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Preparation method and medical application of benzisothiazole and benzothiophene

A technology of benzisothiazole and benzothiophene is applied in the field of preparation of benzisothiazole and benzothiophene or their pharmaceutically acceptable salts, benzisothiazole and benzothiophene, and can solve the problem of increasing renal anemia Patients, high risk of cardiovascular disease and mortality, high price of rhEPO, to achieve good industrialization prospects, enhanced activity, good agonistic effect

Active Publication Date: 2021-08-17
NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0002] The kidney is an important organ of the human body. In addition to the basic functions of the urinary system, it can also secrete erythropoietin (EPO) to promote red blood cell production. It is the main place for EPO production; The incidence of renal anemia exceeds 10%, which has become a global public health problem; renal anemia is one of the main complications of CKD, mainly due to insufficient EPO output after renal injury; currently, the main treatment for renal anemia is Inject recombinant human EPO (recombinant human EPO, rhEPO) and its related products, that is, erythropoiesis-stimulating agents (ESAs); ESAs can increase the hemoglobin level of patients with renal anemia, reduce the need for blood transfusion, and greatly improve quality of life of patients; however, clinical studies have shown that injection of rhEPO to CKD patients can lead to higher risk of cardiovascular disease and mortality, and the price of rhEPO is relatively high, and its application is limited; ESAs with low side effects are important

Method used

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  • Preparation method and medical application of benzisothiazole and benzothiophene
  • Preparation method and medical application of benzisothiazole and benzothiophene
  • Preparation method and medical application of benzisothiazole and benzothiophene

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Preparation of (I-1) of 3-((3,5-bis(trifluoromethyl)phenyl)(phenyl)amino)benzo[d]isothiazole 1,1-dioxide:

[0100]

[0101] Synthesis of 1a: Palladium acetate (11mg, 0.05mmol) and DPPE were dissolved in toluene (39mg, 0.1mmol), stirred at 110°C for ten minutes, iodobenzene (204mg, 1mmol) and 3,5-ditrifluoromethyl A mixed solution of aniline (229mg, 1mmol) dissolved in toluene (5mL) was added, and finally sodium methoxide (59.4mg, 1.1mmol) was added, and reacted for 24h; after the reaction was completed, cooled to room temperature, concentrated under reduced pressure, and column chromatography (PE: EtOAc=120:1) gave an oily solid in 70% yield. 1 H NMR (500MHz, CDCl 3 )δ(ppm):7.56(s,2H),7.49(s,1H),7.40-7.33(m,2H),7.21-7.01(m,3H).

[0102]

[0103] Synthesis of I-1: Refer to Method 1, using saccharin and 1a as raw materials to obtain a yellow solid with a yield of 45%. 1 H NMR (500MHz, CDCl 3 )δ(ppm):8.50-8.43(m,1H),8.31(s,2H),8.02(m,1H),7.96-7.89(m,2H),7.49(s,1H...

Embodiment 2

[0105] 3-((3,5-Bis(trifluoromethyl)phenyl)(cyclopropyl)amino)benzo[d]isothiazole 1,1-dioxide (I-5) Preparation:

[0106]

[0107] Synthesis of 2a: 2b (200mg, 1.2mmol) and 3,5-bistrifluoromethylaniline (229mg, 1mmol) were dissolved in methanol (4mL) and acetic acid (5mL) was added, stirred at 80°C for 2.5h, and cyanide was added at room temperature Sodium borohydride (126mg, 2mmol), stirred at 80°C for 3h; after the reaction was completed, cooled to room temperature, quenched with saturated sodium bicarbonate solution, then extracted with ethyl acetate, the organic phase was washed with saturated brine, anhydrous sulfuric acid It was dried over sodium, filtered, and the filtrate was concentrated under reduced pressure, followed by column chromatography (PE:EtOAc=120:1) to obtain a yellow oily solid with a yield of 55%. 1 H NMR (CDCl 3 ,500MHz)δ(ppm):7.25(s,1H),7.05(s,2H),2.25(m,1H),0.90-0.80(m,2H),0.69-0.60(m,2H).

[0108]

[0109] Synthesis of I-2: refer to method 1, u...

Embodiment 3

[0111] Preparation of 5-((1,1-dioxybenzo[d]isothiazol-3-yl)amino)dimethylisophthalate (I-3):

[0112]

[0113] Synthesis of I-3: Refer to Method 1, using 3a and saccharin as raw materials to obtain a white solid with a yield of 40%. 1H NMR (500MHz, DMSO-d 6 )δ(ppm):11.16(s,1H),8.82(s,2H),8.50(d,J=7.5Hz,1H),8.33(s,1H),8.13(d,J=7.5Hz,1H) ,7.95(m,2H),3.95(s,6H).13C NMR(126MHz,DMSO-d 6 )δ(ppm): 165.49×2, 157.52, 140.89, 139.50, 134.41, 134.01, 131.44×2, 128.59, 126.56, 126.35×2, 124.18, 122.08, 53.22×2.HRMS(ESI):m / z[M+H] + calcd for C 17 h 15 N 2 o 6 S 375.0651; found 375.0644.

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Abstract

The invention discloses a preparation method and medical application of benzisothiazole and benzothiophene, and telates to the field of pharmaceutical chemistry. According to the invention, benzisothiazole and benzothiophene are the first type of HIF-2 agonists; compared with a compound M1001 found by the applicant in the earlier stage, the invention has better HIF-2 agonist activity, and has remarkable enhancement activity on expression of mRNA and protein of EPO, VGEF, Glut1, NDRG1 and the like at the downstream of HIF-2, so that the invention can be used for preparing drugs for treating and / or preventing chronic kidney diseases / chronic renal anemia, dyslipidemia and high cholesterol caused by abnormal expression of HIF-2; and the method has a good industrialization prospect.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, and relates to a preparation method of benzisothiazole and benzothiophene and their medical use; more specifically, to a kind of benzisothiazole and benzothiophene or pharmaceutically acceptable salts thereof, Isomers, prodrugs, polymorphs or solvates, methods for their preparation and medical uses. Background technique [0002] The kidney is an important organ of the human body. In addition to the basic functions of the urinary system, it can also secrete erythropoietin (EPO) to promote red blood cell production. It is the main place for EPO production; The incidence of renal anemia exceeds 10%, which has become a global public health problem; renal anemia is one of the main complications of CKD, mainly due to insufficient EPO output after renal injury; currently, the main treatment for renal anemia is Inject recombinant human EPO (recombinant human EPO, rhEPO) and its related product...

Claims

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Application Information

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IPC IPC(8): C07D275/06C07D333/66A61K31/428A61K31/381A61P3/06A61P13/12A61P7/06A61P9/10A61P9/12
CPCC07D275/06C07D333/66A61P3/06A61P13/12A61P7/06A61P9/10A61P9/12
Inventor 张毅楠武大雷庄静静宋万斌张楠任欣桐
Owner NANJING UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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