PL228425B1 - 1'-(3,7,11-Trimethyl-3-vinyldodeca-6,10-dienyl)-2'-palmitoyl-sn-glycero-3'-phosphfocholine and method for obtaining it - Google Patents

Description

(12) PATENT DESCRIPTION ₍ i ₉₎ PL ₍ n) 228425 (13) B1 (21) Application Number: 419201 (®1) Int.CI.

C07F 9/10 (2006.01) C07C 67/04 (2006.01) A61P 35/00 (2006.01) (22) Filed on: 21.10.2016 - (3,7,11-Trimethyl-3-vinyl dodeca-6,10-dienyl ) -2 ^, -palmitoyl-sn-glycero-3 ^, -phosphocholine and the method of obtaining it (73) Authorized by the patent:

UNIVERSITY OF NATURE IN WROCŁAW, Wrocław, PL (43) Application was announced:

27.02.2017 BUP 05/17 (45) The following was announced about the grant of the patent:

30/03/2018 WUP 03/18 (72) Inventor (s):

ANNA GLISZCZYŃSKA, Wrocław, PL NATALIA NIEZGODA, Wrocław, PL WITOLD GŁADKOWSKI, Wrocław, PL (74) Representative:

thing, pat. Anna Olszewska m

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PL 228 425 B1

Description of the invention

The subject of the invention is 1 '- (3,7,11-trimethyl-3-vinyl dodeca-6,10-dienyl) -2'-palmitoyl-sn-glycero-3'-phosphocholine of the formula 1, shown in the figure, and the method of its receiving.

The invention may find application in the pharmaceutical and chemical industries as well as in the treatment of neoplastic diseases.

From the description of the application P. 418653 there is known a phospholipid derivative containing 3,7,11-trimethyl-3-vinylododeca-6,10-diene acid molecules simultaneously in the sn-1 and sn-2 positions of phosphatidylcholine. There is also known heterosubstituted phosphatidylcholine which has a palmitic acid molecule in the sn-1 position and a 3,7,11-trimethyl-3-vinyl dodeca-6,10-diene acid in the sn-2 position, known from the application description P. 418943 and 2 - lysophosphatidylcholine containing 3,7,11-trimethyl-3-vinyl dodeca-6,10-diene acid in the sn-1 position known from the application description P. 419069.

There is no known phosphatidylcholine containing a 3,7,11-trimethyl-3-vinyl dodeca-6,10-diene acid molecule in the sn-1 position and a palmitic acid molecule in the sn-2 position.

The essence of the invention is 1 '- (3,7,11-trimethyl-3-vinylododeca-6,10-dienyl) -2'-palmitoyl-sn-glycero-3'-phosphocholine, shown in the drawing and the method of its preparation.

The essence of the method of obtaining a phospholipid with a molecule of 3,7,11-trimethyl-3-vinyl dodeca-6,10-diene acid, which is 1 '- (3,7,11-trimethyl-3-vinyl dodeca-6,10-dienyl) - 2'-palmitoyl-sn-glycero-3'-phosphocholine, is that palmitic acid is esterified with 1 '- (3,7,11-trimethyl-3-vinyl dodeca-6,10-dienyl) -2' -hydroxy-sn-glycero-3'-phosphocholine in the presence of 4-dimethylaminopyridine with WW-dicyclohexylcarbodiimide as a coupling agent. The reaction is carried out in anhydrous methylene chloride for at least 24 hours and then the product formed is isolated.

Preferably, the esterification process is carried out at a temperature of 18 to 55 ° C.

The method according to the invention is explained in more detail using an exemplary embodiment.

P r z k ł a d 1

Up to 71 mg (0.14 mmol) of dried 1 '- (3,7,11-trimethyl-3-vinyl dodeca-6,10-dienyl) -2'-hydroxysn-glycero-3'-phosphocholine dissolved in anhydrous methylene chloride ( CH 2 Cl 2, 1 cm ³ ), 144 mg (0.56 mmol) of palmitic acid dissolved in 3 cm ^{3 of} anhydrous methylene chloride are added,

4-dimethylaminopyridine (DMAP) (34 mg, 0.28 mmol) dissolved in 3 cm ³ of dry methylene chloride and N, N- dicyclohexylcarbodiimide (DCC) (120 mg, 0.58 mmol) was also dissolved in dry methylene chloride (CH2Cl2, 3 cm ³ ). The suspension is stirred vigorously at 40 ° C under N2 for 72 hours. After this time, the reaction mixture was filtered under reduced pressure on a Schott funnel, and an ion-exchange resin of H + form was added to the filtrate and stirred for 30 minutes. The ion exchange resin is then filtered off and the solvent is evaporated off under reduced pressure. The crude product is purified by column chromatography on silica gel using a solvent mixture of CHCl 2: MeOH: H 2 O 65: 25: 4 (v / v / v) as the eluent.

67 mg (0.09 mmol) of 1 '- (3,7,11-trimethyl-3-vinyl dodeca-6,10-dienyl) -2'-palmitoyl-sn-glycero-3'-phosphocholine are obtained with a yield of 64 % as a greasy substance.

The purity, as confirmed by high performance liquid chromatography (HPLC), is> 99%.

The spectroscopic data of the obtained compound are as follows:

¹ H NMR (600 MHz, CDCl3 / CD3OD 2: 1 (v / v)) δ: 0.64 (t, J = 6.6 Hz, 6H, CH3 (CH2) 13CH2C (O) (A) CH3 (CH2) 13CH2C (O) (B)), 0.89 (s, 6H, CH3-15 (A), CH3-15 (B)), 1.02-1.05 (m, 48H, CH3 (CH2) 12CH2CH2C (O) (A), CH3 (CH2) 12CH2CH2C (O) (B)), 1.16-1.19 (m, 4H, CH2-4 (A), CH2-4 (B)), 1.34, 1.43 (two s, 12H, CH3-12 (A) , CH3-12 (B), CH3-17 (A), CH3-17 (B)), 1.35-1.40 (m, 4H, CH3 (CH2) 12CH2CH2C (O) (A), CH3 (CH2) 12CH2CH2C (O ) (B)) 1.36 (s, 6H, CH3-16 (A), CH3-16 (B)), 1.66-1.73 (two m, 8H, CH2-5 (A), CH2-5 (B), CH2 -8 (A), CH2-8 (B)), 1.80-1.83 (m, 4H, CH2-9 (A), CH2-9 (B)), 2.06-2.14 (m, 4H, CH2-2 (A ), CH2-2 (B)), 2.09 (t, J = 7.8 Hz, 4H, CH3 (CH2) 13CH2C (O) (A), CH3 (CH2) 13CH2C (O) (B)), 2.99 (s, 18H, -N (CH3) 3 (A), -N (CH3) 3 (B)), 3.37-3.40 (broad s, 4H, CH2-3 (A), CH2-3 (B)), 3.76-3.78 (m, 4H, CH2-3 '(A), CH2-3' (B)), 3.88-3.91 (dd, J = 12.0, 6.6 Hz, 2H, one of CH2-1 '(A), one of CH2 -1 '(B)), 4.00-4.05 (broad s, 4H, CH2-a (A), CH2-a (B)), 4.15 (m, 2H, one of CH2-1' (A), one of CH2-1 '(B)), 4.72 (d, J = 1 7.4, 2H, one of CH2-14 (A), one of CH2-14 (B)), 4.79 (d, J = 10.8 Hz, 2H, one of CH2-14 (A), one of CH2-14 (B )), 4.83-4.85 (m, 4H, H-6 (A), H-6 (B), H-10 (A), H-10 (B)), 4.95-4.98 (m, 2H, H- 2 '(A), H-2' (B)), 5.56 (dd, J = 17.4, 10.8 Hz, 2H, H-13 (A), H-13 (B));

¹³ C NMR (151 MHz, CDCl3 / CD3OD 2: 1 (v / v)) δ: 13.58 (CH3 (CH2) i3CH2C (O) (A), CH3 (CH2) i3CH2C (O) (B) ), 15.41, 25.15 ((C-12 (A), C-12 (B), C-17 (A), C-17 (B)), 17.13 (C-16 (A), C-16 (B )), 22.30 (CH3CH2 (CH2) 12CH2C (O) (A), CH3CH2 (CH2) 12CH2C (O) (B)), 22.37 (C-5 (A), C-5 (B)), 22.50, 22.52 (C-15 (A), C-15 (B)), 24.51 (CH3 (CH ₂ ) 12CH2CH2C (O) (A), CH3 (CH ₂ ) 12CH2CH2C (O) (B)), 26.33 (C-9 (A), C-9 (B)), 28.77, 28.97, 28.98, 29.15, 29.28, 29.30, 29.32, 31.56 (CH3CH2 (CH2) nCH2CH2C (O) (A), CH3CH2 (CH2) 11CH2CH2C (O) (B )), 33.87 CH3 (CH ₂ ) 13CH ₂ C (O) (A), CH3 (CH ₂ ) 13CH ₂ C (O) (B)), 38.84 (C-3 (A), C-3 (B) ), 39.34 (C-8 (A), C-8 (B)), 40.49, 40.51 (C-4 (A), C-4 (B)), 44.55, 44.58 (C-2 (A), C -2 (B)), 53.79 (t, J = 3.6 Hz, -N (CH3) 3 (A), -N (CH3) 3 (B)), 58.78 (d, J = 4.9 Hz, C-α ( A), Ca (B)), 62.12 (C-1 '(A), C-1' (B)), 63.42 (d, J = 5.1 Hz, C-3 '(A), C-3' ( B)) 66.10 (m, C-β (A), C-β (B)), 70.02 (d, J = 7.7 Hz, C-2 '(A)), 70.03 (d, J = 8.0 Hz, C -2 '(B)), 111.94 (C-14 (A), C-14 (B)), 123.79 (C-10 ( A), C-10 (B)), 123.93 (C-6 (A), C-6 (B)), 130.94 (C-11 (A), C-11 (B)), 134.79 (C-7 (A), C-7 (B)), 144.84 (C-13 (A), C-13 (B)), 171.43 (C-1 (A), C-1 (B)), 173.22 (CH3 ( _CH2) 13CH ₂ C (O) (A) CH3 _(CH2) 13CH ₂ C (O) (B));

³¹ P NMR (243 MHz, CDCl3 / CD3OD 2: 1 (v / v)) δ: - 0.82;

(a, β) - indicates choline-derived signals.

Claims (3)

Patent claims 1. 1 '- (3,7,11-Trimethyl-3-vinyl dodeca-6,10-dienyl) -2'-palmitoyl-sn-glycero-3'-phosphocholine, as shown in the drawing. 2. The method of obtaining the phospholipid derivative of 3,7,11-trimethyl-3-vinyl dodeca-6,10-diene, characterized in that palmitic acid dissolved in anhydrous methylene chloride is subjected to esterification with 1 '- (3,7,11 -trimethyl-3-vinyl dodeca-6,10-dienyl) -2'-hydroxy-sn-glycero-3'-phosphocholine in the presence of 4-dimethylaminopyridine with a coupling agent such as H, W-dicyclohexylcarbodiimide, where the reaction is carried out in anhydrous methylene chloride, and the suspension is stirred for at least one day, then the resulting 1 '- (3,7,11-trimethyl-3-vinyl dodeca-6,10-dienyl) -2'-palmitoyl-sn- is isolated glycero-3'-phosphocholine. 3. The method according to p. The process of claim 2, wherein the esterification process is carried out at a temperature of 18 to 55 ° C.