Conjugate formed by conjugating one Arg-Gly-Asp-Val chain and two fatty alcohol chains by Asp, synthesis thereof and medical application thereof
A technology of arg-gly-asp-val-asp and conjugates, applied in the field of biomedicine, can solve the problems of short half-life, low immunogenicity, and small side effects
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Embodiment 1A
[0044] Embodiment 1Arg-Gly-Asp-Val-Asp[OCH 2 (CH 2 ) 6 CH 3 ] 2 Preparation of (9a)
[0045] 1) Boc-Arg (NO 2 )-Gly-OBzl:
[0046] 1.600g (5.0mmol) Boc-Arg (NO 2 ) was dissolved in 20ml of anhydrous THF to form a white emulsion, 0.745g (5.5mmol) of N-hydroxybenzotriazole (HOBt) was added under ice cooling, and 1.23g (6mmol) of dicyclohexylcarbonyldioxide was added after 10 minutes Amine (DCC), to obtain the reaction solution A, stand-by. Suspend 1.61g (5.25mmol) TOSH·Gly-OBzl in 20ml anhydrous THF under ice-cooling, then add N-methylmorpholine (NMM) to adjust the pH to 8-9. Stir for 35 minutes to obtain reaction solution B, which is ready for use. Add reaction solution A to reaction solution B under ice bath, first stir under ice bath for 1 h, then stir at room temperature for 12 h, TLC (chloroform / methanol, 10:1) showed that Boc-Arg (NO 2 )disappear. Dicyclohexylurea (DCU) was filtered off, and the filtrate was concentrated under reduced pressure to obtain a yellow...
Embodiment 2A
[0067] Example 2Arg-Gly-Asp-Val-Asp[-OCH 2 (CH 2 ) 8 CH 3 ]-OCH 2 (CH 2 ) 8 CH 3 Preparation of (9b)
[0068] 1) Boc-Asp[-OCH 2 (CH 2 ) 8 CH 3 ]-OCH 2 (CH 2 ) 8 CH 3 (1b)
[0069] According to the preparation method of 1a, by 1.165g (5mmol) Boc-Asp and 1.659g (10.5mmol) CH 3 -(CH 2 ) 9 -OH yielded 2.565 g (99.9%) of the title compound as a colorless oil. ESI-MS (m / z): 536[M+Na] + ,
[0070] 2) HCl·Asp[-OCH 2 (CH 2 ) 8 CH 3 ]-OCH 2 (CH 2 ) 8 CH 3 (2b)
[0071] Using the same method as in the preparation of 2a, 0.449 g (99.9%) of the target compound was prepared from 0.513 g (1 mmol) of 1 b as a colorless oil, which was directly used in the next reaction. ESI-MS(m / z): 414[M+H] + .
[0072] 3) Boc-Val-Asp[-OCH 2 (CH 2 ) 8 CH 3 ]-OCH 2 (CH 2 ) 8 CH 3 (3b)
[0073] Following the procedure of 3a, 3.06 g (99.9%) of the title compound were obtained as a colorless oil from 1.139 g (5.25 mmol) Boc-Val and 2.247 g (5.0 mmol) 2b. ESI-MS (m / z): 6...
Embodiment 3A
[0086] Example 3Arg-Gly-Asp-Val-Asp[-OCH 2 (CH 2 ) 10 CH3 ]-OCH 2 (CH 2 ) 10 CH 3 Preparation of (9c)
[0087] 1) Boc-Asp[-OCH 2 (CH 2 ) 10 CH 3 ]-OCH 2 (CH 2 ) 10 CH 3 (1c)
[0088] According to the preparation method of 1a, by 1.165g (5mmol) Boc-Asp and 1.953g (10.5mmol) CH 3 -(CH 2 ) 10 CH 2 -OH yielded 2.854 g (99.9%) of the title compound as a colorless oil. ESI-MS (m / z): 593[M+Na] + ,
[0089] 2) HCl·H-Asp[-OCH 2 (CH 2 ) 10 CH 3 ]-OCH 2 (CH 2 ) 10 CH 3 (2c)
[0090] Using the same method as in the preparation of 2a, 0.506 g (99.9%) of the target compound was obtained from 0.569 g (1 mmol) of 1c as a colorless oil, which was directly used in the next reaction. ESI-MS(m / z): 471[M+H] + .
[0091] 3) Boc-Val-Asp[-OCH 2 (CH 2 ) 10 CH 3 ]-OCH 2 (CH 2 ) 10 CH 3 (3c)
[0092] Following the preparation method of 3a, 3.34 g (99.9%) of the title compound were obtained as a colorless oil from 1.139 g (5.25 mmol) of Boc-Val and 1.07 g (5.0 m...
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