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A pyrrolophenothiazine-1,3-dione derivative and its preparation method and application

A technology of phenothiazine and derivatives is applied in the field of pyrrolophenothiazine-1,3-dione derivatives and their preparation, which can solve problems such as affecting the polymerization process of tau protein, and achieve protection of nerve cells and treatment of Alzheimer's disease. Zheimer's disease, the effect of strong stabilizing effect

Inactive Publication Date: 2019-03-05
GUANGDONG UNIV OF TECH
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  • Abstract
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Problems solved by technology

[0005] The research on treating Alzheimer's disease with tau protein as a target is still in its infancy. Most small drug molecules are still in the stage of theoretical design, and only a small part has entered the second phase of clinical trials, such as methylene blue ( MTC), a phenothiazine compound that prevents tau-tau interactions, not only partially disintegrates isolated double-helix filaments (PHFs), but also affects the polymerization process of tau protein

Method used

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  • A pyrrolophenothiazine-1,3-dione derivative and its preparation method and application
  • A pyrrolophenothiazine-1,3-dione derivative and its preparation method and application
  • A pyrrolophenothiazine-1,3-dione derivative and its preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Synthesis of 2-(2,6-diisopropylphenyl)pyrrolo[3,4-b]phenothiazine-1,3(2H,10H)-dione 3a1

[0028] From the commercial compound 4,5-dichlorophthalic anhydride (430mg, 2mmol, 1eq) mixed with 2,6-diisopropylaniline (387mg, 2.2mmol, 1.1eq) in glacial acetic acid (10mL) Finally, the reaction temperature was raised to 120°C and refluxed for nearly 8 hours. The color change of the reaction solution could be observed, and the degree of reaction was detected by TLC. After the reaction solution was spin-dried, it was purified by column chromatography to obtain compound 1a, melting point : 180°C, yield 98%.

[0029] 1 H NMR (400MHz, CDCl 3 )δ8.06(s, 2H), 7.47(t, J=7.8Hz, 1H), 7.28(d, J=7.8Hz, 1H), 2.64(hept, J=7.8Hz, 2H), 1.16(d, 12H).

[0030] Afterwards, compound 1a (400mg, 1.06mmol, 1eq) was added into N,N-dimethylformamide (6mL) in which 2-aminothiophenol (133mg, 1.06mmol, 1eq) was dissolved, and then slowly added dropwise Triethylamine (737μL, 5.3mmol, 5eq), after uniform...

Embodiment 2

[0035] Synthesis of 7-chloro-2-(2,6-diisopropylphenyl)pyrrolo[3,4-b]phenothiazine-1,3(2H,10H)-dione 3a2 from commercially available 2- Amino-5-chlorothiophenol (424mg, 2.66mmol, 1eq) and compound 1a (1g, 2.66mmol, 1eq) refer to the synthesis process of Example 1 to obtain compound 3a2, a red solid, melting point: melting point: >300 ° C, The total yield is 54%.

[0036] 2a2: Melting point: 259℃, 1 H NMR (400MHz, CDCl 3 )δ:7.94(s,1H),7.45(m,2H),7.33(dd,J=7.5,3.0Hz,1H),7.28(d,J=7.5Hz,2H),7.17(s,1H), 6.84 (d, J=7.5Hz, 1H), 2.67 (hept, J=7.0Hz, 2H), 1.16 (d, J=7.5Hz, 12H).

[0037] 3a2: 1 H NMR (400MHz, DMSO) δ9.55(s, 1H), 7.51(s, 1H), 7.46(t, J=7.5Hz, 1H), 7.31(d, J=7.5Hz, 1H), 7.10-7.06 (m,2H),7.01(s,1H),6.67(d,J=9.0Hz,1H),2.61(hept,J=7.0Hz,2H),1.06(dd,J=7.0,2.0Hz,12H) ;ESI-MS m / z:463.2[M+H] + .

Embodiment 3

[0039] Synthesis of 8-chloro-2-(2,6-diisopropylphenyl)pyrrolo[3,4-b]phenothiazine-1,3(2H,10H)-dione 3a3 from commercial 2- Amino-4-chlorothiophenol (382mg, 2.39mmol, 1eq) and compound 1a (900mg, 2.39mmol, 1eq) refer to the synthesis process of Example 1 to obtain compound 3a3, a red solid, melting point: 340 ° C, total yield 55%.

[0040] 2a3: Melting point: 267℃, 1 H NMR (400MHz, CDCl 3 )δ:7.42-7.46(m,2H),7.29(s,1H),7.1(s,1H),6.84(m,2H),6.6(s,1H),6.44(d,J=3.0Hz,1H ), 2.67 (hept, J=7.0Hz, 2H), 1.16 (d, J=7.0Hz, 12H).

[0041] 3a3: 1 H NMR (400MHz, CDCl 3 )δ7.42-7.46(m,2H),7.29(d,J=7.5Hz,2H),7.10(s,1H),6.84(m,2H),6.54(s,1H),6.45(d,J =3.0Hz, 1H), 2.68(hept, J=7.0Hz, 2H) 1.16(d, J=7.0Hz, 12H); ESI-MS m / z: 463.2[M+H] + .

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Abstract

The invention discloses a pyrrolo-phenothiazine-1,3-diketone containing derivative as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The derivative disclosed by the invention comprises a compound of formula I as shown in the specification, and pharmaceutically applicable salts, wherein in the formula, R1 is hydrogen or chlorine, R2 is hydrogen or methyl, and R3 is one of hydrogen, isopropyl or methoxyl. Most compounds of the type have inhibition functions on tau protein polymerization, have functions of stabilizing tubulin, and can be adopted to effectively treat the Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a pyrrolophenothiazine-1,3-dione derivative and its preparation method and application. Background technique [0002] Alzheimer's disease is a neurodegenerative disease that is often found in the elderly population, so it is also called Alzheimer's disease. The clinical manifestations of the disease include impairment of social skills, memory function, cognitive function, spatiotemporal disorientation, and loss of daily self-care ability. Currently, the disease is one of the largest medical problems in developed countries. At the same time, with the prominent problem of population aging in our country, senile dementia has also become a serious impact on the normal life and health of the elderly. According to World Health Organization (WHO) estimates, the overall prevalence of the global population will quadruple in the next few decades, with an estimated 114 mil...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04A61P25/28
CPCC07D513/04
Inventor 陈惠雄帕斯卡·道叶飞飞黄广华
Owner GUANGDONG UNIV OF TECH
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