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Nitrogen monoxide synthase inhibitor, its preparation method and application

A compound, methoxyl technology, applied in the field of nitric oxide synthase inhibitors, can solve problems such as affecting application value

Inactive Publication Date: 2005-03-02
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 1997, Shearer BG et al. (Shearer BG, et al. J Med Chem.1997, 40 (12): 1901-1905) reported that S-ethyl-N-substituted phenylisothiourea has a strong NOS inhibitory effect, And it is selective to nNOS, but they are eliminated rapidly in the body, which affects its application value

Method used

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  • Nitrogen monoxide synthase inhibitor, its preparation method and application
  • Nitrogen monoxide synthase inhibitor, its preparation method and application
  • Nitrogen monoxide synthase inhibitor, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0105] Preparation of S-methyl-N-[4-(benzimidazole-2-mercapto)phenyl]isothiourea hydroiodide (I-1)

[0106] 2-(4-nitrophenylthio)benzimidazole (III-1):

[0107] Add 9.5g (63.3mmol) of 2-mercaptobenzimidazole, 60ml of anhydrous acetonitrile, 2.53g (63.3mmol) of powdered sodium hydroxide, 9.98g (63.3mmol) of p-nitrochlorobenzene and 1.0g of PEG-400 into the pressure-resistant In the bottle, place it in an oil bath at 120°C under electromagnetic stirring for 28 hours, cool, filter with suction, wash twice with cold acetonitrile, and then wash with water to pH 7 to obtain 15.1 g (87.9%) of yellow solid (III-1), mp 185~ 186°C.

[0108] 1 HNMR (90MHz, CDCl 3 +DMSO-d 6 ), δ(ppm): 7.17~7.32(2H, m, ArH), 7.47~7.62(4H, m, ArH), 8.04~8.20(2H, m, ArH)

[0109] 2-(4-Aminophenylthio)benzimidazole (IV-1):

[0110] Add 10 g (179 mmol) of reduced iron powder and 200 ml of 95% ethanol into a three-neck flask, add 8.4 ml of 10% HCl dropwise under mechanical stirring, and after 10 min, add ...

example 2

[0126] Preparation of S-ethyl-N-[4-(benzimidazole-2-mercapto)phenyl]isothiourea hydroiodide (I-2)

[0127] Using compound (VI-1) and iodoethane (molar ratio 1:3) as raw materials, a method similar to compound (I-1) was used to obtain pale yellow crystals (I-2, 54.8%), mp 148-150°C.

[0128] IR (cm -1 ): 3443, 3407(NH), 3135~2835( + NH 3 ), 3082 (ArH), 2977, 2930 (CH), 1628, 1546, 1524 (C=C, C=N), 1426, 1403 (imidazole), 1269 (-SCH 2 -), 749 (ArH, ortho-disubstituted)

[0129] 1 HNMR (90MHz, DMSO-d 6 +CDCl 3 ), δ (ppm): 1.38 (3H, t, J=7.33Hz, -S-CH 2 -CH 3 ), 3.30 (2H, q, J=7.08Hz, -S-CH 2 -), 7.16~7.58 (8H, m, ArH), 7.58~9.80 (4H, br, + NH 3 +NH)

[0130] MS(SCI 70eV, m / z): 329(M+1), 312(M-16), 284, 254, 242(base peak)

[0131] Anal (C 16 h 16 N 4 S 2 HI; C%, H%, N%): Req 42.11, 3.75, 12.28 Found 41.89, 3.84, 12.06

example 3

[0133] Preparation of S-n-butyl-N-[4-(benzimidazole-2-mercapto)phenyl]isothiourea hydroiodide (I-3)

[0134] Using compound (VI-1) and iodo-n-butane (molar ratio 1:3) as raw materials, a method similar to compound (I-1) was used to obtain light yellow crystals (I-3, 62%), mp 176-177 ℃

[0135] IR (cm -1 ): 3149~2734 ( + NH 3 ), 3077 (ArH), 2958, 2928 (CH), 1627, 1587, 1544, 1516 (C=C, C=N), 1422, 1407 (imidazole), 1269 (-SCH 2 -), 737 (ArH, ortho-disubstituted)

[0136] 1 HNMR (90MHz, DMSO-d 6 +CDCl 3 ), δ (ppm): 0.95 (3H, t, J=6.48Hz, -S-(CH 2 ) 3 -CH 3 ), 1.33~1.77 (4H, m, -S-CH 2 -CH2 CH 2 -CH 3 ), 3.26 (2H, t, J=7.02Hz, -S-CH 2 -), 7.14~7.67 (8H, m, ArH), 7.7~10.0 (4H, br, + NH 3 +NH)

[0137] MS (SCI 70eV, m / z): 357 (M+1), 284, 242, 184, 57 (base peak)

[0138] Anal (C 18 h 20 N 4 S 2 HI; C%, H%, N%): Req 44.63, 4.37, 11.57 Found 44.36, 4.55, 11.29

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Abstract

The present invention relates to a compound-laughing gas synthase inhibitor. Said invention also provides its general formula and its preparation method, and also discloses the medicine containing said compound and its application for curing the diseases of septic shock, enteritis, rheumatoid arthritis, diabetes mellitus, cerebral ischemic injury and presenile dementia, etc.

Description

technical field [0001] The present invention relates to novel isothiourea compounds, their preparation methods, pharmaceutical compositions containing these compounds and their medical use, especially as nitric oxide synthase inhibitors. Background technique [0002] Septic shock is currently a refractory disease, there is no effective drug in clinical practice, and the mortality rate is extremely high. Certain diseases such as arthritis still do not have good treatment medicines at present. The excess NO catalyzed by iNOS is an important cause of septic shock and inflammation. Therefore, the development of iNOS inhibitors has potential therapeutic value for these diseases. [0003] In recent years, a lot of progress has been made in the study of NOS inhibitors, among which, compounds containing isothiourea structures have better NOS inhibitory activity (Southan GJ, Szabo C. Biochem Pharmacol. 1996, 51: 383-394). In 1997, Shearer BG et al. (Shearer BG, et al. J Med Chem.19...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/4188A61K31/428A61P1/00A61P3/10A61P9/10A61P25/28A61P29/00C07D235/28C07D277/70
Inventor 徐云根华维一朱东亚罗穗
Owner CHINA PHARM UNIV
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