran sulfate sodium
• Sphingomyelinase 2 small molecule inhibitors may be used to prevent and treat inflammation-related diseases such as enteritis and intestinal cancer.
• the sphingomyelin synthase small molecule inhibitor compound D2 was discovered (Xiaodong Deng, Fu Lin, et al. European Journal of Medicinal Chemistry, 2014, 73, 1). -7), although its inhibitory activity against SMS2 in vitro is enhanced compared with D609, it still has the following defects: the inhibitory activity against SMS2 needs to be improved, it contains a cyano group with a high potential toxicity risk, and water solubility and stability, etc. Physical and chemical properties are not good.
• the cell homogenate supernatant was used as the enzyme source, the measured 2- quinolone derivative of the inhibitory activity of IC 50 value of 6.5nM (R.Adachi et al .European Journal of Medicinal Chemistry, 2017, 136, 283-293); its activity and selectivity are higher, but due to its relatively large molecular weight and high cLogP (MW 625.57; cLogP 6.47), it may have certain drug-forming problems.
• the inventors of the present application intend to provide novel alkoxybenzopenta(6-membered) heterocyclic amine compounds and their pharmaceutical use.
• the object of the present invention is to overcome the defects and deficiencies of the prior art, and to provide alkoxybenzo-5-e (heterocyclic) heterocyclic amine compounds and their pharmaceutical uses, in particular to alkoxybenzoquinone (six-membered) a cyclic amine compound or a pharmaceutically acceptable salt thereof and use thereof in the preparation of a sphingomyelin synthase inhibitor, and in the preparation of a prophylactic or therapeutic atherosclerosis, type II diabetes, fatty liver and obesity and metabolic syndrome thereof Use in medicines including inflammatory diseases such as enteritis.
• a first object of the present invention is to provide an alkoxybenzopenta(6-membered) heterocyclic amine compound or a pharmaceutically acceptable salt thereof; said alkoxybenzo-5-element (hexagonal) heterocyclic ring
• the amine compound is a free base or a salt having a structure represented by the formula (I).
• X is selected from any one or two of O, N, S, and C.
• Y is selected from any one or two of O, N, S, and C.
• R 4 may be methyl or hydrogen, ethyl
• R 1 is selected from benzene, heterocyclic ring or acyl group.
• heterocyclic structure is, but not limited to, the following structure:
• the acyl structure is, but not limited to, the following structure:
• R 2 is selected from any one of hydrogen, methyl, ethyl, and propyl
• R 3 is selected from the group consisting of alkoxy, phenylcyclomethylene and heterocyclic methylene including, but not limited to, benzyloxy, pyridylmethylene, alkane of 1-8 carbons or alkaneamine of 1-8 carbons;
• the R 3 structure is but not limited to the following structure:
• R is selected from the group consisting of oF, mF, pF, o-Cl, m-Cl, p-Cl, o-Me, m-Me, p-Me, o-CF 3 , m-CF 3 , p-CF 3 , o- Any one or two of OCF 3 , m-OCF 3 , p-OCF 3 , o-OMe, m-OMe, p-OMe, o-CN, m-CN, p-CN, o-Et or phenyl Substituent
• m 0-5.
• the compound of the present invention contains a basic group which can form a salt with an acid, and can form a salt of a derivative by an ordinary means, including an organic acid salt such as acetate, citrate, fumarate, maleate or oxalic acid.
• Salt malate, citrate, succinate, tartrate, lactate, camphorsulfonate, besylate, p-toluenesulfonate, methanesulfonate, trifluoroacetate, trifluoro Methanesulfonate and the like; inorganic acid salts such as hydrohalic acid (hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid) salts, sulfates, phosphates, nitrates and the like. Or may form glutamate or aspartate with an amino acid such as glutamic acid or aspartic acid.
• Preferred salts are the hydrochloride salt, the hydrobromide salt.
• the alkoxybenzopenta(6-membered) heterocyclic amine compound of the present invention further includes a solvate thereof, and the solvent thereof is preferably water, ethanol or methanol.
• a second object of the present invention is to provide the use of the alkoxybenzopenta(6-membered) heterocyclic amine compound represented by the formula (I) for the preparation of a sphingomyelin synthase 2 small molecule inhibitor.
• the present invention uses a high performance liquid chromatography (HPLC) fluorescence quantitative detection method reported in the literature to determine the inhibitory activity of the alkoxybenzoquinone (hexa) heterocyclic amine compound represented by the formula (I) on sphingomyelin synthase ( Xiaodong Deng; Hong Sun; et al.
• a further object of the present invention is to provide an alkoxybenzopentagon (hexagonal) heterocyclic amine compound represented by the formula (I) and a salt or solvate thereof for the preparation and use thereof for the prevention and treatment of abnormal levels of sphingomyelin Increased use in diseases including atherosclerosis, type 2 diabetes, fatty liver and obesity and its metabolic syndrome, and inflammatory diseases including enteritis.
• an alkoxybenzopentagon (hexagonal) heterocyclic amine compound represented by the formula (I) and a salt or solvate thereof for the preparation and use thereof for the prevention and treatment of abnormal levels of sphingomyelin Increased use in diseases including atherosclerosis, type 2 diabetes, fatty liver and obesity and its metabolic syndrome, and inflammatory diseases including enteritis.
• the present invention proves by experiments that the disclosed compound has remarkable inhibitory activity against SMS2; ideal physicochemical properties such as stability and water solubility; and it does not contain potential toxic groups, and has potential toxic and side effects, and can be used as a therapeutic level by sphingomyelin. Drugs caused by abnormally increased diseases such as atherosclerosis, type 2 diabetes, fatty liver and obesity and inflammation.
• the above medicament may further comprise one or more pharmaceutically acceptable carriers, including conventional diluents, excipients, fillers, binders, humectants, disintegrants, absorption promotion in the pharmaceutical field.
• a surfactant, a surfactant, an adsorption carrier, a lubricant, etc., if necessary, a flavoring agent, a sweetener or the like may be added.
• the invention has the beneficial effects that the provided alkoxybenzo five-membered (hexa-membered) heterocyclic amine compound is a novel structure of a sphingomyelin synthase inhibitor having a submicromolar level of molecular level inhibitory activity and
• the selectivity of subtype SMS2 can be further developed into drugs for the treatment of inflammatory diseases including atherosclerosis, type II diabetes, fatty liver and obesity and its metabolic syndrome, and including enteritis.
• the target compounds are of the formulae I-2 and I-4 to I-27, specifically: 4-(2-chloro-5-fluorobenzyloxy)-3-(pyridin-3-ylamino)benzo[d]isoxine Azole (Formula I-2); 4-(2-Fluorobenzyloxy)-3-(pyridin-3-ylamino)benzo[d]isoxazole (Formula I-4); 4-(3-Fluorine Benzyloxy)-3-(pyridin-3-ylamino)benzo[d]isoxazole (Formula I-5); 4-(4-Fluorobenzyloxy)-3-(pyridin-3-ylamino)-3-(pyridin-3-ylamino)
• the corresponding target compound 25 was obtained by reacting the corresponding hydroxy compound 24 with benzyl bromide.
• the corresponding alkylamine is reacted with the intermediate 31 to obtain the corresponding target compound of the formula I-35 to I-38, specifically: 4-(2- Chloro-5-fluorobenzyloxy)-3-(2-(N,N-diethyl)acetamido)benzo[d]isoxazole (Formula I-35); 4-(2-Chlor-5 -fluorobenzyloxy)-3-(2-(1-pyrrolidinyl)acetamido)benzo[d]isoxazole (Formula I-36); 4-(2-Chloro-5-fluorobenzyloxy) 3-(2-(1-piperidinyl)acetamido)benzo[d]isoxazole (Formula I-37); 4-(2-Chloro-5-fluorobenzyloxy)-3-(2- (4-morpholine)acetamido)benzo[d]
• Example 12 Synthesis of 3-(pyridin-3-ylamino)-4-((2-phenylpyridin-4-yl)methoxy)-benzo[d]isoxazole (Formula I-39) .
• the substituted benzyl bromide was prepared with the corresponding substituted benzyl alcohol, and then with 3-(pyridin-3-ylamino)-4-hydroxybenzo[d].
• the isoxazole reaction gave the corresponding target compound I-39.
• the compound 38 was used instead of the substituted benzyl bromide to react with 3-(pyridin-3-ylamino)-4-hydroxybenzo[d]isoxazole.
• Target compound I-40 was used instead of the substituted benzyl bromide to react with 3-(pyridin-3-ylamino)-4-hydroxybenzo[d]isoxazole.
• Example 15 Inhibition of sphingomyelin synthase 2 in vitro by alkoxybenzopentagon (hexagonal) heterocyclic amine compounds
• Vortex mixer (Shanghai Jingke Industrial Co., Ltd. model XW-80A).
• HPLC column COSMOSIL 5C18-MS-II (4.6 mm I.D. x 250 mm).
• DMPC Purchased from Santa Cruz (USA), dissolved in ethanol at a concentration of 40 mmol/L.
• the organic solvents used were purchased from Shanghai Sinopharm Co., Ltd., methanol was chromatographically pure, water was Milli-Q pump filtered, deionized, ultra-pure water ultrafiltration through 0.22 ⁇ m membrane, and other bio-consumable materials were purchased from domestic companies.
• test compound solution accurately weigh 1 to 2 mg of each test compound, firstly add an appropriate amount of DMSO to prepare a 3 mmol/L stock solution. Take a volume of the DMSO stock solution of the test compound, and then add an appropriate amount of DMSO to dilute the test compound to the desired concentration of the solution.
• SMS1 SMS2 pure enzyme DDM solution and buffer were provided by the National Protein Science Center (Shanghai) Cao Yu Group.
• SMS2 pure enzyme DDM solution (total protein content 1.5 ⁇ g/ ⁇ L), 1 ⁇ L of test compound in DMSO or blank DMSO solution, 79.7 ⁇ L DDM buffer to 1.5 mL eppendorf tube, vortex 30 In seconds, it was allowed to stand at room temperature for 5 min. Then, 20 ⁇ L of DDM buffer containing 1 ⁇ L of DMPC in ethanol (40 mmol/L) and 1 ⁇ L of C6-NBD-Ceramide in DMSO (1.16 mmol/L) was added, vortexed for 30 seconds, and then incubated at 37 ° C in a water bath. h. Take out, add 200 ⁇ L of absolute ethanol, and vortex for 30 seconds. 200 ⁇ L of the mixture was taken and stored at 4 ° C for high performance liquid chromatography analysis.
• the corresponding operation can be carried out by using SMS1 pure enzyme instead of SMS2 pure enzyme.
• the 6 mM DMSO stock solution of the test compound was subjected to gradient dilution to prepare 5 concentration gradient solutions, and 1 ⁇ L of each was added to the test system of the first step of Example 15, and the sample was prepared according to the method of the first step of Example 15.
• Alkoxybenzopenta-penta-membered (hexa-membered) heterocyclic amine compounds I-1 to I-38 were determined for inhibition rate and half-inhibitory concentration (IC 50 ) of sphingomyelin synthase 1 at 50 ⁇ M.
• the experiment can be carried out by the operation of measuring the concentration corresponding to the half inhibitory concentration (IC 50 ) of sphingomyelin synthase 2 with the corresponding concentration.

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