Pharmaceutical compositions comprising cyclic glycerophosphates and analogs thereof for promoting neural cell differentiation

A technology of nerve cells and compositions, which is applied in the field of treating nerve-related diseases and diseases, and can solve the problems of not being able to prevent the degeneration and loss of efficacy of dopamine neurons

Inactive Publication Date: 2002-05-08
YEDA RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current commonly used treatment method is mainly to continuously stimulate dopamine receptors with drugs. Although this method can cause relief of symptoms at the beginning, it will gradually lose its effectiveness
In addition, the drugs did not prevent the progressive degeneration of dopamine neurons that is characteristic of these disorders

Method used

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  • Pharmaceutical compositions comprising cyclic glycerophosphates and analogs thereof for promoting neural cell differentiation
  • Pharmaceutical compositions comprising cyclic glycerophosphates and analogs thereof for promoting neural cell differentiation
  • Pharmaceutical compositions comprising cyclic glycerophosphates and analogs thereof for promoting neural cell differentiation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] The synthesis of a series of known and novel 5- and 6-membered cyclic phosphates is illustrated below. Example 1: Synthesis of 1,3 cyclic glycerophosphate (1,3 cGP)

[0053] The procedure was essentially as described by Buchnea (Buchnea, 1973). Briefly, 2-benzyloxy-1,3-propanediol (Aldrich) was reacted with equimolar amounts of phosphorus oxychloride (Aldrich) in dichloromethane. The resulting 2-benzyl-1,3 cGP was treated with hydrogen in methanol under the catalysis of palladium black to remove the benzyl residue. 1,3 cGP was isolated as the barium salt, which was pure on paper chromatography (n-propanol:ammonia:water 6:3:1, R f = 0.52).

[0054] 1,3 cGP can also be prepared by cleavage of phosphatidylglycerol (PG) with phospholipase C as described in the literature (Shinitzky et al., 1993). Paper chromatography indicated that the product contained about 10-20% α-GP. Example 2: Synthesis of 1,2 cyclic glycerophosphate (1,2 cGP)

Embodiment 2

[0055] The compound was prepared as described in the literature (Kugel, L. and Halmann, M., J. Am. Chem. Soc., 89:4125-4128 (1967). The disodium salt of β-glycerophosphate (Sigma) First convert to the form of acid, then use dicyclohexylcarbodiimide (Aldrich) cyclization. The product is isolated in the form of barium salt, which is pure on paper chromatography. Embodiment 3: phenyl 1,3 ring Synthesis of Glycerophosphate (P-1,3 cGP)

Embodiment 3

[0056] Following the procedure described in Example 1 for the preparation of 1,3 cGP, 2-benzyloxy-1,3-propanediol was reacted with phenyl dichlorophosphate (Aldrich). The benzylated intermediate product was analyzed by thin layer chromatography (ethyl acetate: hexane 3: 2 R f =0.58) is pure, melting point 136 ° C. This was hydrogenated as described in Example 1 to selectively remove the benzyl residue. The resulting P-1,3 cGP (compound III) was pure on TLC (supra), R f =0.15, the melting point is 116°C. Example 4: Synthesis of 1,3 cyclic propylene glycol phosphate (1,3 cPP)

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Abstract

Cyclic glycerophosphates and analogs thereof (CGs) are shown to exert neutral promoting activities in target cells. Such activities include promotion of neuronal outgrowth, promotion of nerve growth, provision of dopaminotrophic supporting envrionment in a diseased portion of the brain, prevention of nerve degeneration and nerve rescue. These activities of the CGs render them useful for treatment of various disorders including but not limited to mental disorders such as, for example, schizophrenia, dementia or disorders resulting in learning disablities. In addition, these CGs may be used for the treatment of neurodegenerative conditions such as Altzheimer's diesease, Parkinson's disease, conditions resulting from exposure to harmful environmental factors or resulting from a mechanical injury. The CGs may also be used to treat an individual suffering from a primary neurodengenerative condition in order to prevent or reduce the appearance of secondary degeneration in additional nerves ("nerve rescue").

Description

field of invention [0001] The present invention relates to pharmaceutical compositions containing cyclic glycerophosphates and analogs thereof and methods of treating neurologically related diseases and conditions. [0002] current technology [0003] The following is a list of references for the purpose of better understanding the background of the present invention. Boyd, R.K., De Freitas, A.S.W., Hoyle, J., McCulloch, A.W., McInnes.A.G., Rogerson, A. and Walter, J.A., J. Biol. Chem., 262:12406-12408 (1987 ). Clarke, N. and Dawson, R.M.C., Biochem. J., 216:867-874 (1976). Dawson, R.M.C., Ann. Rept. Progr. Chem. 55:365, (1958). Dawson, R.M.C., Freinkel, N., Jungalwala, F.B. and Clarke, N., Biochem. J. 122:605-607, (1971). Forrest, H.S. and Todd, A.R., J. Chem. Soc., 1950, 3925, (1950). Friedman, P., Haimovitz, R., Markman, O., Roberts, M.F., and Shinitzky, M., Conversion of lysophospholipids to cyclic lysophosphatidic acid by phospholipases, D.J.Biol.Chem., 271: 953-95...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/665A61KA61K31/00A61K31/66A61K31/6615A61P3/10A61P25/00A61P25/16A61P25/18A61P25/28A61P35/00A61P35/02A61P43/00C07F9/6574
CPCA61K31/665A61P25/00A61P25/16A61P25/18A61P25/28A61P35/00A61P35/02A61P43/00A61P3/10A61K31/6615
Inventor M·辛尼茨基
Owner YEDA RES & DEV CO LTD
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