 Inositol polyphosphate derivatives and methods of using same
专利摘要:
The present invention seeks to provide a cell permeable antagonist composition of inositol polyphosphate. In another aspect, the present invention is to provide a method for promoting the secretion of chlorine ions in cells by contacting the cell-permeable antagonist of inositol polyphosphate to the cells. In another aspect, the present invention is to provide a method for promoting the secretion of chloride ions in a subject by administering a cell permeable antagonist of inositol polyphosphate to the subject. The present invention also relates to a method of alleviating signs or symptoms associated with cystic fibrosis in a subject by administering to the subject a cell permeable antagonist of inositol polyphosphate. The present invention also seeks to provide a cell permeable agent composition of inositol polyphosphate. It is another object of the present invention to provide a method for inhibiting the secretion of chlorine ions in a cell by contacting a cell permeable agent of inositol polyphosphate to the cell. It is also an object of the present invention to provide a method of inhibiting the secretion of chlorine ions in a subject by administering a cell permeable agent of inositol polyphosphate to the subject. The invention also relates to a method of alleviating signs or symptoms associated with secretory diarrhea in a subject by administering to the subject a cell permeable antagonist of inositol polyphosphate. 公开号:KR20000048499A 申请号:KR1019990702388 申请日:1997-09-19 公开日:2000-07-25 发明作者:알렉시스 트레이노어-카프란 申请人:린다 에스. 스티븐슨；더 리전트 오브 더 유니버시티 오브 캘리포니아； IPC主号:
专利说明:
INOSITOL POLYPHOSPHATE DERIVATIVES AND METHODS OF USING SAME} All living things are made up of cells. The edges of these cells are defined by plasma membranes that act to separate the material inside the cell from the material outside. Cell membranes act to regulate the transport of substances such as nutrients into or out of cells. The movement of ions through the cell membrane is involved in many important functions in the cell, such as the regulation of the oncotic pressure of the cell. By controlling the movement of ions, it is possible to adjust the concentration appropriate to the cell to maintain the cell's integrity (integrity) and function. Under improper conditions, the cell cannot maintain its function, for example, if the concentration of ions in the cell becomes too high, water moves into the cell causing the cell to expand and burst, and if the concentration of ions in the cell becomes too low, It will shrink. The organism uses the transport properties of ions in the cell membrane to regulate body fluids, especially in tissues. For example, cells in the gut regulate water uptake by the movement of ions. Particularly important ions carried by the cell are chlorine ions. Chlorine ions play a major role in various cellular functions such as osmotic regulation, intracellular pH regulation and secretion of salts and body fluids. In the intestine, high levels of chlorine ions are associated with diseases such as secretory diarrhea. Secretory diarrhea occurs due to various causes, such as infection by microorganisms such as a series of strains of Salmonella, Shigella, and Escherichia coli. Other conditions associated with the regulation of body fluids and the secretion of chlorine ions in tissues include tissue expansion associated with inflammation, infection, or trauma. Therefore, preventing the chlorine ion from becoming abnormal can alleviate the symptoms of these symptoms. Cystic fibrosis is the most common fatal disease in Caucasians (Caucasian races), affecting about 1 in 2,000 American-born ancestors in Europe. The disease is characterized by abnormally high viscosity mucus, which leads to chronic lung disease, pancreatic insufficiency and intestinal disorders. In the United States, there are about 30,000 cystic fibrosis patients and about 1,000 new cases occur each year. In the past, affected children often died in infants, but now they can survive in their 20s and 30s. Nevertheless, there is no cure for cystic diseases, and current treatment is not alteration of cell defects, but rather manages the symptoms of the disease. Current treatments for cystic fibrosis are mostly limited to alleviating symptoms or controlling transient infections. For example, vaccination against the pathology of the virus or the use of culture-specific antibiotics for bacterial infection can be used to prevent infection. Corticosteroids can often be used to treat inflammatory responses to infections, but they cause a number of undesirable long-term side effects. Other treatments focus on the symptoms of chronic lung disease associated with abnormal mucus secretion in the lungs. For example, physical means, such as chest percussion and postural drainage aid, aid in the discharge of secretions from the lungs. Bronchodilation benefits some patients but reduces gas exchange in others. Other symptoms associated with abnormal viscous mucus include intestinal disorders and pancreatic insufficiency. Intestinal disorders occur in 20% of adults, treated with enema, or surgery if the enema is inappropriate. Pancreatic insufficiency occurs in 80-90% of patients due to impaired recycling of chlorine ions out of the cell resulting in reduced secretion of bicarbonate ions and body fluids. In this case, the protein of the pancreatic fluid is highly concentrated and becomes thick, causing disorders of the pancreatic duct and consequently causing atrophy of the pancreatic vesicles. Pancreatic insufficiency is treated to overcome malnutrition symptoms by supplementing enzymes to restore proper digestive and absorption functions. However, if the underlying disease is not treated, it often causes atrophy of the pancreas, causing pancreatitis to recur repeatedly. Treatment methods that allow for normal pulmonary function, normal excretion of the colon, or normal pancreatic function will provide significant advantages over current methods of treatment. Gene therapy has been used in cystic fibrosis patients. However, attempts at gene therapy have not been successful for a variety of reasons, such as oversized genes and immune responses to adenovirus vectors used for gene transfer and rapid turnover of epithelial tissue. Thus, there is a need for means to convert chlorine ion secretion to ameliorate conditions such as secretory diarrhea and cystic fibrosis associated with abnormal chlorine migration. The present invention satisfies these needs and also provides advantages in this regard. FIELD OF THE INVENTION The present invention relates to compounds and methods for controlling the movement of chlorine ions, and more particularly to agents and antagonists against inositol polyphosphate. 1 shows the structure of 2-Bt-1-Me-Ins (3,4,5,6) P 4 / AM, myo-inositol, scyllo-inositol and representative cell permeable inositol polyphosphate derivatives. Figure 2 shows chloride ion inhibition of Bt 2 -Ins (3,4,5,6) P 4 / AM in the colon of rabbits. Figure 3 shows 2-Bt-1-Me-Ins (3,4, due to reversal of Bt 2 -Ins (3,4,5,6) P 4 / AM-mediated inhibition of histamine stimulated goat ion secretion. 5,6) Diagram showing promoted chloride ion secretion in T 84 cells of epithelium of colon treated with P 4 / AM 200 μM. 4 shows that Bt 2 -Ins (3,4,5,6) P 4 / AM does not increase intracellular calcium and does not affect calcium in response to thapsigargin. 5 shows D, L-1,2-cyclohexylidene-Ins (3,4,5,6) P 4 / AM (FIG. 5A); 1-Bu-2-Bt-Ins (3,4,5,6) P 4 / AM (FIG. 5B); Bu 2 -Ins (3,4,5,6) P 4 / AM (FIG. 5C); 3-Bt-2-Bu-Ins (1,4,5,6) P 4 / AM (FIG. 5D); Bu 2 -Ins (1,4,5,6) P 4 / AM (FIG. 5E); 1-Bt-2-Bu-Ins (3,4,5,6) P 4 / AM (FIG. 5F); And 3-Bu-2-Bt-Ins (1,4,5,6) P 4 / AM (FIG. 5G) Diagram showing promoted chloride ion secretion in T 84 cells of crystalline epithelium treated with. Figure 6 shows promoted chloride ion secretion in T 84 cells of the epithelium of the colon treated with Bt 2 -Ins (1,4,5,6) P 4 / AM due to reversal of EGF-mediated inhibition of goat ion secretion. Drawing showing. FIG. 7 shows the inhibition of chloride ion secretion in T 84 cells of epithelial cells treated with EGF or cell permeable derivatives of PtdInsP 3 , wherein Bt 2 -Ins (1,4,5,6) P 4 / AM Promotes chlorine ion secretion due to reversal of inhibition of EGF- and PtdInsP 3 mediated chlorine ion secretion. FIG. 8 shows inhibited chloride ion secretion in T 84 cells of epithelium of colon treated with increased concentrations of PtdInsP 3 / AM. 9 shows the structures of cell permeable PtdInsP 3 and diC 16 -Bt-PtdInsP 3 / AM. 10 is a schematic of the synthesis of cell permeable PtdInsP 3 / AM derivatives. 11 is a schematic of the synthesis of 1,2-cyclohexylidene-Ins (3,4,5,6) P 4 // AM. FIG. 12 shows the structure of myo-inositol 1,3,4-trisphosphate and 2,5,6-Bt 3 -Ins (1,3,4) P 3 / AM. Only the D-array of the compounds is shown. 13 is a schematic of the synthesis of cell permeable inositol polyphosphate derivatives. The present invention provides a composition that is a cell permeable antagonist of inositol polyphosphate. For example, the present invention provides antagonists of myo-inositol 3,4,5,6-tetrakisphosphate and phosphatidylinositol trisphosphate. The present invention also provides a method of promoting the secretion of chlorine ions in a cell by contacting the cell with a cell permeable antagonist of inositol polyphosphate. The invention also provides a method of promoting secretion of chlorine ions in a subject by administering to the subject a cell permeable antagonist of inositol polyphosphate. The invention also provides a method of alleviating signs or symptoms associated with cystic fibrosis in a subject by administering a cell permeable antagonist of inositol polyphosphate in the subject. The present invention also provides a composition which is a cell permeable agent of inositol polyphosphate. For example, the present invention provides agents of myo-inositol 3,4,5,6-tetrakisphosphate and phosphatidylinositol trisphosphate. The present invention also provides a method of inhibiting the secretion of chlorine ions in a cell by contacting the cell with a cell permeable agent of inositol polyphosphate. The present invention also provides a method of inhibiting the secretion of chlorine ions in a subject by administering to the subject a cell permeable agent of inositol polyphosphate. The invention also provides a method of alleviating the signs or symptoms associated with secretory diarrhea in a subject by administering a cell permeable agent of inositol polyphosphate in the subject. The present invention provides compositions and methods for contacting cells with a cell permeable compound that is an antagonist or agonist of inositol polyphosphate to change chlorine ion secretion. As used herein, the term "altering" refers to the release of chlorine ions such that the migration of chlorine ions into or out of the cell differs from the secretion of chlorine ions in cells not treated with the agent or antagonist of the present invention. It means to promote or inhibit. As used herein, "antagonist" refers to a compound that has the function of inhibiting the physiological activity of other compounds. For example, antagonists of compounds that inhibit the secretion of chlorine ions reverse this inhibition. Similarly, the term "agonist" refers to a compound that has a similar function of physiological activity of another compound. Antagonists of the invention promote the secretion of chloride ions in cells. As used herein, the term "enhancing" means that when used with respect to the promotion of chlorine ion secretion, the level of chlorine ion migration out of the cell is higher than the secretion level in that cell not treated with the antagonist. Conversely, the term "decreasing" means that when chlorine ion secretion is used with respect to inhibition, the level of chlorine ion transfer out of the cell is lower than that in those cells not treated with the agent. As used herein, the term "contacting" refers to culturing or exposing a cell in a cell permeable compound that is a compound that can cross the cell membrane. Abnormal chlorine ion secretion is associated with various pathological conditions. Thus, the compounds of the present invention are useful for promoting or inhibiting the release of chlorine ions and for alleviating the symptoms of such diseases, and in a series of disease symptoms, such as cystic fibrosis, by promoting the secretion of chlorine ions Although it can be used to alleviate the symptoms, disease symptoms such as secretory diarrhea can alleviate the symptoms by inhibiting the release of chloride ions. Thus, in accordance with abnormal secretion of chlorine ions, the present invention provides compositions and methods that compensate for abnormal secretion of chlorine ions associated with a particular disease. The present invention provides compounds that are agonists or antagonists of inositol polyphosphate. Inositol polyphosphate derivatives can act as inositol polyphosphate agonists and antagonists. The effect of the compounds of the invention on Ins (3,4,5,6) P 4 -and PtdInsP 3 -mediated inhibition of calcium mediated chloride ion secretion is described in the Examples and summarized in Table 1. The present invention is similar to or antagonizes the activity of Ins (3,4,5,6) P 4 or PtdInsP 3 , which is an endogenous inhibitor of calcium-mediated chloride ion secretion, which regulates the release of chloride ion through calcium-dependent chloride ion channels. Provide a cell permeable compound. Compounds that increase the intracellular concentration of Ins (3,4,5,6) P 4 or PtdInsP 3 as used herein are useful for inhibiting chloride ion secretion. In contrast, compounds that inhibit the effect of Ins (3,4,5,6) P 4 or PtdInsP 3 are useful for promoting the release of chlorine ions. Table 1 Effect of Inositol Polyphosphate Derivatives on Chlorine Ion Secretion Derivative 1 Abbreviation 2 Inhibition of Cl - SecretionInhibition PreventionAffected Mechanisms and Inositol Polyphosphate Pathway 1,2-di-O-butyryl-myo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) esterBt 2 -Ins (3,4,5,6) P 4 / AM+ Agents of Ins (3,4,5,6) P 42-O-butyryl-1-O-methyl-myo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) ester2-Bt-1-Me-Ins (3,4,5,6) P 4 / AM-+Antagonist of Ins (3,4,5,6) P 41,2-di-O-methyl-myo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) esterMe 2 -Ins (3,4,5,6) P 4 / AM-+Antagonist of Ins (3,4,5,6) P 4 Derivative 1 Abbreviation 2 Inhibition of Cl - SecretionInhibition PreventionAffected Mechanisms and Inositol Polyphosphate Pathway D, L-1,2-di-cyclohexylidene-myo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) esterD, L-1,2, -cyclohexylidene-Ins (3,4,5,6) P 4 / AM +Antagonist of Ins (3,4,5,6) P 41-O-Butyl-2-O-butyryl-myo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) ester1-Bu-2-Bt-Ins (3,4,5,6) P 4 / AM +Antagonist of Ins (3,4,5,6) P 41,2-di-O-butyl-myo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) esterBu 2 -Ins (3,4,5,6) P 4 / AM +Antagonist of Ins (3,4,5,6) P 41-O-butyryl-2-O-butyl-myo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) ester1-Bt-2-Bu-Ins (3,4,5,6) P 4 / AM - Derivative 1 Abbreviation 2 Inhibition of Cl - SecretionInhibition PreventionAffected Mechanisms and Inositol Polyphosphate Pathway 2,3-di-O-methyl-myo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) esterMe 2 -Ins (1,4,5,6) P 4 / AM--2-O-butyryl-3-O-methyl-myo-inositol-3,4,5,6-TK phosphate oct (acetoxymethyl) ester2-Bt-3-Me-Ins (1,4,5,6) P 4 / AM--D, L-1,2-O-butyryl-scyllo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) esterD, L-Bt 2 -scyllo-Ins (3,4,5,6) P 4 / AM+ Agents of Ins (3,4,5,6) P 4D, L-1-O-butyryl-2-O-methyl-myo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) esterD, L-1-Bt-2-Me-Ins (3,4,5,6) P 4 / AM+ Agents of Ins (3,4,5,6) P 4 Derivative 1 Abbreviation 2 Inhibition of Cl - SecretionInhibition PreventionAffected Mechanisms and Inositol Polyphosphate Pathway D, L-1,2-dichloro-1,2-dideoxy-myo-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) esterD, L-1,2 Cl 2 -1,2 dideoxy-Ins (3,4,5,6) P 4 / AM- 3-O-butyryl-2-O-butyl-myo-inositol 1,4,5,6-TK phosphate oct (acetoxymethyl) ester3-Bt-2-Bu-Ins (1,4,5,6) P 4 / AM -2,3-di-O-butyl-myo-inositol 1,4,5,6-TK phosphate oct (acetoxymethyl) esterBu 2 -Ins (1,4,5,6) P 4 / AM -3-O-butyl-2-O-butyryl-myo-inositol 1,4,5,6-TK phosphate oct (acetoxymethyl) ester3-Bu-2-Bt-Ins (1,4,5,6) P 4 / AM - Derivative 1 Abbreviation 2 Inhibition of Cl - SecretionInhibition PreventionAffected Mechanisms and Inositol Polyphosphate Pathway D, L-2,5,6-tri-O-butyryl-myo-inositol 1,3,4-trisphosphate hex (acetoxymethyl) esterD, L-Bt 3 -Ins (1,3,4) P 3 / AM+ Agents of Ins (3,4,5,6) P 42,3-di-O-butyryl-myo-inositol 1,4,5,6-TK phosphate oct (acetoxymethyl) esterBt 2 -Ins (1,4,5,6) P 4 / AM +Antagonist of PtdInsP 3sn-di-O-palmitoyl-D, L-6-O-butyryl-phosphatidyl-inositol 3,4,5-trisphosphate hepta (acetoxymethyl) esterdiC 16 -Bt-PtdIns P 3 / AM+ Agents of PtdInsP 3 Derivative 1 Abbreviation 2 Inhibition of Cl - SecretionInhibition PreventionAffected Mechanisms and Inositol Polyphosphate Pathway sn-di-O-octanoyl-D, L-6-O-butyryl-phosphatidyl-inositol 3,4,5-trisphosphate hepta (acetoxymethyl) esterdiC 8 -Bt-PtdIns (3,4,5) P 3 / AM+ Agents of PtdInsP 3D, L-1-O-butyryl-2-O-deoxy-inositol 3,4,5,6-TK phosphate oct (acetoxymethyl) esterD, L-1-Bt-2-deoxy-Ins (3,4,5,6) P 4 / AM Agents of Ins (3,4,5,6) P 4 1 listed derivatives using the following abbreviations: TK - tetrakis phosphate; oct-octakis; hex-hexakis. Unless otherwise indicated, all compounds are form D. 2 The tables and abbreviations used throughout the specification represent the following: Ins-inositol; P-phosphate; Number of n-phosphates at P n ; AM-acetoxymethyl ester; Bt-butyryl; Me-methyl; Bu-butyl; C 16 -palmitoyl; C 8 -octanoyl; PtdIns-Phosphatidyl Inositol. Unless otherwise indicated, all derivatives are myo-inositol derivatives. The cell permeable compounds of the present invention directly increase the intracellular concentration of Ins (3,4,5,6) P 4 or PtdInsP 3 due to structural similarity or Ins (3,4,5,6) P 4 or PtdInsP It is useful for producing a similar effect to 3 . In addition, the cell permeable compounds of the present invention are useful for antagonizing the action of Ins (3,4,5,6) P 4 or PtdInsP 3 . Inositol polyphosphate derivatives herein can act as cell permeable agents or antagonists of Ins (3,4,5,6) P 4 or PtdInsP 3 . Cell-permeable inositol polyphosphate derivatives were synthesized as described in Example XI. This compound has cell permeability because the charged phosphate group is surrounded by the acetoxymethylester group and the hydroxy group is surrounded by the hydrophobic functional group (see FIG. 1). Hydrophobic functional groups used to enclose a hydrophilic group can be, for example, a hydrophobic functional group that can surround a hydrophilic group in an acyl group, an alkyl group, an alkylidene group or another inositol polyphosphate. Alkyl groups are methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, sec-butyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, Cyclic chains of carbon atoms such as pentyl and hexyl and alkylene groups, cyclohexyl and cyclopentyl groups and mixtures of linear or branched chains and cyclic chains of carbon atoms such as methyl-cyclohexyl or cyclopropyl-methylene groups . However, for methyl derivatives 2-Bt-1-Me-Ins (3,4,5,6) P 4 / AM, Me 2 -Ins (3,4,5,6) P 4 / AM, Me 2 -Ins (1,4,5,6) P 4 / AM, 2-Bt-3-Me-Ins (1,4,5,6) P 4 / AM and D, L-1-Bt-2-Me-Ins (3,4,5,6) P 4 / AM is not included in the scope of the claimed compositions. It should also be appreciated that the alkyl defined herein may be substituted with a substituent. The alkylidene group is an acetal group, for example methylidene, ethylidene, propylidene, butylidene, pentidene, hexylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, and cyclohep Tilidene (see Kemp and Vellaccio, Organic Chemistry, Worth Publishers, New York (1980), incorporated herein by reference). Acyl groups include, for example, acetyl, propaneyl, butyryl, hexanoyl and valeryl. However, for acyl derivatives, Bt 2 -Ins (3,4,5,6) P 4 / AM, D, L-Bt 2 -scyllo-Ins (3,4,5,6) P 4 / AM and Bt 2 -Ins (1,4,5,6) P 4 / AM is not included within the scope of the composition. Once inside the cell, the butyryl and acetoxymethyl ester groups are degraded by intracellular esterases. Thus, when qusgudd l at these hydrophobic functional groups occurs, the compound can cross the cell membrane and the compound is hydrolyzed to expose the hydrophilic group of the compound that is not induced. However, alkyl and alkylidene groups are functional groups that do not hydrolyze and remain in the derivative even after passing through the cell membrane. Further modifications of inositol polyphosphate provide cell permeable derivatives. For example, Ins (3,4,5,6) P 4 is 1,2-dideoxy-Ins (3,4,5,6) P 4 / AM, 1-Bt-2-deoxy-Ins ( 3,4,5,6) P 4 / AM, 2-Bt-1-deoxy-Ins (3,4,5,6) P 4 / AM, and 1,2-dichloro-1,2-dideoxy It is also a cell permeable derivative that contains -myo-Ins (3,4,5,6) P 4 / AM (see Table 1). In addition, the cell-permeable PtdInsP 3 derivative, for example, diC 16 -6-O-Bt -PtdIns (3,4,5) P 3 / AM and diC 8 -2-O-Bt- PtdIns (3,4,5 P 3 / AM and diC 16 -2-O-Bt-PtdIns (3,4,5) P 3 / AM, diC 8 -6-O-Bt-PtdIns (3,4,5) P 3 / AM, diC 16 -2,6-O-Bt 2 -PtdIns (3,4,5) P 3 / AM and diC 8 -2,6-O-Bt 2 -PtdIns (3,4,5) P 3 / AM Include. Methods for the synthesis of acylated acetoxymethyl ester derivatives are described in Roemer et al., Incorporated herein by reference. (J. Chem. Soc., Chem. Commun. N4: 411 (fat 1995); J. Chem. Soc., Perkins Trans, 1 N14: 1683 (fat 1996). The present invention provides a cell permeable compound that is an antagonist of inositol polyphosphate. In one embodiment, the cell permeable compound is an antagonist of Ins (3,4,5,6) P 4 . As disclosed herein, Ins (3,4,5,6) P 4 derivatives act as antagonists of Ins (3,4,5,6) P 4 . For example, an Ins (3,4,5,6) P 4 derivative having an alkyl group at the hydroxy group at the first, second or both positions may be Ins (3,4,5,6) P It acts as an antagonist of 4 (see Table 1 and Examples III and IV). Particularly useful alkyl group derivatives are methyl (Me) and butyl (Bu) derivatives. For example, 2-Bt-1-Me-Ins (3,4,5,6) P 4 / AM, Me 2 -Ins (3,4,5,6) P 4 / AM, 1-Bu-2 -Bt-Ins (3,4,5,6) P 4 / AM and Bu 2 -Ins (3,4,5,6) P 4 / AM are each Ins (3,4,5,6) of chlorine ion secretion Reversal) P 4 -mediated inhibition, an antagonist of Ins (3,4,5,6) P 4 . Another useful Ins (3,4,5,6) P 4 derivative is one containing an alkylidene group in the first and second positions. For example, D, L-1,2-cyclohexylidene-Ins (3,4,5,6) P 4 / AM reverses carbachol-mediated inhibition of chlorine ion secretion. It is an antagonist of (3,4,5,6) P 4 . Alternatively, the Ins (1,4,5,6) P 4 / AM derivative having alkylidene groups in the second and third positions may serve as the Ins (1,4,5,6) P 4 derivative. In another embodiment, the cell permeable compound is an antagonist of PtdInsP 3 . As disclosed herein, the cell permeable Ins (1,4,5,6) P 4 derivative is an antagonist of PtdInsP 3 . For example, an Ins (1,4,5,6) P 4 derivative having a butyryl group attached at the second and third positions is characterized by the calcium-mediated chlorine ion secretion induced by EGF- and PtdInsP 3- . Inverting inhibition acts as an antagonist of PtdInsP 3 (see Table 1 and Examples VII and VIII). The present invention also provides a cell permeable compound that is an agent of inositol polyphosphate. In one embodiment, the cell permeable compound is an Ins (3,4,5,6) P 4 agonist. As disclosed herein, Ins (3,4,5,6) P 4 derivatives are Ins (3,4,5,6) P 4 agonists. For example Bt 2 -Ins (3,4,5,6) P 4 / AM, Bt 2 -scyllo-Ins (3,4,5,6) P 4 / AM and 1-Bt-2- deoxy- Ins (3,4,5,6) P 4 / AM (36% inhibition) inhibits calcium-mediated chlorine secretion by separating chlorine ion secretion from intracellular calcium concentrates, resulting in Ins (3,4,5 , 6) P 4 agonist (see Table 1 and Examples I-III). Ins (1,3,4) P 3 derivatives are also Ins (3,4,5,6) P 4 agonists. For example, Bt 3 -Ins (1,3,4) P 3 / AM increases the concentration of Ins (3,4,5,6) P 4 in cells, thus inhibiting calcium-mediated chloride ion secretion. Ins (3,4,5,6) P 4 agonist (see Example V). In another embodiment, the cell permeable compound is an agent of PtdInsP 3 . As described herein, PtdInsP 3 derivatives are agents of PtdInsP 3 . For example diC 16 -Bt-PtdInsP 3 / AM and diC 8 -Bt-PtdInsP 3 / AM are agents of PtdInsP 3 by inhibiting the secretion of calcium-mediated chlorine ions (see Table 1 and Example III). Molecular modeling of the structure of the inositol polyphosphate derivatives can be used to design the desired activity of the inositol polyphosphate derivatives into synthetic compounds having similar structural properties. In addition, the cell-permeable synthetic compound that acts as an agonist or antagonist of inositol polyphosphate can be identified, for example, by searching a combinatorial chemical library. Using the methods disclosed herein, synthetic compounds can be searched for whether they exhibit or antagonize similar effects to a given inositol polyphosphate on the secretion of calcium-mediated chlorine ions. Methods of preparing and searching combinatorial compound libraries are well known to those skilled in the art (see Combinatotial Peptide and Nonpeptide Libraries: A Handbook, Jung, ed., VCH, New York (1996), which is incorporated herein by reference). The present invention also provides a method of changing the secretion of chlorine ions by contacting a cell with a cell permeable compound that is an antagonist or agonist of inositol polyphosphate. Cells regulate the movement of water in organisms through the movement of chlorine ions. The cell has a specific chlorine ion channel that allows chlorine ions to pass through the membrane when the channel is open. These channels are especially important in cells on the mucosa that secrete mucin and regulate the flow of water. When there is a lack of water flow into and out of the cells, mucin secretion becomes a viscous plug that closes the gas passages in the mucous membranes inside the lungs hk intestine, leading to diseases such as cystic fibrosis. Not all chlorine ion channels are the same, and other channels are controlled by different methods. Certain chlorine ion channels, such as calcium-dependent chlorine ion channels, are involved in the movement of calcium ions. As the intracellular concentration of calcium ions increases, the secretion of chlorine ions increases. As used herein, the term "secretion of chlorine ions" refers to the movement of chlorine ions through the plasma membrane of a cell. Treatment of cells with a series of compounds such as histamine, histamine, and physiologically appropriate agents that do not have a measurable long-term effect on inositol polyphosphate metabolism can lead to an increase in intracellular calcium ion concentration leading to an increase in chloride ion secretion. Carbachol, a muscarinic choline-based compound, increases intracellular calcium ion concentration and stimulates chloride ion concentration in short-term treatment. However, long-term treatment of T 84 cells in colon epithelium with carbacol increased the concentration of calcium ions in the cells but no longer stimulated the secretion of chlorine ions (Kachintorn et al., Incorporated herein by reference). Am. J. Physiol.Cell 264: C671 (1993). Long-term treatment of carbacol leads to a long-term, gentle rise of intracellular Ins (3,4,5,6) P 4 levels (Vajanaphanich, et al., Nature 371: 711 (incorporated herein by reference). 1994). Treatment of T 84 cells with a mixture of Bt 2 -Ins (3,4,5,6) P 4 / AM and Bt 2 -Ins (1,4,5,6) P 4 / AM is a thapsigargin. Inhibition of chlorine ions in response to the increase of intracellular calcium concentration, Bt 2 -Ins (1,4,5,6) P 4 / AM had no effect. As illustrated herein, enantiomerically pure Bt 2 -Ins (3,4,5,6) P 4 / AM does not contain enantiomers in response to increased concentrations of calcium in cells. Secretion is inhibited (see Example I). Thus, Ins (3,4,5,6) P 4 is an endogenous counter regulator of the secretion of calcium-mediated chlorine ions because it separates chlorine ions from the calcium ion concentrate. Another mechanism that inhibits calcium-mediated chloride ion secretion, which is distinct from that mediated by Ins (3,4,5,6) P 4, is by increasing the level of PtdInsP 3 . EGF inhibits the secretion of calcium-mediated goat ions induced by carbacol and topsigargin in T 84 cells (see Uribe et al., Am. J. Physiol. 271: C914 (1996a)). EGF stimulates the Ins (3,4,5,6) P 4 1.7-fold increase in the levels as compared to Carbachol to stimulate increased to 20 times of Ins (3,4,5,6) P 4 levels. These results suggest that EGF regulates the release of calcium-mediated chlorine ions through a mechanism different from Ins (3,4,5,6) P 4 . EGF activates phosphatidylinositol 3-kinase (PI 3-kinase) and the inhibitory effect of EGF on the secretion of calcium-mediated chlorine ions is controlled by PI 3-kinase (Uribe et al., J. Biol. Chem 271: 26588 (1996b). EGF stimulates an increase in PI 3-kinase product, phosphatidyl-inositol 3,4-bisphosphate (PtdInsP 2 ) and PtdInsP 3 levels. These PI 3-kinase products increased for a period similar to EGF inhibition of the secretion of chloride ions. Watmannin, a high specificity PI 3-kinase inhibitor, prevented the formation of PtdInsP 3 and PtdInsP 3 and reversed the inhibition of the secretion of EGF mediated goat ions. Thus, the metabolism involved in PtdInsP 3 contributes to the secretion of EGF mediated calcium-mediated chloride ions. Since the compounds of the present invention are agents and antagonists of inositol polyphosphate that regulate the secretion of chlorine ions, these compounds are useful for changing the secretion of chlorine ions in cells. Because these compounds are cell permeable, they are transported to the cytoplasm, where the inositol polyphosphate acts upon contact with the cells. The present invention provides a method of contacting a cell with a cell permeable antagonist of inositol polyphosphate to promote secretion of chlorine ions across the cell membrane. In one embodiment, the antagonist of Ins (3,4,5,6) P 4 is used to promote the secretion of chlorine ions. As disclosed herein, Ins (3,4,5,6) P 4 derivatives may be used as Ins (3,4,5,6) P 4 antagonists. In another embodiment, PtdInsP 3 antagonist may be used to promote the secretion of chlorine ions. As disclosed herein, Ins (1,4,5,6) P 4 derivatives may be used as antagonists of PtdInsP 3 . The present invention also provides a method of contacting a cell with a cell permeable agent of inositol polyphosphate to inhibit the secretion of chlorine ions across the cell membrane. In one embodiment, an agent of Ins (3,4,5,6) P 4 is used to inhibit the secretion of chlorine ions. As disclosed herein, Ins (3,4,5,6) P 4 derivatives may be used as Ins (3,4,5,6) P 4 agonists. Ins (1,3,4) P 3 derivatives can also be used as Ins (3,4,5,6) P 4 agonists. In another embodiment, PtdInsP 3 agonists can be used to inhibit the secretion of chlorine ions. As disclosed herein, PtdInsP 3 derivatives can be used as agents of PtdInsP 3 . The present invention provides a method of promoting secretion of chlorine ions in a subject by administering to the subject an antagonist of Ins (3,4,5,6) P 4 or PtdInsP 3 . As used herein, the term "individual" refers to an organism, generally a mammal, in particular a human being, to be treated with an agent or antagonist compound of the invention that promotes or inhibits the secretion of chlorine ions. An increase or decrease in chloride ion secretion occurs in one or more tissue organs, including cells in an individual. As used herein, the term "administering or administration" refers to inducing an antagonist or agent to an individual in a manner and in a manner in which the antagonist or agent is delivered to a suitable target tissue, in contact with the target tissue. Changes the secretion of chlorine ions in the cell. The invention also provides a method of alleviating the signs or symptoms associated with cystic fibrosis by administering an antagonist of Ins (3,4,5,6) P 4 or PtdInsP 3 or both to a subject having symptoms and signs of cystic fibrosis. to provide. The present invention also provides a method of inhibiting the secretion of chlorine ions by administering an agent of Ins (3,4,5,6) P 4 or PtdInsP 3 to the subject. The present invention also provides a method of alleviating the symptoms and signs associated with secretory diarrhea by administering an agent of Ins (3,4,5,6) P 4 or PtdInsP 3 to a subject having signs or symptoms of secretory diarrhea. . Generally, the antagonist or agent is administered to the subject in a pharmaceutical composition. Such pharmaceutical compositions comprise an antagonist or agent and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include aqueous solutions such as physiologically buffered saline or oils such as glycols, glycerol, olive oil, or other solvents or carriers such as injectable organic esters. Pharmaceutically acceptable carriers include, for example, physiologically acceptable compounds that act to stabilize the antagonist or agent or to increase the absorption of the drug. Such physiologically acceptable compounds include, for example, carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or additives. Those skilled in the art will appreciate that the choice of a pharmaceutically acceptable carrier, such as a pharmaceutically acceptable compound, depends for example on the route of administration and target tissue of the antagonist or agent of the invention. Various routes of administration can be used depending on the subject to be treated and the target tissue or tissue. Pharmaceutical compositions may be administered by a variety of routes including, for example, oral, rectal, or intravenous, intramuscular, subcutaneous, intraocular, capillary, intraperitoneal, intraclinical, or for example skin patches, transdermal It may also be administered using passive or accelerated absorption through the skin using iontophoresis therapy. In addition, the compositions may be administered by injection, intubation, or topically, for example, may be manual by direct application of ointments or powders, or may be active using nasal sprays or inhalations. The total effective amount may be administered to the subject in a single dose within a relatively short time, such as a large bolus or infusion, or may be administered using a divided regimen in which multiple doses are administered over an extended period of time. One skilled in the art knows that the concentration of agent required to obtain an effective amount in a subject depends on many factors, including the subject's age and general health and route of administration, and the number of treatments to be administered. For these factors, those skilled in the art will control the specific dosage so that an effective amount will be obtained. The dosage of a particular compound is determined by the intracellular concentration required to achieve the desired effect of, for example, promoting or inhibiting the secretion of chlorine ions. Effective intracellular concentrations can be measured by methods as disclosed herein or by methods known in the art. For example, the effective intracellular concentration of the Bt 2 -Ins (3,4,5,6) P 4 / AM agonist can be determined in the laboratory by the Ins (1,3,4) P 3-5 / 6-kinase assay (Vajanaphanich). et al., et al., 1994) to be about 4 μM. Thus, for Bt 2 -Ins (3,4,5,6) P 4 / AM the dosage is chosen to give intracellular derivative concentrations of about 4-20 μM, preferably 4 μM. Initial studies are conducted in model systems to determine the effects of certain compounds. Judgment of the effective concentration required to treat the condition in the subject is made in clinical trials of stages 1 and 2. The compounds of the present invention may be used alone or in admixture with each other, or in admixture with other therapeutic agents associated with abnormal chlorine ion secretion. For example, a therapeutic regimen may begin with one compound and additional compounds may be administered with the first compound if the effect of the first compound is insufficient. Treatment can be combined with other modes of treatment, such as the administration of uridine 5'-triphosphate and amyloide (Bennett et al., Am. J. Respir. Crit. Care Med. 153: 1796 (1996). The compositions and methods of the present invention are effective in treating a variety of conditions, such as cystic fibrosis or secretory diarrhea, characterized in part by abnormal secretion of chlorine ions. Incomplete secretion of chlorine ions causes cystic fibrosis due to mutations in the cystic fibrosis dura modulator (CFTR), a channel of chlorine ions in epithelial cells. Chlorine ion channels associated with the outermost surface of epithelial cells are, in principle, the control points that regulate salt and fluid secretion. Most cystic fibrosis results in a single point mutation known as the ΔF508 mutation, resulting in a deletion of the amino acid phenylalanine at amino acid position 508. This mutation interferes with the transfer of CFTR into the cell membrane and inhibits the release of chloride ions by the cell. One approach to the treatment of cystic fibrosis is to artificially activate other chlorine ion channels. For example, an externally corrected goat channel (ORCC) in epithelial cells is a goat ion channel regulated by cyclic AMP. However, ORCC is believed to be regulated by CFTR and thus lowers the activity of cystic fibrosis (Schwiebert et al., Cell 81: 1063 (1995); Egan, et al., Nature 358: 581 (1992); and Gabriel, et al., Nature 363: 263 (1993). In contrast, calcium dependent goat ion channels are more abundant in the cells of the mouse model of cystic fibrosis (see Grubb et al., Am. J. Physiol. 266: C1478 (1994)). Calcium-dependent chlorine ion channels are different from CFTR and are more abundant in cells of patients with cystic fibrosis, so they may be supplemented with CFTR through these channels to compensate for the lack of solvent through CFTR. As disclosed herein, one or more antagonists of Ins (3,4,5,6) P 4 or PtdInsP 3 may be used to restore goat ion secretion in epithelial cells affected by damage in CFTR. Various model systems are used to verify the ability of the inositol polyphosphate of the present invention to promote chlorine ion secretion. One such model is the T 84 cell line of the epithelium of human colon, which has been extended as a model secretory epithelial cell (Dharmsathaphorn et al., Am. J. Physiol. 246: G204 (1984)). T 84 cells show a relatively distinct phenotype that, when grown conjugated in the permeable support, forms a polar monolayer with dense conjugation and transfer of the vector. The T 84 monolayer maintains many receptor-mediated goat ion secretion metabolism, including changes in free cytosolic calcium and CFTR (Cohn et al., Proc. Natl. Acad. Sci. USA 89: 2340 (1992)). Agents such as histamine, carbacol, calcium ion carriers, and topsigargin elevate intracellular calcium ions and stimulate changes in the secretion of chlorine ions across the T 84 monolayer (Dharmsathaphorn et al., J. Clin. Invest. 84: 945 (1989); Kachintorn et al., Sangga 1993). Cyclic AMP also stimulates the secretion of chlorine ions via CFTR in T 84 cells (Anderson and Welsh, Proc. Natl. Acad. Sci. USA, 88: 6003 (1991)). Thus, T 84 cells provide an in vitro model for regulating chloride ion secretion in normal and pathological conditions including deficient goat ion migration such as cystic fibrosis. In addition, epithelial cells of the rabbit colon provide a model of colon epithelial cells. Three worse symptoms of cystic fibrosis are chronic lung disease, pancreatic insufficiency and bowel disorders. Various model systems can be used to specify the therapeutic effect of the inositol polyphosphate derivatives of the invention for treating these symptoms. For example, CFTR gene from the T 84 cells provide a model of (CFTR T 84 cells) knockout (knockout), the cystic fibrosis patient's colon the epithelial cells of the colon with a genetic background (background) is similar to the genes of cells of the (See Example X). The CFTR - T 84 cell line is useful for examining the efficacy of the chlorine ion secretion of the compounds of the invention that are antagonists of Ins (3,4,5,6) P 4 and PtdInsP 3 . Human nasal epithelial cells are a model of respiratory epithelium to verify the effect of various compounds on the secretion of chloride ions. Human nasal epithelial cells are useful for verifying the function of the secretion of chloride ions in these cells of the compounds of the invention that are antagonists of Ins (3,4,5,6) P 4 and PtdInsP 3 (see Example IX). . A suitable model system for studying pancreatic function uses CFPAC, a pancreatic ductal epithelial cell CFTR - cell line, a human cell line derived from pancreatic adenocarcinoma of a homogeneous patient with ΔF508 mutation. CFPAC cells lack cAMP-stimulated channel function but exhibit calcium-activated goat ion channel function (Shoemacher et al., Proc. Natl. Acad. Sci. USA 87: 4012 (1990)). Pancreatic duct epithelial cells in dogs are also effective for verifying the effect in these cells on the secretion of chlorine ions of the compounds of the invention, which are the antagonists of Ins (3,4,5,6) P 4 and PtdInsP 3 of the invention (as described herein) Nguyen et al., Am. J. Physiol. 272: G172 (1997). Animal models of cystic fibrosis are also used to investigate the antagonist activity of Ins (3,4,5,6) P 4 and PtdInsP 3 . For example, CFTR knockout mice have been grown to serve as a model of cystic fibrosis (Rozmahel et al. Nature Gen. 12: 280 (1996); Snouwaert et al., Science 257: 1083 (1992); Ratiff et al., Nature Gen. 4:35 (1992); O 'Neal et al., Hum.Molec. Genet. 2: 1561 (1993); and Dorin et al., Nature 359: 211 (1992). Increased levels of expression of calcium dependent goat ion channels correspond to improved viability in CFTR knockout mice (Clarke et al., Proc. Natl. Acad. Sci USA 91: 479 (1994); and Rozmahel et al. Thesis, 1996). Animal models are used to verify the efficacy of the chlorine ion secretion in these animals of the compounds of the invention that are antagonists of Ins (3,4,5,6) P 4 and PtdInsP 3 . Animal models are also used to verify the efficacy of the compounds of the invention on specific tissues in these animals. Since cystic fibrosis occurs in a variety of organs, those skilled in the art will select the particular method and route of administration of the compound depending on the condition to be treated. The compound is somewhat amphipathic and soluble in aqueous solution. In addition, the compound may be dissolved in dimethyl sulfoxide containing a surfactant. The compound can also be dissolved in a solution containing FREON (1,1,2 trichlorotrifluoromethane), which has low viscosity and is accessible to worse tissues for treatment during acute inflammation or during the early stages of the disease. useful. For example, in patients suffering from respiratory disease, the antagonists of the present invention may be suspended or dissolved in a suitable pharmaceutically acceptable carrier and administered directly to the lung using an inhalation device such as an inhalation nebulizer or turbo inhaler. Thus, to alleviate the accumulation of mucus in the lung, the compound can be administered directly to the target lung tissue in the form of an aerosol. In addition, the compound may be dissolved in FREON and transported by sparging of the lungs. Such treatment may be maintained by periodic breathing of the sprayed aqueous solution. Clinical signs of cystic fibrosis, such as viscous containing mucus, are well known, and those skilled in the art will know how to determine effective prescriptions for alleviating or preventing the respiratory symptoms and signs of cystic fibrosis. For example, determination of mucus releasability using ( 99M Tc) iron oxide particles can be used to determine the effectiveness of treatment with the compounds of the present invention. Other clinical signs of cystic fibrosis can also be treated with antagonists of Ins (3,4,5,6) P 4 or PtdInsP 3 using appropriate methods of administration. For example, sinus complications can be treated by administering a pharmaceutical composition of the nasal spray. This treatment is advantageous over current methods of treating Cynthia's Complications, which often require multiple endoscopic surgery that can result in facial malformations in patients with cystic fibrosis. To alleviate intestinal abnormalities in cystic fibrosis, the medicament may also be administered as a suppository or enema in an appropriate pharmaceutical carrier. In addition, enteric coated tablets may be administered orally. The pharmaceutical composition can be administered to a subject suffering from pancreatitis by intravenous, buccal or other methods in which the compound is distributed systemically including the pancreas. In addition to cystic fibrosis, other conditions associated with body fluids produced in tissues are alleviated by changing the secretion of chloride ions. For example, swelling, such as brain expansion associated with inflammation, infection, or trauma can be alleviated by inhibiting the release of chlorine ions (Berger et al., Acta Neurochir. Suppl. (Wien) 60: 534 (1994); and Staub et al., J. Neurotrauma 11: 679 (1994)). In contrast to conditions such as cystic fibrosis, where the secretion of chlorine ions is abnormally low, other conditions are characterized in part by abnormally high levels of secretion of chlorine ions. For example, high levels of secretion of chlorine ions result in secretory diarrhea. Salmonella, an infectious gut bacterium, causes secretory diarrhea and is one of the leading causes of infant mortality in developing countries and one of the leading causes of health problems in developed countries. Salmonella infection causes gastroenteritis symptoms in more than 1.3 billion people and about 3 million people die. Secretory diarrhea is associated with increased chlorine ion secretion through the epithelial cells of the digestive tract, and reducing the secretion of chlorine ions may alleviate the symptoms of secretory diarrhea. Those skilled in the art will recognize that the method of treating an individual with an agent of inositol polyphosphate to alleviate the symptoms of secretory diarrhea is similar to that described above. The present invention provides compositions and methods for contacting cells with a cell permeable or antagonist of inositol polyphosphate to alter the secretion of chlorine ions across the cell membrane. The invention also provides a method of varying the secretion of chlorine ions in a subject by administering to the subject an agent or antagonist of inositol polyphosphate. The present invention also provides a method of alleviating the symptoms associated with the conditions associated with abnormal secretion of chlorine ions by administering a pharmaceutical composition containing an agonist or antagonist of inositol polyphosphate. Accordingly, the compounds of the present invention are useful as drugs to alleviate the symptoms and signs of a condition characterized in part by abnormal secretion of chlorine ions. The following examples are intended to illustrate the invention and not to limit it. Example I Inhibition of Calcium-mediated Chloride Ion Secretion by Cell Permeable Derivatives of Ins (3,4,5,6) P 4 in T 84 Cells This embodiment is Ins (3,4,5,6) P 4 by a cell permeable derivative of increasing the cell concentration of Ins (3,4,5,6) P 4 on the T 84 cell line of colon epithelial calcium-mediated Decreases the secretion of chlorine ions. Pure 1,2-Bt 2 -Ins (3,4,5,6) P 4 / AM without enantiomers has 1,2-Bt 2 -Ins (3,4,5,6) P 4 / AM cells It was synthesized to investigate the mediation of dissociation of chlorine ion secretion in my calcium concentrate. T 84 cells (paths 18-48) were maintained as previously described (Weymer, et al., J. Clin. Invest. 76: 1828 (1985), incorporated herein by reference). After 7-10 days of culture in SNAP-WELLs (Corning Costar; Cambridge, Mass.), A single membrane formed a tight junction. Cell monolayers were preincubated for 30 min before starting with 100, 200 or 400 μM Bt 2 -Ins (3,4,5,6) P 4 / AM. After another 30 minutes, 0.1 mM of histamine was added and secretion of chlorine ions was monitored. The secretion of chlorine ions was measured as a short circuit current (I SC ) through a T 84 monolayer grown to be bonded and fixed in a Ussing chamber (Physiologic Instruments, San Diego, Calif.) Equipped with a voltage clamp. Data was acquired and analyzed using "Acquire and Analyze" software (Physiologic Instruments). The maximum reduction in histamine-stimulated chloride ion secretion was observed at 1,2-Bt 2 -Ins (3,4,5,6) P 4 / AM 200 μM and no longer reduced at 400 μM (Table II). This result is in agreement with previous studies that intracellular levels of Ins (3,4,5,6) P 4 equivalent to an extracellular concentration of 200 μM express maximum inhibition (Vajanaphanich, et al., Sangh, 1994). . TABLE 2 Reduction of Calcium-mediated Chloride Ion Secretion by Cell Permeable Derivatives of Ins (3,4,5,6) P 4 Bt 2 -Ins (3,4,5,6) P 4 / AM (concentration)Peak ΔIsc (% control) mean ± SEM after histamine (100 μM) administrationnvs control (100%) 100 μM75.1 ± 7.48p <0.012 200 μM57.2 ± 15.16p <0.037 400 μM69.3 ± 8.74p <0.041 In contrast to the decrease in the secretion of chlorine ions by the cell permeable derivative of Ins (3,4,5,6) P 4 , no inhibition of the secretion of dibutyryl cyclic AMP acetoxymethyl ester stimulated chlorine ions was observed. (Peak ΔI sc = 96.3 ± 9.1% or control; mean ± SEM; n = 4). This result is consistent with the observation that cyclic AMP-mediated chlorine ion secretion occurs through a chlorine ion channel different from the channel involved in the secretion of calcium-mediated chlorine ions (McRoberts et al., J. Biol. Chem. 260: 14163 (1985). These results Ins (3,4,5,6) by exposing the cells to a cell permeable derivative of the P 4 Ins (3,4,5,6) to the cells in the calcium concentrate to increase the concentration of cells of P 4 dissociated by the secretion of chloride ions calcium that inhibits secretion mediated chloride ion as Ins (3,4,5,6) P 4 agonist of a cell permeable derivative of the Ins (3,4,5,6) P 4 Shows that Example II Reduction of Calcium-mediated Chloride Ion Secretion by Cell Permeable Derivatives of Ins (3,4,5,6) P 4 in Rabbit Colon This embodiment is Ins (3,4,5,6) is calcium in colon tissue of the rabbits to increase the concentration of cells of Ins (3,4,5,6) P 4 with a cell permeable derivative of the P 4 - Reduces the secretion of mediated chlorine ions. The results obtained above in culture using T 84 colon epithelial cells were confirmed in a rabbit colon model system (Frizzell et al., J. Membrane Biol. 27: 297 (1976); and Frizzell, which are incorporated herein by reference). And Schults, Int. Rev. Physiol. 19: 205 (1976)). Pieces of rabbit colon were cut out and used as raw material for rabbit colon epithelium. Briefly, pieces of rabbit colon were 141 mM Na + , 5 mM K + , 1.2 mM Ca 2+ , 1.2 mM Mg 2+ , 122 mM Cl − , 25 mM HCO 3 . Washed with Ringers solution containing 1.6 mM HPO 4 , 0.4 mM H 2 PO 4 and 10 mM glucose. At 37 ° C., this solution is pH 7.4 when gasified with 5% CO 2 and 95% O 2 . Epithelial tissue was stripped of the underlying muscle layer and fixed in modified SNAP WELLS (Frizzell et al., Sangga Paper, 1976). Epithelial tissues were pre-incubated with 1,2-Bt 2 -Ins (3,4,5,6) P 4 / AM 200 μM at 37 ° C. for 30 minutes and fixed in Ussing chambers. Short circuit current, conductance and resistance were measured at intervals of 4 seconds as described in Example 1. Peak I sc was 50.9% ± 10.4 of controls incubated with carriers (FIG. 2; mean ± SEM in Student's two tailed t-test, n = 3; p <0.05). The% control shown in FIG. 2 shows ΔI sc for the peak I sc of the monolayer of the histamine stimulated control. The results showed that Bt 2 -Ins (3,4,5,6) P 4 / AM cell permeable derivatives increased the intracellular concentration of Ins (3,4,5,6) P 4 , resulting in Ins (3,4,5, 6) acts as an agonist of P 4 and inhibits the secretion of chlorine ions in rabbit colon. This result also demonstrates that the increase of Ins (3,4,5,6) P 4 intracellularly results in the release of chloride ions in intracellular calcium concentrate in colon epithelial tissue. Example III Reversal of Ins (3,4,5,6) P 4 Inhibition of Histamine-Stimulated Chlorine Ion Secretion Using Ins (3,4,5,6) P 4 Antagonists In this example, Ins (3,4,5,6) P 4 inhibitory effect on the release of histamine-stimulated chlorine ion acts as an antagonist of Ins (3,4,5,6) P 4 . , 4,5,6) P 4 can be reversed by cell permeable derivatives. The results shown in Examples I and II show that increasing the concentration of Ins (3,4,5,6) P 4 inhibits the secretion of calcium-mediated chlorine ions. Thus, compounds that antagonize the action of Ins (3,4,5,6) P 4 in cells will reverse this inhibition. The initial study was to understand the structural determinants of Ins (3,4,5,6) P 4 involved in the inhibitory effect on the secretion of calcium-mediated chloride ions. A series of cell permeable inositol polyphosphate derivatives was synthesized. These derivatives contained one or two non-hydrolysable functional groups in the 1, 2, or 3 position. T 84 monolayer is 2-Bt-1-Me-Ins (3,4,5,6) P 4 / AM, Me 2 -Ins (3,4,5,6) P 4 / AM, Me 2 -Ins Pre-incubated with (1,4,5,6) P 4 / AM or 2-Bt-3-Me-Ins (1,4,5,6) P 4 / AM 200 μM for 30 minutes. After incubation, the cells were fixed in Ussing chamber. The secretion of calcium-mediated chlorine ions was stimulated with histamine ( 10-4 M). Control value is the response to histamine in a monolayer coincubated. Data is shown as mean peak ΔI sc ± SEM, expressed as% control for 8-10 experiments. Significant differences were identified using Student's two-tailed t-test. As shown in Table 3, there was no inhibitory effect in cells treated with any derivative. These results participate in the hydrogen-bond donor potential at positions 1 and 2 mediating the inhibitory effect of Ins (3,4,5,6) P 4 on the secretion of calcium-mediated chlorine ions. The scyllo derivatives of the cell permeable Bt 2 -Ins (3,4,5,6) P 4 / AM are effective as inhibitors, at least as myo derivatives, indicating that the aromatic in the 2-hydroxy position is not related to inhibitor activity. . As it described above inositol polyphosphate which is a calcium derivative - in order to determine whether acting as antagonists of the inhibition of Ins (3,4,5,6) of the secretion of chloride ions mediated P 4 T 84 cell poly inositol Precultured with phosphate. After histamine stimulation, a short circuit current was measured. As shown in FIG. 3, Bt 2 -Ins (3,4,5,6) P 4 / AM inhibited the secretion of histamine-stimulated goat ions compared to cells of the control group. The% control shown in FIG. 3 shows ΔI sc for peak I sc in a single membrane of histamine stimulated control. However, pre-incubation with 2-Bt-1-Me-Ins (3,4,5,6) P 4 / AM reversed the inhibitory effect of Bt 2 -Ins (3,4,5,6) P 4 / AM. It was. TABLE 2 In the release of chlorine ions by the Ins (3,4,5,6) derivatives of P 4 Ins (3,4,5,6) P 4 - reversal of the inhibitory interventions Bt 2 -Ins (3,4,5,6) P 4 / AM (concentration)AntagonistPeak ΔI sc mean ± SEM after histamine (100 μM) administrationnControl (100%) 100 μM 75.1 ± 7.48p <0.012 200 μM 57.2 ± 15.16p <0.037 400 μM 69.3 ± 8.74p <0.041 -2-Bt-1-Me-Ins (3,4,5,6) P 4 / AM (200 μM)87.3 ± 6.68ns -Me 2 -Ins (3,4,5,6) P 4 / AM (200μM)103.9 ± 11.18ns -Me 2 -Ins (1,4,5,6) P 4 / AM (200μM)120.8 ± 10.68ns -2-Bt-3-Me-Ins (1,4,5,6) P 4 / AM (200 μM)105.5 ± 3.710ns 200 μM2-Bt-1-Me-Ins (3,4,5,6) P 4 / AM (200 μM)117.7 ± 10.68ns 200 μMMe 2 -Ins (3,4,5,6) P 4 / AM (200μM)107.13 ± 10.28ns 200 μM2-Bt-3-Me-Ins (1,4,5,6) P 4 / AM (200 μM)69.7 ± 5.048p <0.0005 200 μMMe 2 -Ins (1,4,5,6) P 4 / AM (200μM)68.4 ± 7.38p <0.003 -Bt 2 AMP / AM (2μM)96.3 ± 9.14ns -Bt 2 -Ins (1,4,5,6) P 4 / AM (400 μM)137.9 ± 20.74ns -D, L-1-Bt-2-Me-Ins (3,4,5,6) P 4 / AM (800μM)114.2 ± 23.78ns 200 μMD, L-1-Bt-2-Me-Ins (3,4,5,6) P 4 / AM (400μM)96.7 ± 14.83ns -D, L-1,2-Cl 2 -dideoxy-Ins (3,4,5,6) P 4 / AM (400 μM)89.39 ± 7.88ns The effect of various inositol polyphosphate derivatives on the secretion of histamine-stimulated chloride ions is shown in Table 3. 2-Bt-1-Me-Ins (1,4,5,6) P 4 / AM (200 μM) and Me 2 -Ins (3,4, which are derivatives of Ins (3,4,5,6) P 4 5,6) P 4 / AM reverses the inhibitory effect of Bt 2 -Ins (3,4,5,6) P 4 / AM on the secretion of histamine-stimulated chloride ions. Conversely, Ins (1,4,5,6) P 4 of the derivative Me 2 -Ins (1,4,5,6) P 4 / AM and 2-Bt-3-Me- Ins (1,4,5 6) P 4 / AM has essentially no effect. This result indicates that the reversal of Bt 2 -Ins (3,4,5,6) P 4 / AM inhibition on the secretion of chlorine ions is stereospecific and an alkyl derivative of Ins (3,4,5,6) P 4 Shows that it acts as an antagonist of Ins (3,4,5,6) P 4 . Other derivatives were also tested. Preculturing with Bt 2 -Ins (1,4,5,6) P 4 / AM did not inhibit the release of chlorine ions and actually promoted the release of chlorine ions slightly. Ins (3,4,5,6) of D, L-1,2-Cl derivative of P 4 2 - dideoxy -Ins (3,4,5,6) P 4 / AM is for the secretion of chloride ions There was a slight inhibitory effect. D, L-1-Bt-2-Me-Ins (3,4,5,6) P 4 / AM does not inhibit the secretion of chlorine ions and Bt 2 -Ins (1,4,5,6) P 4 Inhibition of / AM was not reversed. Raising intracellular calcium concentrations leads to the release of chlorine ions. To contend that none of the effects of inositol polyphosphate derivatives on secretion of chlorine ions were due to variations in calcium levels, the concentration of intracellular calcium was measured in cells treated with inositol polyphosphate derivatives. As shown in FIG. 4, Bt 2 -Ins (1,4,5,6) P 4 / AM did not elevate intracellular calcium or calcium in response to topsigargin. None of the compounds tested itself changed intracellular calcium levels and altered the levels of intracellular calcium stimulated with carbacol or thapsigargin. Thus, the effect of inositol polyphosphate on the secretion of chlorine ions is not due to the effect on intracellular calcium concentration. These results are due to the treatment of Ins (3,4,5,6) P 4 of the cell permeable derivative is 1,2-Bt 2 -Ins (3,4,5,6) cells to P 4 / AM Ins ( Increasing the intracellular concentration of 3,4,5,6) P 4 promotes the secretion of calcium-mediated chlorine ions in these cells to reverse the inhibition of the secretion of calcium-mediated chlorine ions. In contrast, derivatives of stereoisomer Ins (1,4,5,6) P 4 have no effect on inhibition of the secretion of chlorine ions mediated by Ins (3,4,5,6) P 4 . Thus, Ins (3,4,5,6) P 4 of the cell permeable derivative acts as an antagonist of Ins (3,4,5,6) P 4. Example IV Reversal of inhibition of carbacol-mediated chloride ion secretion using antagonists of Ins (3,4,5,6) P 4 This example is based on the cell permeable derivative of Ins (3,4,5,6) P 4 where the inhibition of carbacol-mediated chloride ion secretion acts as an antagonist of Ins (3,4,5,6) P 4 . It shows that it can be reversed. In Example III, intracellular Ins (3,4,5,6) P 4 is a cell that is hydrolyzed by an endogenous esterase producing Ins (3,4,5,6) P 4 Increased by the addition of permeable Bt 2 -Ins (3,4,5,6) P 4 / AM. In this example, intracellular Ins (3,4,5,6) P 4 is increased by long term treatment of the cells with carbacol. Epithelial cells of T 84 colon were D, L-1,2-cyclohexylidene-Ins (3,4,5,6) P 4 / AM, 1-Bu-2-Bt-Ins (3,4,5 , 6) P 4 / AM, Bu 2 -Ins (3,4,5,6) P 4 / AM, 3-Bt-2-Bu-Ins (1,4,5,6) P 4 / AM, Bu 2 -Ins (1,4,5,6) P 4 / AM, 1-Bt-2-Bu-Ins (3,4,5,6) P 4 / AM or 3-Bu-2-Bt-Ins ( Cells were treated with 3,4, 5,6) P 4 / AM and short circuit currents were measured. Sorts of cells were preincubated for 30 minutes with inositol polyphosphate derivatives. The other two cells were precultured with carrier only. Measurement of I sc was started at 0 hours. In 5 minutes, Carbachol (10 -4 M) is added to a pre-culture of cells with only a kind of carrier (is set to "Carbachol" in Figure 5) is a kind of cells were pre-incubated with the inositol polyphosphate derivatives (Figure 5A "Carbacol + D, L-1,2-cyclohexylidene-Ins (3,4,5,6) P 4 / AM"). At 30 minutes, 1 μM topsigargin was added. Data was collected for n = 4-6 experiments. 5A shows an experiment with D, L-1,2-cyclohexylidene-Ins (3,4,5,6) P 4 / AM. The addition of carbacol induced a transient increase in short circuit in cells pre-cultured with Ins (3,4,5,6) P 4 derivatives and cells treated with carbacol alone. At 30 minutes, after regression of the control level of ΔI sc , Topsigargin 1 μM was added to stimulate an increase in intracellular calcium. Planned increase in ΔI sc has been observed with long pointed tapsi treated with the control cells, ΔI sc has been weakened in cells receiving long-term treatment with Carbachol. Pretreatment with D, L-1,2-cyclohexylidene-Ins (3,4,5,6) P 4 / AM reversed the inhibitory effect of carbacol on the secretion of calcium-mediated chlorine ions . Thus, D, L-1,2-cyclohexylidene-Ins (3,4,5,6) P 4 / AM acts as an antagonist of Ins (3,4,5,6) P 4 . As shown in FIG. 5, Ins (3,4,5,6) P 4 derivative D, L-1,2-cyclohexylidene-Ins (3,4,5,6) P 4 / AM, 1-Bu-2-Bt-Ins (3,4,5,6) P 4 / AM and Bu 2 -Ins (3,4,5,6) P 4 / AM are chlorine ions stimulated by Topsigargin Inverting the carbacol-mediated inhibition of the secretion of, indicates that these Ins (3,4,5,6) P 4 derivatives act as antagonists of Ins (3,4,5,6) P 4 . Conversely, 3-Bt-2-Bu-Ins (1,4,5,6) P 4 / AM, 2,3-Bu 2 -Ins (1,4,5,6) P 4 / AM and 3-Bu -2-Bt-Ins (1,4,5,6) P 4 / AM as well as 1-Bt-2-Bu-Ins (3,4,5,6) P 4 / AM are stimulated by Topsigargin The inhibition of the secretion of carbacol-mediated chlorine ions was not reversed (FIGS. 5D-5G, respectively). These results reverse the inhibitory effect of long-term treatment with carbacol on the secretion of calcium-mediated chlorine ions by the cell-permeable derivatives of Ins (3,4,5,6) P 4 , and therefore Ins (3,4,5 6) acts as an antagonist of P 4 . Example V Increasing intracellular Ins (1,3,4) P 3 levels increases Ins (3,4,5,6) P 4 and decreases calcium-mediated chloride ion secretion. In this example, treatment of cells with cell-permeable derivatives of Ins (1,3,4) P 3 / AM increased Ins (3,4,5,6) P 4 , resulting in the release of calcium-mediated chlorine ions. Show inhibition. About 30 inositol polyphosphates have been identified in cells. Ins (1,4,5,6) P 4 is converted to Ins (1,3,4) P 4 by 5 ′ inositol polyphosphate phosphatase. In an in-lab assay system, Ins (1,3,4) P 3 is a system in which Ins (3,4,5,6) P 4 calls Ins (1,3,4,5,6) P 5 / AM Inhibits the inositol 1 kinase which catalyzes (Tan et al., J. Biol. Chem. 272: 2285 (1997), herein incorporated by reference). A cell permeable derivative, D, L-Bt 3 -Ins (1,3,4) P 3 / AM, was synthesized. T 84 cells of colonic epithelium were pre-incubated for 30 min with D, L-Bt 3 -Ins (1,3,4) P 3 / AM 400 μM and fixed in Ussing chamber to measure ΔT sc . In 10 minutes, the Carbachol (10 -4 M) Calcium was added in order to temporarily stimulate the secretion of chloride ions intervention. Data were provided as the average of eight experiments with p <0.04 on unpaired two-sided students' t-test. Ins (3,4,5,6) P measured in cells labeled with ( 3 H) -inositol by treating cells with D, L-Bt 3 -Ins (1,3,4) P 3 / AM 400 μM A 3-fold increase in 4 indicates that Ins (1,3,4) P 3 increased Ins (3,4,5,6) P 4 / AM in vivo. Cells of the control group pre-cultured with the carrier have a peak ΔT sc of 15.2 ± 2.8. Cells pre-cultured with D, L-Bt 3 -Ins (1,3,4) P 3 / AM had a peak ΔT sc of 7.9 ± 1.6. Therefore, the secretion of calcium-mediated chlorine ions was reduced by about 50% by treating the cells with cell-permeable derivatives of D, L-Bt 3 -Ins (1,3,4) P 3 / AM. This result suggests that the cell-permeable Ins (1,3,4) P 3 derivative increases the intracellular concentration of Ins (3,4,5,6) P 4 / AM resulting in a decrease in the secretion of calcium-mediated chloride ions. It acts as an agonist of Ins (3,4,5,6) P 4 . Example VI Infection of Human Colon Epithelial Cells with Salmonella Increases Ins (1,4,5,6) P 4 / AM Concentration Infectious intestinal bacteria enter and pass through the intestinal epithelium to penetrate the mucous membranes below to initiate systemic infection. Previous studies showing that Salmonella invasion of epithelial cells leads to an increase in inositol polyphosphate turnover have shown that inositol polyphosphate may play a role in epithelial cell responses to bacterial infections (Ruschkowski et al. FEMS Microbiol. Lett. 74: 121 (1992). To characterize the change of inositol polyphosphate caused by bacterial infection, the effect of bacterial infection on colonic epithelial cells was investigated. Of colon epithelial junction in six-well plates T 84 cells are non-inositol for 4 days and 50% Dulbecco's modified Eagle's ( DME) medium, and a new born calf supplemented with serum 5% dialyzed 50% Ham's F12 in a medium (3 H Incubated with 50 μCi / well of) -inositol. Cultures were washed three times with preheated medium (50% DME, 50% Ham's F12 and 1 mg / ml bovine serum albumin) and inoculated with 5 × 10 8 bacteria / well in the same medium for several periods of time. Cultures were sterilized twice with ice-cold phosphate buffered saline (PBS) and frozen on ice for 5 minutes in 10% trichloroacetic acid and 10 mM phytic acid. The extract was neutralized with FREON / Alamine and analyzed on an Adsorbosphere SAX column to separate ( 3 H) -inositol polyphosphate. Radioactive peaks were quantified as previously described using HPLC equipped with on-line radioactive detectors (Kachintorn et al., Sangga, 1993). In order to quantify undegraded enantiomers on HPLC, the peaks corresponding to ( 3 H) -Ins (3,4,5,6) P 4 and Ins (1,4,5,6) P 4 were determined by HPLC. Ins (separated from other ( 3 H) -InsP 4 isomers and then partially desalted and then partially purified with ( 32 P) -labeled Ins (1,4,5,6) P 4 as previously described) 1,4,5,6) P 4 3-kinase (Vajanaphanich et al., Sang Paper, 1994). Formed (3 H) -, and (32 P) - from the original peak (3 H) -Ins (3,4,5 compared the relative amount of the labeled Ins (1,3,4,5,6) P 5 , 6) P 4 to ( 3 H) -Ins (1,4,5,6) P 4 ratio was determined. Monolayers of T 84 cells were labeled with ( 3 H) -inositol and infected with Salmonella dublin for various periods of time. For 60 minutes immediately after infection, significant changes in the levels of other inositol polyphosphates, such as Ins (1,4,5) P 3 , which typically accumulate when myo-inositol hexakisphosphate (InsO 6 ) or phospholipase C is activated Was not. In contrast, the concentrations of ( 3 H) -Ins (3,4,5,6) P 4 and ( 3 H) -Ins (1,4,5,6) P 4 , which were unanalyzed enantiomers, were S. dublin Increased within 10 minutes after infection. About 85% of this peak corresponds to ( 3 H) -Ins (1,4,5,6) P 4 . Up to a 14-fold increase in control of uninfected cells reached 30-40 minutes post infection. Levels of ( 3 H) -Ins (1,4,5,6) P 4 decreased slowly after 40 minutes and returned to baseline at 3 hours post infection (see Table IV). Similar observations were provided using LS174T, another human intestinal epithelial cell line. ( 3 H) -Ins (1,4,5,6) P 4 increased 11.3 fold after S. dublin infection, indicating that changes in inositol polyphosphate in cells after infection indicate a general response of epithelial cells. . Infection of T 84 cells with another infectious Salmonella strain, Salmonella typhi BRD 691, also increased ( 3 H) -Ins (1,4,5,6) P 4 levels (see Table IV). Conversely, SB133, a mutant strain of S. doblin that normally attaches to but does not infect epithelial cells, minimizes the levels of ( 3 H) -Ins (1,4,5,6) P 4 and is a host by Salmonella. Infection of the cells is required for this reaction. However, infection of T 84 cells by several infectious Gram-negative bacteria, including Shigella Flexeri, Shigella dysenteriae, Yersinia enterocolitica, and enteric infectious Escherichia coli (serotype O29: NM), has been shown to affect ( 3 H) -Ins (1,4,5, 6) due to import only a slight increase in the level of bacterial infection P 4 million was not enough to increase the Ins (1,4,5,6) P 4 level. In addition, the addition of non-infectious Gram-negative bacteria, such as intestinal hemorrhagic E. coli (serotype O157) or non-pathogenic E. coli (DH5α), to the T 84 monolayer is ( 3 H) -Ins (1,4,5,6). almost no effect on the P 4 level. The addition of 10 μg / ml bacteria lipopolysaccharide (LPS) was ineffective at ( 3 H) -Ins (1,4,5,6) P 4 levels. Table 4 Increased Ins (3,4,5,6) P 4 Levels after Salmonella Infection of Epithelial Cells Added bacteriaElapsed time( 3 H) -Ins (1,4,5,6) P 4 levels (infected / control ratio)n Salmonella dublin cell line3013.9 ± 0.84 Salmonella dublin cell line6010.3 ± 1.35 Salmonella dublin cell line1203.62 Salmonella dublin cell line1801.92 Salmonella dublin cell line3010.52 Salmonella dublin cell line301.9 ± 0.13 Shigella flexneri601.92 Shigella dysenteriae602.32 Yersinia enterocolitica602.6 ± 0.13 Escherichia coli 029: NM602.0 ± 0.15 Escherichia coli O157602.3 ± 0.24 Escherichia coli DH5α602.1 ± 0.24 LPS601.02 The results show that infection with Salmonella of colonic epithelial cells increases the intracellular concentration of Ins (3,4,5,6) P 4 . Promoted chlorine ion secretion is associated with Ins (3,4,5,6) P 4 concentrations, which causes pathogenesis of secretory diarrhea and Salmonella infection. Example VII Ins (1,4,5,6) P 4 / AM reverses the inhibition of the secretion of EGF-induced goat ions. In this embodiment, the growth factor of the epidermis (EGF) is to increase the intracellular concentration of Ins (1,4,5,6) P 4 by culturing the cells with a cell permeable Ins (3,4,5,6) P 4 derivative Inhibition of the secretion of chlorine ions induced by) was reversed. In Examples III and IV, Ins (1,4,5,6) P 4 derivatives did not affect the inhibition of the secretion of Ins (3,4,5,6) P 4 -mediated chlorine ions. To test whether Ins (1,4,5,6) P 4 influences the inhibition of the secretion of EGF-induced goat ions, T 84 cell monolayers were prepared using Bt 2 -Ins (1,4,5,6) Pre-incubation for 30 min with P 4 / AM. Measurement of ΔT sc was initiated (see Example I), and after 5 minutes of measurement, 16.3 nM EGF was added to the basolateral surface of the cells. After an additional 15 min incubation, 100 μM carbacol was added to sharply raise intracellular calcium concentration. Controls were stimulated by carbacol but were not pretreated with EGF. Data is the average of two measurements in a representative experiment (sum of three experiments). As shown in FIGS. 6 and 7 (planes a and b), EGF inhibited the secretion of carbacol stimulated chloride ions. Preculturing with Bt 2 -Ins (1,4,5,6) P 4 / AM, a cell permeable derivative hydrolyzed to Ins (1,4,5,6) P 4 by endogenous cell esterase Inhibition of the secretion of EGF induced chloride ions is significantly reversed. In contrast, the inhibitory action of EGF was not mitigated by the addition of cell permeable derivatives of Ins (1,3,4,5,6) P 5 (FIG. 7, Caus). The addition of the cell-permeable Ins (3,4,5,6) P 4 derivative, an enantiomer of Ins (1,4,5,6) P 4 , did not mitigate the effect of EGF inhibition on the secretion of chloride ions. Addition of Bt 2 -Ins (1,4,5,6) P 4 / AM did not reverse EGF inhibition of the secretion of cyclic AMP-mediated chlorine ions, Ins (1,4,5,6) P 4 indicates that the action of 4 is specific for the secretion of calcium-mediated chloride ions. These results indicate that increased levels of Ins (1,4,5,6) P 4 delivered to cells such as cell permeability reverse the inhibition of the secretion of EGF-mediated chlorine ions resulting in the release of calcium-mediated chlorine ions. Explain that it promotes. Example VIII Ins (1,4,5,6) P 4 reverses the inhibition of PtdInsP 3 in the secretion of calcium-mediated chlorine ions. This example shows that cell permeable derivatives of PtdInsP 3 inhibit the secretion of calcium-mediated chlorine ions. Cell-permeable Ins (1,4,5,6) P 4 derivatives reverse PtdInsP 3 -mediated inhibition in the secretion of chlorine ions. T 84 cell monolayers were preincubated with PtdInsP 3 / AM for 30 minutes and ΔT sc was measured. As shown in FIG. 8, increasing the concentration of PtdInsP 3 / AM inhibits the secretion of carbacol-stimulated chlorine ions and inositol polys different from Ins (3,4,5,6) P 4 / AM It is indicated that phosphate inhibits the secretion of calcium-mediated chloride ions. Additional cell permeable derivatives of the 3 -kinase product PtdInsP 3 were synthesized and examined for the effect on the secretion of chlorine ions. Cells were measured as described in Example VII, pre-cultured with diC 16 -Bt-PtdInsP 3 / AM or diC 8 -Bt-PtdInsP 3 / AM. As shown in FIG. 7, pretreatment of T 84 cells with diC 16 -Bt-PtdInsP 3 / AM (FIG. 7D) inhibited the secretion of calcium-mediated goat ions by 74%. Similarly, diC 8 -Bt-PtdInsP 3 / AM inhibited the release of chlorine ions by 79%. Inhibition of the secretion of calcium-mediated chlorine ions was not observed when the cells were pretreated with PtdInsP 3 and did not appear to enter the cells. These cell permeable derivatives of PtdInsP 3 had no effect on calcium levels after carbacol stimulation. The level of inhibition observed in the derivative of PtdInsP 3 was comparable to that observed in EGF treatment of cells. In addition, the addition of EGF into a monolayer pre-cultured with a derivative of cell permeable PtdInsP 3 did not result in further inhibition of the secretion of calcium-mediated chlorine ions, indicating that PtdInsP 3 and EGF react through the same mechanism. T 84 cells were cell permeable Ins (1,4,5,6) P to determine if Ins (1,4,5,6) P 4 could reverse the inhibition of PtdInsP 3 -mediated chloride ion secretion. Pre-cultured with 4 derivatives. The results indicate that PtdInsP 3 inhibits the secretion of calcium-mediated chlorine ions. Ins (1,4,5,6) P 4 / AM also reverses the inhibition of secretion of calcium-mediated chlorine ions by PtdInsP 3 . Example IX Transfer of Chloride Ions from Human Nasal Epithelium This example provides a human nasal epithelial cell system useful as a model for examining the efficacy of compounds that alter the secretion of chloride ions in respiratory epithelium. Human nasal epithelium was obtained by biopsy. In bioelectrical and calcium measurements in monolayers, human nasal epithelial cells were placed in a porous Transwell Coll filter attached to an O-ring and studied for a time equal to the development of maximal percutaneous potential difference 5-7 days after sowing. It was. Cells were insulin (10 μg / ml), transferrin (5 μg / ml), epithelial growth supplement (3.75 μg / ml), hydrocortisone (5 nM), epithelial cell growth supplement (3.75 μg / ml), tree It was maintained in serum-free Hams' F12 medium supplemented with iodotyronine (30 nM) and 1 mM CaCl 2 . Human nasal epithelial monolayers were fixed for 5-7 days after inoculation in a reduced Ussing chamber. Percutaneous potential difference was examined by Voltage-Clamp / Pulse Generator (Physiologic Instruments, San Diego, Calif.), And bioelectronics were recorded on two channel recorders. The monolayer was exposed to Ringer's solution without sodium to yield a change in transdermal chlorine resistance, and the amount of change from the original sodium absorbent state to the chlorine ion secreted state was measured. In intracellular calcium measurements, monolayers were added to Fura-2 and fixed with a microscope objective coupled with a microfluorimeter. The fluorescence intensity ratio was collected in a field of 30-40 cells or in single cells. ΔT sc for intracellular calcium levels is normalized in each preparation. To confirm that the results reflect the response to the real monolayers, the monolayers were periodically fixed and tested with cross-section specimens. Human nasal epithelial cells are useful for treatment with antagonists of Ins (3,4,5,6) P 4 and PtdInsP 3 as described in Examples III, IV, VII and VIII. Compounds effective in stimulating the secretion of chlorine ions in human nasal epithelium are excellent candidates for alleviating the symptoms of cystic fibrosis, such as lung dysfunction. Example X Development of CFTR - T 84 Cells This example provides a method of making CFTR - T 84 cells useful as a model of cystic fibrosis. Search for Ins (3,4,5,6) P 4 Derivatives and Determine If CFTR Regulates Expression of Factors That Inhibit Secretion of Ins (3,4,5,6) P 4 -mediated Chlorine Ions Ultimately To do this, CFTR - T 84 cells were generated. CFTR genes in T 84 cells were inactivated in a double-selective approach to develop gene knockout mutations in mouse liver cells (ES cells) (Mansour et al., Nature 336: 348, incorporated herein by reference). 1988). Mutagenic CFTR gene target constructs are generated in the pSSC-9 vector (Chauhan and Gottesman, Gene 120: 281 (1992), incorporated herein by reference). This vector carries a neomycin resistance gene and is driven by a thymidine kinase promoter and is located on both sides of the hsv-tk gene. PSSC-9 also carries a convenient colon site on either side of the gene that can be used to insert a gene target site and two Sfil restriction sites that can be used to incise a linear mutagenesis cassette. Selecting the expression of the neomycin gene in response to G418 allows for a stable search for the truncated clones. The choice for hsv-tk expression expands clones, a structure that integrates homologous recombination into a targeted site using cyclovir (Mansour et al., Sangga, 1988). 8.5 kb of CFTR gene. The fragment (containing TE 2611E8.5 exon 21) is used as the source of the CFTR gene sequence (Rommen wt al., Science 245: 1059 (1989); and Rommens et al., Am. J. Hum Genet. 45: 932 (1989). In addition, polymerase chain reaction (PCR) can be used directly for clones of the appropriate sequence in T 84 cells. Various PCR primers for amplifying the CFTR gene sequence are disclosed (Zielinski et al., Gnomics 10: 214 (1991), incorporated herein by reference). Fragments at least 2-4 kb in length will be amplified to sufficiently ensure similar sequences for cognate recombination. PCR primers carry restriction site expansion compatible with the pSSC-9 clone site. Mutant constructs are transfected into T 84 cells using DNA transfection methods such as calcium phosphate or an electrical poration-based protocol (Molecular Biology, A Laboratory Manual, 2nd edition, incorporated herein by reference). , Sambrook et al., Eds. Cold Spring Harbor Laboratory, Press, Plainview, NY (1989) .Stable transfectors are expanded using G418 and secondarily selected using cyclovires. Selection is carried out using an increased amount of G418 by driving into a CFTR community by means of this approach, with an additional selection step to enable the generation of double knockout mutations using ES cells in mice. (Chen et al., Proc. Natl. Acad. Sci. USA 90: 4528 (1993), incorporated herein by reference); and Mort enson, Hypertension 22: 646 (1993)). Selected clones were analyzed by Southern block and PCR assays to verify that the neo cassette was inserted into the CFTR gene. The "dual rescue method" can optionally be used by mutagenesis of target genes using two different mutagenic constructs, performed by sequences (Mortenson, Sang et al., 1993; Feldhaus et. al., EMBO J. 12: 2763 (1992); and Porter and Itshaki Eur. J. Bioche. 218: 273 (1993). These constructs carry a neo gene or gpt gene cassette to allow for sequence transfection and the selection of the gpt gene using mycophenolic acid and xanthine and the neo gene with G418. Double knockout CFTR mutations in T 84 cells are used to test the efficacy of the antagonists of Ins (3,4,5,6) P 4 and PtdInsP 3 . These results illustrate the development of CFTR − mutations in T 84 cells that can be used as a model of cystic fibrosis. These cells provide a genetic background similar to that found in epithelial cells of cystic fibrosis patients. Antagonists of Ins (3,4,5,6) P 4 and PtdInsP 3 are excellent candidates for promoting the release of chloride ions in cystic fibrosis patients. Example XI Preparation of Cell Permeable Inositol Polyphosphate Derivatives This example discloses cell permeable inositol polyphosphate derivatives. Synthetic reactions of certain cell-permeable inositol polyphosphate derivatives have already been disclosed (Roemer et al. Sang, 1996; and Roemer et al., Sang, 1995). The synthesis reaction of additional inositol polyphosphate derivatives is described below. 9 shows the structures of cell permeable PtdInsP 3 and diC 16 -Bt-PtdInsP 3 / AM. 10 shows a schematic synthesis of derivatives of PtdInsP 3 / AM. FIG. 11 shows a schematic synthesis of 1,2-cyclohexylidene-Ins (3,4,5,6) P 4 // AM. 12 shows the structure of myo-inositol 1,3,4-trisphosphate and 2,5,6-Bt 3 -Ins (1,3,4) P 3 / AM. Only the D-array of the compounds is shown. Figure 13 shows a schematic of the synthesis of cell permeable inositol polyphosphate. In Figure 13, the following conditions were used: (i) Bt 2 O, DMAP, pyr .; (ii) TFA, CH 3 CN / H 2 O; (iii) Bu 2 SnO, toluene, refl., b BnBr, CsF, DMF; (iv) Bt 2 O, DMAP, pyr., v Pd / C (10%), AcOH; (vi) a (BnO) 2 PNiPr 2 , tetrazole, CH 3 CN, b AcOOOH, −40 ° C .; (Vii) Pd / C (10%), AcOH; And (Viii) AMBr, DIEA, CH 3 CN. All reaction reagents were chosen to be of the highest purity. If necessary, the solvent was dried and / or distilled before use. Acetonitrile was distilled from phosphorus (V) oxide and stored at 3 μg as in dimethylformamide (DMF). Pyridine and toluene were stored at 4 μg particle size. Ethyl-diisopropylamine (DIEA) was dried over sodium wire. Palladium and trifluoroacetic acid in charcoal are from Acros chemie. Dibenzyl N, N-diisopropylphosphoramidite, peracetic acid (32% v / w), tetrazole and acetoxymethyl bromide are from Aldrich. Milwaukee, Wisconsin butyric anhydride, DIEA and tris (triphenylphosphine) -rhodium (I) -chloride are from Merck. Benzyl bromide, alkyl bromide, butyl, amide, cesium fluoride and 4-dimethylamino pyridine (DMAP) are from Fluka. The ion-exchange resin Dowex 50 WX 8, H + -type is from Serva, Heidelberg, Germany. All other reagents are from Riedel-de Haёn. High performance liquid chromatography (HPLC) was performed on LDC / Milton Roy UV Monitor D (254 nm) or LDC / Milton Roy Consta Metric III pumps with Knaur reflective index detectors. An analytical column is a Merck Hibar steel tube (250 mm x 4 mm) filled with RP 18 material (Merck, Lichrosrb; 10 μm). Preparative HPLC is a Merck Prepbarr steel tube (25 ° mm × 50 mm) filled with a preparative LDC UV III monitor (254 nm) or Shimadzu LC 8A pump with Knaur reflective index detector and RP 18 material (Merck, Lichrospher 100; 10 μm) Was run using Elution was methanol-water mixture; The composition was given in% methanol (MeOH). The 1 H-NMR and 31 P-NMR spectra were measured in ppm on the Brucker AM 360 AM spectrometer Chemical Shift for tetramethylsilane in the 1 H NMR spectrum and for the external 85% H 3 PO 4 in the 31 P NMR spectrum. . J-volume is given in Hz. The mass spectra were recorded with a Finnigan Mat 822 mass spectrometer with fast atomic bombardment (FAB) ionization. High resolution masses were determined for known compounds with masses that did not differ by more than 10%. Melting point (MP) (not modified) was measured using a Bucji B-540 apparatus. Optical turnover was measured on sodium D-ray with Perkin-Elmer 1231 polarizer in 10 cm cells. Ultrafiltration of the palladium / charcoal catalyst was performed with a Sartorius filtration device using a regenerated cellulose filter (Sartorius SM 116 04, Sartorius Edgewood, NY). Factor analysis was performed with Mikroanalytisches (Labor Beller, Gottingen, Germany). D-1,4,5,6-tetra-O-benzyl-myo-inositol (ent-9) and D-3,4,5,6-tetra-O-benzyl-myo-inositol (9) were previously Synthesized as described (Roemer et al., Sang, 1996) Compound rac-1,2-di-O-cyclohexylidene-myo-inositol is prepared by Angyal and Tate methods (incorporated herein by reference). Angyal and Tate, J. Chem. Soc. 1965: 6949 (1965). Standardization of phosphorylation The selectively protected myo-inositol derivatives and tetrazole were dissolved in dry acetonitrile under argon atmosphere and dibenzyl N, N-diisopropylphosphoramide was added. After stirring for the indicated time at room temperature, the reaction mixture was cooled to -40 ° C and peracetic acid (32% v / w; 1 molar equivalent for each molar equivalent of phosphoramidite) was added. After the mixture was reacted at room temperature, the solvent was removed under reduced pressure and the residual oil was purified by preparative HPLC to give the desired inositol tetrakisphosphate derivative. Standard Process for Removing Benzyl Groups by Hydrocracking Fully protected myo-inositol tetrakisphosphate or tetrabenzyl-inositol is heated for a specified time in a palladium of carbon (10%; 0.1 molar palladium for each mole of benzyl group) and self-manufacturing hydrogenation unit under an atmosphere of hydrogen in acetic acid, respectively. Was stirred. The catalyst was removed by ultrafiltration and the filtrate was lyophilized to give the product. Standard Process for Introduction of Acetoxymethyl Ester The completely dried inositol tetrakisphosphate derivative (free acid) was suspended in dry acetonitrile under argon atmosphere followed by the addition of dry DIEA (2.25 mol DIEA per mol of hydroxyl group). After stirring the mixture for 4 days in the dark at room temperature, all volatile components were evaporated and the crude residue was purified by preparative HPLC with the specified solvent to give a tetrakisphosphate octakis (acetoxymethyl) ester on syrup. D-3,4,5,6-tetra-O benzyl 1-O-butyl-myo-inositol (10) Dry toluene (100 mL) in a Soxhlet device with a molecular sieve (3 ms) with dry 9 (250 mg, 463 μmol) and dry dibutyltin oxide (116 mg, 167 μmol) activated for 18 hours. Dried under reflux). The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. CsF (140 mg, 926 μmol) was added to the residual oil and the mixture was maintained under high vacuum. The remaining syrup was dissolved in dry DMF (10 mL) under argon atmosphere and 1-butyryl iodide (300 μl, 2.62 mmol) was added. After stirring the solution for 48 hours, HPLC analysis (90% MeOH; 1.5 mL / min; t R = 7.43 min) showed no further reaction. Excess 1-butyl iodide and DMF were removed under high vacuum. The crude product was chromatographed by preparative HPLC (93% MeOH; 40 mL / min; t R = 22.30 min) to give solid compound 10 (175 mg, 74%). Mp: 75.4-75.9 ° C. (from methanol). D-1,4,5,6-tetra-O-benzyl 3-O-butyl-myoInositol (ent-10) Similar reactions and operations of diol ent-9 provided compound ent-10. [a] 24 D -8.7 ° (1.01 at c = CHCl 3 ). The spectral data is identical to the data obtained from enantiomer 10. D-3,4,5,6-tetra-O-benzyl-1-O-butyl-2-O-Butyryl-myo-inositol (11) A solution of 10 (178 mg, 298 μmol), butyric anhydride (210 μl, 596 μmol) and DMAP (38 mg, 30 μmol) of dry pyrimidine (3 mL) was stirred at room temperature for 18 hours. The solvent was evaporated under high vacuum to give an oil. Residual pyridine was removed by distillation three times with octane. The residue was dissolved in tert-butyl methyl ether (10 mL), once phosphate buffer (10 mL), sodium hydrogen carbonate (10 mL), sodium hydrogen sulfate (10 mL), again phosphate buffer (10 mL), And brine (10 mL). The organic layer was dried over Na 2 SO 4 and filtered. Evaporation of the solvent gave pure compound 11 (194 mg, 98%) in the oil phase. D-1,4,5,6-tetra-O-benzyl-3-O-butyl-2-O-Butyryl-myo-inositol (ent-11) Compound ent-10 was butyrylated as described above for the other enantiomers to afford compound ent-11. [a] 24 D : + 10.7 ° (2.05 in c-CHCl 3 ). The spectral data is identical to that of the enantiomer 11. D-1-O-butyl-2-O-butyryl-myo-inositol (12) Compound 11 (178 mg, 267 μmol) was lyophilized by hydrogenation of palladium (10%) of carbon under hydrogen atmosphere as described in the general procedure to give solid Tetron 12 (81 mg, 99%). D-3-O-butyl-2-O-butyl-2-O-butyryl-myo-inositol (ent-12) Reaction and operation similar to that of fully protected compound ent-11 provided Tetron ent-12. [a] 24 D :-26.6 ° (0.76 in c = MeOH). The spectral data is the same as the data obtained from enantiomer 12. D-1-O-butyryl-myo-inositol 3,4,5,6-tetrakis (dibenzyl) phosphate (20) Acetonitrile (2 mL) solution of tetrol 12 (63 mg 206 μmol) and tetrazole (174 mg, 2.47 mmol) was converted to dibenzyl N, N-diisopropylphosphoramidite (834 μl, 2.47 mmol). Treated for 18 hours, oxidized with peracetic acid and worked as described. Purification by preparative HPLC (93% MeOH; 40 mL / min; t R = 26.45 min) gave compound 20 (165 mg, 60%) in oily form. D-3-O-butyl-2-O-butyryl-myo-inositol 1,4,5,6-tetrakis (dibenzyl) phosphate (ent-20) Tetrol ent-12 was phosphitylated and oxidized as described in compound 20 to provide phosphate ent-20 which is fully protected. [a] 24 D : + 4.8 ° (c = 2.09 with CHCl 3 ). The spectral data were according to the data obtained on enantiomer 20. D-1-O-butyl-2-O-butyryl-myo-inositol 3,4,5,6-tetrakis phosphate (21) Compound 20 (160 mg, 118 μmol) was hydrogenated with palladium of carbon (10%) as described in the standard process to give the title compound 21 as a solid after lyophilization (73 mg, 99%). MS: m / z (+ ve ion FAB) 627 [(M + H) + , 4], 71 [Bt + , 100]. MS: m / z (−ve ion FAB) 625 [(M−H + ) 100]. D-3-O-butyl-2-O-butyryl-myo-inositol 1,4,5,6-tetrakisphosphate (ent-21) Reaction similar to the fully protected material ent-20 provided the free acid ent-21 after lyophilization. [a] 24 D : 4.1 ° (0.78 at c = H 2 O, pH 1.6). The spectral data was the same as the data obtained in enantiomer 21. D-1-O-butyl-myo-inositol 3,4,5,6-tetrakis phosphate (5) Compound 21 (17 mg, 27 μmol) was treated with 1M KOH (260 μl) to adjust the 12.8 pH value. The solution was stirred for 2 days at room temperature. The reaction mixture was placed directly on an ion exchange column (Dowex 50 WX 8, Ht) for purification. Lyophilization gave compound 5 (14 mL, 94%). D-3-O-butyl-myo-inositol 1,4,5,6-tetrakisphosphate (ent-5) The butyryl group of substance ent-21 was hydrolyzed in the same manner described above to give tetrakisphosphate ent-5-[α] 24 D : + 4.6 ° (0.35 at c = H 2 O, pH 1.6). The data in the spectrum were the same as those obtained in enantiomer 5. D-1-O-butyl-2-O-butyryl-myo-inositol 3,4,5,6-tetrakis octakis (acetoxymethyl) ester (1) As described in the standard process, DIEA (131 μl, 768 μmol) and acetoxymethyl bromide (77 μl, 768 μmol) were added to a dispersion of acetonitrile (2 mL) of compound 21 (30 mg, 47 μmol). It became. Purification by preparative HPLC (73% MeOH, 37.5 mL / min, t R = 19.30) gave Syrup phase Compound 1 (31 mg, 55%). D-3-O-butyl-2-O-butyryl-myo-inositol 1,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester (ent-1) Phosphate ent-21 was alkylated as described above to provide the octakis (acetoxymethyl) ester ent-1. [a] 24 D : + 1.9 ° (c = 1.46 in toluene). The data in the spectrum were the same as those obtained in enantiomer 1. D-1-O-alkyl-3,4,5,6-tetra-O-benzyl-myoInositol (13) Dry 9 (690 mg, 1.28 mmol) and dry dibutyltin oxide (324 mg, 1.3 mmol) were heated under reflux with dry toluene for 20 hours in a Soxhlet apparatus with activated particulate (3x). The reaction mixture was cooled to room temperature and distilled to dryness under reduced pressure. CsF (399 mg, 2.56 mol) was added to the residual oil and the mixture was maintained under high vacuum for 2 hours. The remaining syrup was dissolved in dry DMF (10 mL) under argon atmosphere and 1-allyl iodide (329 μl, 3.58 mmol) was added. After stirring the solution for 20 hours, HPLC analysis (95% MeOH; 1.5 mL / min; t R = 3.20 min) showed no further reaction. Excess 1-allyl iodide and DMF were removed by high vacuum. The crude product was chromatographed with preparative HPLC (90% MeOH; 40 mL / min; t R = 26.15 min) to give solid compound 13 (448 mg, 60%). D-3-O-allyl-1,4,5,6-tetra-O-benzyl-myoInositol (ent-13) A reaction similar to the operation of diol ent-9 provided compound ent-13-[α] 24 D : + 3.9 ° (0.82 at c = CHCl 3 ). The data in the spectrum are the same as those obtained in enantiomer 13. D-1-O-allyl-3,4,5,6-tetra-O-benzyl-2-O-Butyl-myo-inositol (14) Sodium hydroxide (46 mg, 1.92 mmol) was added to the stirred solution of compound 13 in dry DMF (5 mL) in the dark at room temperature. The mixture was stirred for 5 hours after 1-butyl iodide (306 μl, 2.68 mmol) was added. The suspension was stirred at 80 ° C. for 18 hours before HPLC (95% MeOH; 1.5 mL / min; t R = 7.35) showed the product. Excess 1-butyryl iodide and DMF were evaporated under reduced pressure. The mixture was then dissolved in tert-butyl methyl ether (40 mL) and washed continuously in phosphate buffer (20 mL), aqueous sodium dithionate (20 mL) and brine (20 mL). The organic layer was dried over Na 2 S0 4 , filtered and the ether evaporated to remain in oil phase. The crude oil was purified by preparative HPLC (93% MeOH; 40 mL / min; t R = 37.10 min) to give the title compound 14 (458 mg, 94%) in oil phase. D-3-O-allyl-1,4,5,6-tetra-O-benzyl-2-O-Butyl-myo-inositol (ent-14) A similar reaction to that of compound ent-13 provided compound ent-14. [a] 24 D : -1.6 ° (1.87 at c = CHCl 3 ). Spectral data were obtained from enantiomer 14. D-3,4,5,6-tetra-O-benzyl-2-O-butyl-myoInositol (15) Tris (triphenylphosphine) -rhodium (I) -chloride (140 mg, 150 μmol) and DIEA (25 μl, 140 μmol) were added to a suspension of 14 (458 mg, 720 μmol) in 50% ethanol (90 mL). The suspension was then heated at reflux for 7 hours. The reaction mixture was cooled to room temperature, then trifluoroacetic acid (7 mL) was added and the solution stirred for an additional 24 hours. There was no starting material on HPLC (90% MeOH; 1.5 mL / min; t R = 4.03 min). Neutralized with water. 2N NH 4 OH ethanol was evaporated under reduced pressure to give a syrup. This syrup was dissolved in tert-butyl methyl ether (40 mL) and washed successively with phosphate buffer (20 mL) and brine (20 mL). The organic layer was dried over Na 2 S0 4 , filtered and the ether was evaporated to give an oil. The crude oil was purified by preparative HPLC (92% MeOH; 40 mL / min; t R = 27.40 min) to give solid compound 15 (275 mg, 74%). C: calculated 76.48, found 76.52; H: calculated 7.43, experimental 7.40. D-1,4,5,6-tetra-O-benzyl-2-O-butyl-myoInositol (ent-15) A reaction similar to the operation of diol ent-15 provided compound ent-15. [a] 24 D : + 24.9 ° (1.00 in c = CHCl 3 ). Spectral data were obtained from enantiomer 15. D-3,4,5,6-tetra-O-benzyl-2-O-butyl-1-O-Butyryl myo-inositol (16) A solution of alcohol 15 (178 mg, 298 μmol) in dry pyridine (4 mL) was treated with butyric anhydride (158 μl, 447 μmol) and DMAP (38 mg, 29 μmol) and stirred at room temperature. When HPLC analysis (90% MeOH; 1.5 mL / min; t R = 6.40 min) indicated no further starting material (18 h), the reaction mixture was distilled off under reduced pressure to give crude oil. To remove residual pyridine, the oil was dissolved in octane and evaporated three times. The residue was dissolved in tert-butyl methyl ether and washed with phosphate buffer (10 mL), sodium hydrogen carbonate (10 mL) and sodium hydrogen sulfate (10 mL), again phosphate buffer (10 mL) and saline (10 mL). Washed. The organic layer was dried over Na 2 SO 4 and filtered. Evaporation of the solvent gave pure 16 (176 mg, 89%). D-1,4,5,6-tetra-O-benzyl-3-O-butyl-2-O-Butyryl-myo-inositol (ent-16) Compound ent-15 was butyrylated as described above for the other enantiomers to afford compound ent-16. -[α] 24 D : + 15.9 ° (1.10 in c = CHCl 3 ). The data in the spectrum correspond to those obtained in enantiomer 16. D-2-O-butyl-1-O-butyryl-myo-inositol (17) Compound 16 (170 mg, 255 μmol) was hydrogenated to palladium of carbon (10%) in a hydrogen atmosphere according to standard procedures to give lyophilized solid Tetro 17 (75 mg, 97%). D-2-O-butyl-3-O-butyryl-myo-inositol (ent-17) A reaction similar to that of fully protected Compound ent-16 provided Tetrol ent-17. [a] 24 D :-40.5 ° (c = 1.00 in MeOH). The data in the spectrum were the same as those obtained in enantiomer 17. D-2-O-butyl-1-O-butyryl-myo-inositol 3,4,5,6-tetrakis (dibenzyl) phosphate (22) A solution of acetonitrile (2 mL) of compound 17 (55 mg, 178 μmol) and tetrazole (152 mg, 2.15 mmol) was diluted with dibenzyl N, N-diisopropylphosphoramidite (726 μL, 2.15 for 22 hours). mmol), oxidized with peracetic acid and worked as described above. Purification by preparative HPLC (92% MeOH; 40 mL / min; t R = 29.00 min) afforded compound 22 in oily form. D-2-O-butyl-3-O-butyryl-myo-inositol 1,4,5,6-tetrakis (dibenzyl phosphate (ent-22) Compound ent-12 was phosphitylated and oxidized as described for compound 22 to provide a fully protected phosphate ent-22. [a] 24 D : +3. 1 ° (c = 1.10 in CHCl 3 ). The data in the spectra were identical to those obtained in enantiomer 22. D-2-O-butyl-1-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate (23) Compound 22 (190 mg, 141 μmol) was hydrogenated with palladium of carbon (10%) as described in the standard procedure to give the title compound 23 (87 mg, 99%) as a solid after lyophilization. D-2-O-butyl-3-O-butyryl-myo-inositol 1,4,5,6-tetrakisphosphate (ent-23) The fully protected material ent-23 was lyophilized in the same reaction to give the free free acid ent-23. [a] 24 D :-9.7 ° (1.00 in c = H 2 O, pH 1.6). The spectral data was the same as the data obtained from enantiomer 23. D-2-O-butyl-myo-inositol 3,4,5,6-tetrakisphosphate (6) Compound 23 (33 mg, 52 μmol) was treated with 1M KOH (453 μl) to adjust the pH value to 12.8. The solution was stirred for 2 days at room temperature. The reaction mixture was directly provided for purification by ion exchange column. Lyophilization gave compound 6 (27 mg, 93%). D-2-O-butyl-myo-inositol 1,4,5,6-tetrakisphosphate (ent-6) The butyryl group of substance ent-23 was hydrolyzed in the same manner as described above to give tetrakisphosphate ent-6. -[α] 24 D : + 1.6 ° (0.60 at c = H 2 O, pH 1.6). The spectral data was the same as the data obtained in enantiomer 6. D-2-O-butyl-1-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester (2) DIEA (182 mg, 1.06 mmol) and acetoxymethyl bromide (107 μl, 1.06 mmol) were added to a suspension of acetonitrile (2 mL) of compound 23 (37 mg, 59 μmol) as described in the standard procedure. Purification by preparative HPLC (72% MeOH; 40 mL / min; t R = 21.12 min) gave Compound 2 (33 mg, 46%) on syrup. [a] 24 D : + 1.1 ° (c = 1.07 in toluene). D-2-O-butyl-3-O-butyryl-myo-inositol 1,4,5,6-tetrakis phosphate octakis (acetoxymethyl) ester (ent-2) Alkylation of phosphate ent 23 as described above provided the octakis (acetoxymethyl) ester ent-2. [a] 24 D : 1.3 ° (c = 0.60 in toluene). The spectral data was the same as the data obtained in enantiomer 2. D-3,4,5,6-tetra-O-benzyl-1,2-di-O-butyl-myo-inositol (18) Sodium hydroxide (13 mg, 522 μmol) was added to a stirred solution of 9 (94 mg, 174 μmol) in dry DMF (3 mL) at room temperature in the dark at room temperature. The mixture was stirred for 5 hours after 1-butyl iodide (120 μl, 1.04 mmol) was added. The suspension was stirred at 80 ° C. for 36 h after HPLC (95% MeOH; 1.5 mL / min; t R = 7.26) showed the product. Excess 1-butyryl iodide and DMF were evaporated under reduced pressure. The mixture was then dissolved in tert-butyl methyl ether (30 mL) and washed continuously in phosphate buffer (10 mL), aqueous sodium dithionate (10 mL) and brine (10 mL). The organic layer was dried over Na 2 S0 4 , filtered and the ether evaporated to remain in oil phase. The crude oil was purified by preparative HPLC (95% MeOH; 40 mL / min; t R = 27.24 min) to give the title compound 18 (100 mg, 88%) in oil phase. D-1,4,5,6-tetra-O-benzyl-2,3-di-O-butyl-myo-inositol (ent-18) A reaction similar to that of compound ent-9 provided compound ent-18. [a] 24 D : 1.2 ° (c = 2.20 in CHCl 3 ). The data in the spectrum was the same as the data obtained for enantiomer 18. D-1,2-di-O-butyl-myo-inositol (19) Compound 18 (100 mg, 153 μmol) was hydrogenated to palladium of carbon (10%) under hydrogen atmosphere as described in the standard procedure to obtain solid tetrol 19 (40 mg, 92%) after lyophilization. (From ethanol) D-2,3-di-O-butyl-myo-inositol (ent-19) Tetrol ent-19 was provided in a reaction similar to that of fully protected compound ent-18. [a] 24 D :-18.9 ° (c = 1.36 in MeOH). The data in the spectrum were the same as those obtained in enantiomer 19. D-1,2-di-O-butyl-myo-inositol 3,4,5,6-tetrakis (dibenzyl) phosphate (24) A solution of acetonitrile (2 mL) of compound 19 (40 mg, 137 μmol) and tetrazole (115 mg, 1.64 mmol) was converted to dibenzyl N, N-diisopropyl phosphoramidite (552 μL, 1.64 mmol). Treated for 18 hours, oxidized with peracetic acid and treated as described. Preparative by preparative HPLC (93% MeOH; 40 mL / min; t R = 26.05 min) gave compound 24 (133 mg, 73%) in oily form. D-2,3-di-O-butyl-myo-inositol 1,4,5,6-tetrakis (dibenzyl) phosphate (ent-24) Compound ent-19 gave phosphate ent-24, which was phosphitylated and oxidized to complete protection as described above for compound 24. [a] 24 D : + 2.5 ° (1.15 in c = CHCl 3 ). The data in the spectrum were the same as those obtained in enantiomer 24. D-1,2-di-O-butyl-myo-inositol 3,4,5,6-tetrakisphosphate (7) Compound 24 (134 mg, 100 μmol) was hydrogenated with palladium of carbon as described in the standard procedure to give the title compound 7 (52 mg, 87%) as a solid after lyophilization. (1.10 at C = H 2 O, pH 1.6) D-2,3-di-O-butyl-myo-inositol 1,4,5,6-tetrakisphosphate (ent-7) A reaction similar to that of fully protected Compound ent-24 provided free acid ent-7 after lyophilization. (c = 1.00 in H 2 O, pH 1.6). The data in the spectra were identical to those obtained in enantiomer 7. D-1,2-di-O-butyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester (3) DIEA (187 μl, 1.00 mmol) and acetoxymethyl bromide (111 μl, 1.00 mmol) were added to a suspension of acetonitrile (2 mL) of compound 7 (34 mg, 55 μmol) as described in the standard procedure. Purification by preparative HPLC (73% MeOH; 40 mL / min; t R = 20.40 min) gave compound 3 (42 mg, 65%) on syrup. D-2,3-di-O-butyl-myo-inositol 1,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester (ent-3) Alkylation of phosphate ent-7 as described above provided the octakis (acetoxymethyl) ester ent-3. [a] 24 D : + 2.5 ° (c = 1.10 in toluene). The data in the spectra were identical to those obtained in enantiomer 3. rac-1,2-di-O-cyclohexylidene-myo-inositol 3,4,5,6-tetrakis (dibenzyl) phosphate (rac-26) A solution of acetonitrile (6 mL) of compound rac-25 (130 mg, 200 μmol) and tetrazole (350 mg, 5.00 mmol) was treated with dibenzyl N, N-diisopropylpolyphosphoramidite (26 1.68 mL, 5.00 mmol) and oxidized with peracetic acid to work as described. Purification by preparative HPLC (93% MeOH; 40 mL / min; t R = 22.35 min) gave oily compound rac-26 (306 mg, 47%). rac-1,2-di-O-cyclohexylidene-myo-inositol 3,4,5,6-tetrakis phosphate (rac-8) ethyl-diisopropylamino acid salt rac-26 (91 mg, 70 μmol) was dissolved in dry ethanol (4 mL) to add dry ethyl-diisopropylamine (95 μl, 560 μmol) followed by carbon (84 mg, 840 μmol) palladium (10%) Hydrogenated. After stirring the solution under hydrogen atmosphere for 6 days at room temperature, the catalyst was removed by ultrafiltration and the filtrate was lyophilized to give the title compound rac-8 (108 mg, 96%). rac-1,2-di-O-cyclohexylidene-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester (rac-4) DIEA (205 μl, 1.20 mmol) and acetoxymethyl bromide (120 μl, 1.20 mmol) were added to a suspension of acetonitrile (2 mL) of compound rac-8 (108 mg, 66 μmol) as described in the standard procedure. It became. Purification by preparative HPLC (68% MeOH; 40 mL / min; t R = 19.35 min) gave compound rac-4 (50 mg, 65%) on syrup. rac-3,4,5,6-tetra-O-benzyl-2-deoxy-2-iodo-1-O- (4-methoxybenzyl) -myo-inositol (rac-56) Dry rac-55 (rac-3,4,5,6-tetra-O-benzyl-1-O- (4-methoxybenzyl) -myo-inositol) (1.32 g, 2 mmol), triphenylphosphine ( 2.15 g, 8.2 mmol), imidazole (549 mg, 8.2 mmol) and a mixture of iodine (1.52 g, 6 mmol) were stirred under reflux in dry toluene (100 mL) for 41 h. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate (100 mL) was added and the mixture was stirred for 10 minutes. Iodine was added in portions. If the toluene phase remains iodine-coloured, it is stirred for an additional 15 minutes. Excess iodine was removed by adding additional aqueous sodium dithionite solution. The organic and aqueous phases were separated with a separating funnel and the organic phase was washed twice with brine. The toluene phase was dried over Na 2 SO 4 and filtered. The mixture was evaporated and crystallized to give pure rac-56 (1.01 g, 73%). rac-3,4,5,6-tetra-O-benzyl-2-deoxy-1-O- (4-methoxybenzyl) -myo-inositol (rac-57) Compound rac-56 was dissolved in dry toluene (150 mL) and AIBN (63 mg, 355 μmol) and n-Bu 3 SnH (1.63 mL, 6.3 mmol) were added. The solution was heated under argon atmosphere for 2 hours. The reaction mixture was cooled and washed with phosphate buffer (30 mL), and brine (30 mL). The organic layer was dried over Na 2 SO 4 and filtered. Distillation and crystallization of the mixture gave 57 (692 mg, 76%). Mp .: 76.2-76.8 ° C. (from methanol). rac-3,4,5,6-tetra-O-benzyl-2-deoxy-myo-inositol (58) DDQ (367 mg, 1.62 mmol) was added to a solution of CH 2 Cl 2 (10 mL) containing a small amount of rac-57 (600 mg, 931 μmol) water (5%). After the suspension was stirred for 28 minutes at room temperature, HPLC analysis (90% MeOH; 1.5 mL / min; t R = 4.27 min) analysis showed the reaction was complete. The reaction mixture was evaporated under reduced pressure to be purified by preparative HPLC (90% MeOH; 40 mL / min; t R = 20.00 min) to give solid rac-58 (232 mg, 48%). Mp .: 126.7 ° C. (in methanol). rac-3,4,5,6-tetra-O-benzyl-1-O-butyryl-2-deoxy-myo-inositol (rac-59) A solution of rac-58 (186 mg, 355 μmol), butyric anhydride (70 μl, 426 μmol) and DMAP (12 mg, 10 μmol) of dry pyrimidine (5 mL) was stirred at room temperature for 18 hours. The solvent was evaporated to give an oil at high vacuum. Residual pyridine was removed by distillation three times with octane. The residue was dissolved in tert-butyl-methyl ether (30 mL), phosphate buffer (20 mL), sodium bicarbonate (20 mL), sodium hydrogen sulfate (20 mL), again phosphate buffer (20 mL) and saline ( 20 ml). The organic layer was dried over Na 2 SO 4 and filtered. Evaporation of the solvent gave pure rac-59 (196 mg, 94%) as a solid. Mp .: 110.1-110.3 ° C. (from methanol). rac-1-O-butyryl-2-deoxy-myo-inositol (rac-60) Compound rac-59 (177 mg, 297 μmol) was hydrogenated from hydrogen to palladium of carbon (10%) as described in the standard process to give solid tetrol rac-60 (68 mg, 98%) after lyophilization. It became. Mp: 174.9-175.9 ° C. (from ethanol). rac-1-O-butyryl-2-deoxy-myo-inositol 3,4,5,6-tetrakis (dibenzyl) phosphate (rac-61) A solution of acetonitrile (2 mL) of tetrol rac-60 (44 mg, 190 μmol) and tetrazole (160 mg, 2.28 mmol) was dibenzyl N, N-diisopropylpolyphosphoramidite ( 767 μl, 2.28 mmol) and oxidized with peracetic acid to work as described. Purification by preparative HPLC (92% MeOH; 40 mL / min; t R = 21.55 min) gave oily compound rac-61 (172 mg, 71%). rac-1-O-butyryl-2-deoxy-myo-inositol 3,4,5,6-tetrakisphosphate (rac-62) Compound rac-61 (165 mg, 130 μmol) was hydrogenated with palladium of carbon (10%) as described in the standard procedure to give the title compound rac-62 (65 mg, 90%) as a solid after lyophilization. rac-1-O-butyryl-2-deoxy-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester (rac-51) DIEA (201 μl, 1.19 mmol) and acetoxymethyl bromide (119 μl, 1.19 mmol) were added to a suspension of acetonitrile (2 mL) of compound rac-62 (37 mg, 66 μmol) as described in the standard procedure. I was. Purification by preparative HPLC (69% MeOH; 40.00 mL / min; t R = 12.10 min) gave compound rac-51 (31 mg, 50%) on syrup. rac-2-deoxy-myo-inositol 3,4,5,6-tetrakisphosphate (rac-53) Compound 62 was treated with 1M KOH (260 μl) to adjust the pH to 12.8. The solution was stirred for 2 days at room temperature. The reaction mixture was provided to a direct ion exchange column (Dowex 50 WX8, H + ) for purification. Lyophilization gave compound rac-53. rac-1-O-benzyl-6-O-butyryl-2,3,4,5-di-O-Cyclohexylidene-myo-inositol (rac-100) rac-1-O-benzyl-2,3,4,5-di-O-cyclohexylidene-myo-inositol (200 mg, 465 μmol), butyric anhydride (144 μl, 571 μmol) and DMAP (6 mg, 50 μmol) of dry pyrimidine (3 mL) was stirred at room temperature for 36 hours. The solvent was evaporated under high vacuum to give an oil. Residual pyridine was removed by distillation three times with octane. The residue was dissolved in tert-butyl-methyl ether (40 mL), phosphate buffer (20 mL), sodium hydride carbonate (20 mL), sodium hydrogen sulfate (20 mL), again phosphate buffer (20 mL) and Washed with brine (20 mL). The organic layer was dried over Na 2 SO 4 and filtered. Evaporation of the solvent gave pure rac-100 (186 mg, 80%) in oil. rac-1-O-benzyl-6-O-butyryl-myo-inositol (rac-101) A solution of rac-100 (186 mg, 372 μmol) CH 3 CN / H 2 O (100: 1, 8 mL) was stirred with trifluoroacetic acid (4 mL) at rt for 2 h. The solvent was evaporated in high vacuum to afford the title compound rac-101 (125 mg, 98%) in oil. rac-1-O-benzyl-6-O-butyryl-myo-inositol 2,3,4,5-tetrakis (dibenzyl) phosphate (rac-102) A solution of acetonitrile (3 mL) of compound rac-101 (145 mg, 426 μmol) and tetrazole (358 mg, 5.11 mmol) was dibenzyl N, N-diisopropylpolyphosphoramidite ( 1.72 mL, 5.11 mmol) and oxidized with peracetic acid to work as described. Purification by preparative HPLC (94% MeOH; 40 mL / min; t R = 22.40 min) gave oily compound rac-102 (297 mg, 50%). Rac-6-O-butyryl-myo-inositol 2,3,4,5-tetrakisphosphate (rac-103) Compound rac-102 (290 mg, 210 μmol) was hydrogenated with palladium of carbon (10%) to lyophilize to give the title compound rac-103 (119 mg, 99%) as a solid. rac-1-O- [1,2-dipalmitoyl-sn-glycerol] -6-O-butyryl-myo-inositol 3,4,5-trisphosphate hexakis (acetoxymethyl) ester (rac-104) DIEA (190 μl, 1.12 mmol) and acetoxymethyl bromide (126 μl, 1.26 mmol) were added to a suspension of dry acetonitrile (1.5 mL) of compound rac-103 (40 mg, 70 μmol). The mixture was stirred for 3 h in the dark at room temperature, then 1,2-dipalmitoyl-sn-glycerol (20 mg, 35 μmol) was added and the solution stirred for 4 days in 4 ° C. dark. The solvent was evaporated under reduced pressure and the crude residue was extracted with toluene to give the title compound rac-104 on syrup. rac-1-O- [1,2-dioctanoyl-sn-glycerol] -6-O-butyryl-myo-inositol 3,4,5-trisphosphate hexakis (acetoxymethyl) ester (rac-105) DIEA (136 μl, 800 μmol) and acetoxymethyl bromide (90 μl, 900 μmol) were added to a suspension of dry acetonitrile (1.5 mL) of compound rac-103 (28 mg, 50 μmol). The mixture was stirred for 3 h at room temperature in the dark, then 1,2-dipalmitoyl-sn-glycerol (23 mg, 70 μmol) was added and the solution stirred for 4 days in 4 ° C. dark. The solvent was evaporated under reduced pressure and the crude residue was extracted with toluene to give the title compound rac-105 on syrup. Materials-All reaction reagents were chosen to be of the highest purity. If necessary, the solvent was dried and / or distilled before use. Acetonitrile was distilled from phosphorus (V) oxide, such as dimethylformamide (DMF), and stored in 3 μg of particulate matter. Pyridine and toluene were stored at 4 μg particle size. Ethyl-diisopropylamine (DIEA) was dried over sodium wire. Palladium and trifluoroacetic acid in charcoal are from Acros chemie. Dibenzyl N, N-diisopropylphosphoramidite, peracetic acid (32% v / w), tetrazole and acetoxymethyl bromide are from Aldrich. Butyric anhydride, DIEA, is a product of Merck. Benzyl bromide cesium fluoride and 4-dimethylamino pyridine (DMAP) are from Fluka. All other reagents are from Riedel-de Haёn. rac-3,4-di-O-benzyl-1,2-cyclohexylidene-myo-inositol (1) was synthesized in three steps from myo-inositol as previously described (referenced herein by reference) Angyal et al., J. Chem. Soc. 4116 (1961); Jiang and Baker Carbohydr. Chem. 5: 615 (1986)). All compounds are racemic. 3,4-di-O-benzyl-5,6-di-O-butyryl-1,2-cyclohexylidene-myo-inositol (152) A solution of 151 (130 mg, 295 μmol), butyric anhydride (193 μl, 1.18 mmol) and DMAP (40 mg, 33 μmol) of dry pyrimidine (2 mL) was stirred at room temperature for 2 days. The solvent was evaporated at high vacuum to give an oil. Residual pyridine was removed by distillation three times with octane. The residue was dissolved in tert-butyl-methyl ether (10 mL), phosphate buffer (10 mL), sodium hydrogen carbonate (10 mL), sodium hydrogen sulfate (10 mL), again phosphate buffer (10 mL) and Washed with brine (10 mL). The organic layer was dried over Na 2 SO 4 and filtered. Evaporation of the solvent gave pure 152 (171 mg, 98%) in oil phase. 3,4-di-O-benzyl-5,6-di-O-butyryl-myo-inositol (153) A solution of 152 (166 mg, 286 μmol) CH 3 CN / H 2 O (100: 1, 5 mL) was stirred with trifluoroacetic acid (2 mL) at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure and the product extracted with tert-butyl methyl ether. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered and evaporated to give 153 (140 mg, 99%) in oily form. 1,3,4-tri-O-benzyl-5,6-di-O-butyryl-myoInositol (154) Dry 153 (143 mg, 286 μmol) and dry dibutyltin oxide (71 mg, 300 μmol) were heated by refluxing with dry toluene (100 mL) in a soxhlet apparatus with activated particulate (3x) for 4 hours. . The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. CsF (92 mg, 572 μmol) was added to the residual oil and the mixture was maintained under high vacuum for 2 hours. The residual syrup was dissolved in dry DMF (5 mL) under argon atmosphere and benzyl bromide (270 μl, 2.28 mmol) was added. After stirring the solution for 18 hours, HPLC analysis (Merck Hibar steel tube (250 mm × 4 mm) filled with RP 18 material (Merck, Lichrosrb; 10 μm) analysis (95% MeOH; 1.5 mL / min; t R = 3.20 Min) showed no further reaction, excess benzyl bromide and DMF were removed under high vacuum The crude product was a Merck Prepbarr steel tube (250) filled with preparative HPLC (RP 18 material (Merck, LiChrospher; 10 μm) Mm x 50 mm) (88% MeOH; 40 mL / min; t R = 17.20 min) to give solid compound 154 (448 mg, 75%). 1,3,4-Tri-O-benzyl-2,5,6-tri-O-butyryl-myo-inositol (155) A solution of 154 (98 mg, 166 μmol), butyric anhydride (68 μl, 415 μmol) and DMAP (5 mg, 4 μmol) of dry pyrimidine (2 mL) was stirred at room temperature for 2 hours. The same working method as for compound 2 gave 155 (106 mg, 99%) in pure oil. 2,5,6-Tri-O-butyryl-myo-inositol (156) 155 (105 mg, 159 μmol) was dissolved in acetic acid (3 mL) and then palladium (10%) in charcoal (80 mg, 795 μmol) was added. After stirring the solution for 6 hours at room temperature under hydrogen atmosphere, the catalyst was removed by ultrafiltration and the filtrate was lyophilized to give the title compound 156 (53 mg, 86%). M p : 113.4-114.4 ° C. (from MeOH) 2,5,6-Tri-O-butyryl-myo-inositol 1,3,4-tris (dibenzyl) phosphate (157) A solution of tritol 156 (48 mg, 123 μmol) and tetrazole (104 mg, 1.48 mmol) of acetonitrile (2 mL) was dibenzyl N, N-diisopropylpolyphosphoramidite (500 Μl, 1.48 mmol), cooled to −40 ° C. and oxidized with peracetic acid (32% v / w, 340 μl, 1.48 mmol) under vigorous stirring (Yu and Fraiser-Reid, incorporated herein by reference). Tetrahedron Lett. 29: 979 (1988)). The mixture was heated to room temperature. The solvent was removed under reduced pressure and the residual oil was purified by preparative HPLC (92% MeOH; 40 mL / min; t R = 17.50 min) to give compound 157 (104 mg, 72%) in oily form. 2,5,6-Tri-O-butyryl-myo-inositol 1,3,4-trisphosphate (158) Free acid 157 (100 mg, 85 μmol) was hydrogenated as described above to give the title compound 158 (47 mg, 88%) after lyophilization. 2,5,6-Tri-O-butyryl-myo-inositol 1,3,4-triphosphate hexakis (acetoxymethyl) ester (159) DIEA (209 μl, 1.23 mmol) and acetoxymethyl bromide (123 μl, 1.23 mmol) were added to a suspension of acetonitrile (2 mL) of compound 158 (39 mg, 61 μmol). The mixture was stirred for 4 days in the dark at room temperature, then all volatile components were evaporated under reduced pressure and the crude residue was purified by preparative HPLC (73% MeOH; 40 mL / min; t R = 20.25 min) to give syrup-like compound. 159 (44 mg, 67%) was provided. Although the present invention has been described with reference to the embodiments provided above, it will be appreciated that various modifications may be made without departing from the spirit of the invention. Accordingly, the invention will be limited only by the claims.
权利要求:
Claims (157) [1" claim-type="Currently amended] A cell permeable antagonist of inositol polyphosphate comprising an alkyl or alkylidene derivative of myo-inositol 3,4,5,6-tetrakisphosphate or a mimic of said derivative. [2" claim-type="Currently amended] The method of claim 1, A cell permeable antagonist, wherein said derivative is an alkyl derivative selected from the group consisting of 1-O-alkyl, 2-O-alkyl and 1,2-di-O-alkyl derivatives. [3" claim-type="Currently amended] The method of claim 2, A cell permeable antagonist wherein said alkyl is independently butyl. [4" claim-type="Currently amended] The method of claim 2, A cell permeable antagonist wherein said derivative is 1,2-di-O-alkyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [5" claim-type="Currently amended] The method of claim 4, wherein A cell permeable antagonist wherein said alkyl is independently butyl. [6" claim-type="Currently amended] The method of claim 5, And the derivative is 1,2-di-O-butyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [7" claim-type="Currently amended] The method of claim 2, A cell permeable antagonist wherein said derivative is 2-O-acyl-1-O-alkyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [8" claim-type="Currently amended] The method of claim 7, wherein The cell permeable antagonist, wherein the acyl is butyryl. [9" claim-type="Currently amended] The method of claim 7, wherein Wherein said alkyl is independently butyl. [10" claim-type="Currently amended] The method of claim 9, The permeable antagonist, wherein the derivative is 1-O-butyl-2-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [11" claim-type="Currently amended] The method of claim 2, A cell permeable antagonist, wherein the derivative is 2-O-alkyl-1-O-acyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [12" claim-type="Currently amended] The method of claim 11, A cell permeable antagonist, wherein said derivative is 2-O-alkyl-1-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [13" claim-type="Currently amended] The method of claim 12, A cell permeable antagonist wherein said alkyl is independently butyl. [14" claim-type="Currently amended] The method of claim 1, The cell permeable antagonist, wherein the derivative is 1,2-di-O-alkylidene derivative. [15" claim-type="Currently amended] The method of claim 14, A cell permeable antagonist, wherein said derivative is D, L-1,2-di-O-cyclohexylidene-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [16" claim-type="Currently amended] A cell permeable antagonist that is phosphatidylinositol 3,4,5-trisphosphate other than 1,2-di-O-butyryl-myo-inositol 1,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [17" claim-type="Currently amended] A cell permeable antagonist of inositol polyphosphate, wherein the antagonist is an inositol polyphosphate derivative or mimic thereof, the method of promoting secretion of chlorine ions in a cell. [18" claim-type="Currently amended] The method of claim 17, And said inositol polyphosphate promotes secretion of chlorine ions, which is myo-inositol 3,4,5,6-tetrakisphosphate. [19" claim-type="Currently amended] The method of claim 18, Wherein said cell permeable antagonist promotes the secretion of chlorine ions that are derivatives of myo-inositol 3,4,5,6-tetrakisphosphate. [20" claim-type="Currently amended] The method of claim 19, A method for promoting the secretion of chlorine ions wherein said derivative is an alkyl derivative selected from the group consisting of 1-O-alkyl, 2-O-alkyl and 1,2-di-O-alkyl derivatives. [21" claim-type="Currently amended] The method of claim 20, A method for promoting the secretion of chlorine ions wherein said alkyl is independently methyl or butyl. [22" claim-type="Currently amended] The method of claim 20, And said alkyl derivative is 1,2-di-O-alkyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [23" claim-type="Currently amended] The method of claim 22, A method for promoting the secretion of chlorine ions wherein said alkyl is independently methyl or butyl. [24" claim-type="Currently amended] The method of claim 23, wherein And said alkyl derivative is 1,2-di-O-butyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [25" claim-type="Currently amended] The method of claim 20, And said alkyl derivative is 2-O-acyl-1-O-alkyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [26" claim-type="Currently amended] The method of claim 25, A method for promoting the secretion of chlorine ions wherein the acyl is butyryl. [27" claim-type="Currently amended] The method of claim 25, A method for promoting the secretion of chlorine ions wherein said alkyl is independently methyl or butyl. [28" claim-type="Currently amended] The method of claim 27, And said alkyl derivative is 2-O-butyryl-1-O-methyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [29" claim-type="Currently amended] The method of claim 27, A method for promoting the secretion of chlorine ions wherein the alkyl derivative is 1-O-butyl-2-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [30" claim-type="Currently amended] The method of claim 20, And said alkyl derivative is 2-O-alkyl-1-O-acyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [31" claim-type="Currently amended] The method of claim 30, And said alkyl derivative is 2-O-alkyl-1-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [32" claim-type="Currently amended] The method of claim 31, wherein A method for promoting the secretion of chlorine ions wherein said alkyl is independently methyl or butyl. [33" claim-type="Currently amended] The method of claim 19, A method for promoting the secretion of chlorine ions wherein the derivative is a 1,2-di-O-alkylidene derivative. [34" claim-type="Currently amended] The method of claim 33, wherein Secretion of chlorine ions wherein the alkylidene derivative is D, L-1,2-di-O-cyclohexylidene-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester How to promote. [35" claim-type="Currently amended] The method of claim 17, And said inositol polyphosphate promotes secretion of chlorine ions wherein said phosphatidylinositol 3,4,5-trisphosphate. [36" claim-type="Currently amended] 36. The method of claim 35 wherein And said cell permeable antagonist promotes the secretion of chlorine ions which are derivatives of myo-inositol 1,4,5,6-tetrakisphosphate. [37" claim-type="Currently amended] The method of claim 36, A method for promoting the secretion of chlorine ions wherein the derivative is 1,2-di-O-acyl-myo-inositol 1,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [38" claim-type="Currently amended] The method of claim 37, A method for promoting the secretion of chlorine ions wherein the derivative is 1,2-di-O-butyryl-myo-inositol 1,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [39" claim-type="Currently amended] A method of promoting secretion of chlorine ions in a subject comprising administering to the subject a cell permeable antagonist of inositol polyphosphate, wherein the antagonist is an inositol polyphosphate derivative or mimic thereof. [40" claim-type="Currently amended] The method of claim 39, And said inositol polyphosphate promotes secretion of chlorine ions, which is myo-inositol 3,4,5,6-tetrakisphosphate. [41" claim-type="Currently amended] The method of claim 40, Wherein said cell permeable antagonist promotes the secretion of chlorine ions that are derivatives of myo-inositol 3,4,5,6-tetrakisphosphate. [42" claim-type="Currently amended] The method of claim 41, wherein Wherein said derivative promotes secretion of chlorine ions selected from the group consisting of 1-O-alkyl, 2-O-alkyl, and 1,2-di-O-alkyl derivatives. [43" claim-type="Currently amended] The method of claim 42, wherein A method for promoting the secretion of chlorine ions wherein said alkyl is independently methyl or butyl. [44" claim-type="Currently amended] The method of claim 42, wherein And said alkyl derivative is 1,2-di-O-alkyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [45" claim-type="Currently amended] The method of claim 44, A method for promoting the secretion of chlorine ions wherein said alkyl is independently methyl or butyl. [46" claim-type="Currently amended] The method of claim 45, And said alkyl derivative is 1,2-di-O-butyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [47" claim-type="Currently amended] The method of claim 42, wherein And said alkyl derivative is 2-O-acyl-1-O-alkyl-myo-inositol (3,4,5,6) tetrakisphosphate octakis (acetoxymethyl) ester. [48" claim-type="Currently amended] The method of claim 47, A method for promoting the secretion of chlorine ions wherein the acyl is butyryl. [49" claim-type="Currently amended] The method of claim 47, A method for promoting the secretion of chlorine ions wherein said alkyl is independently methyl or butyl. [50" claim-type="Currently amended] The method of claim 49, And said alkyl derivative is 2-O-butyryl-1-O-methyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [51" claim-type="Currently amended] The method of claim 49, A method for promoting the secretion of chlorine ions wherein the alkyl derivative is 1-O-butyl-2-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [52" claim-type="Currently amended] The method of claim 42, wherein And said alkyl derivative is 2-O-alkyl-1-O-acyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [53" claim-type="Currently amended] The method of claim 52, wherein And said alkyl derivative is 2-O-alkyl-1-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [54" claim-type="Currently amended] The method of claim 53, A method for promoting the secretion of chlorine ions wherein said alkyl is independently methyl or butyl. [55" claim-type="Currently amended] The method of claim 41, wherein A method for promoting the secretion of chlorine ions wherein the derivative is a 1,2-di-O-alkylidene derivative. [56" claim-type="Currently amended] The method of claim 55, Secretion of chlorine ions wherein the alkylidene derivative is D, L-1,2-di-O-cyclohexylidene-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester How to promote. [57" claim-type="Currently amended] The method of claim 39, And said inositol polyphosphate promotes secretion of chlorine ions wherein said phosphatidylinositol 3,4,5-trisphosphate. [58" claim-type="Currently amended] The method of claim 57, And said cell permeable antagonist promotes the secretion of chlorine ions which are derivatives of myo-inositol 1,4,5,6-tetrakisphosphate. [59" claim-type="Currently amended] The method of claim 58, A method for promoting the secretion of chlorine ions wherein the derivative is 1,2-di-O-acyl-myo-inositol 1,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [60" claim-type="Currently amended] The method of claim 59, A method for promoting the secretion of chlorine ions wherein the derivative is 1,2-di-O-butyryl-myo-inositol 1,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [61" claim-type="Currently amended] A cell permeable antagonist of inositol polyphosphate, wherein the antagonist is an inositol polyphosphate derivative or mimetic thereof, the method of alleviating the signs or symptoms associated with cystic fibrosis in a subject. [62" claim-type="Currently amended] 62. The method of claim 61, A method of alleviating the signs or symptoms associated with cystic fibrosis wherein the signs or symptoms are dysfunction of the lung. [63" claim-type="Currently amended] 62. The method of claim 61, A method for alleviating the signs or symptoms associated with cystic fibrosis, wherein said administration is via inhalation. [64" claim-type="Currently amended] 62. The method of claim 61, A method for alleviating signs or symptoms associated with cystic fibrosis, wherein said signs or symptoms are selected from the group consisting of intestinal dysfunction and pancreatic insufficiency. [65" claim-type="Currently amended] 62. The method of claim 61, A method of alleviating signs or symptoms associated with cystic fibrosis wherein said inositol polyphosphate is myo-inositol 3,4,5,6-tetrakisphosphate. [66" claim-type="Currently amended] 66. The method of claim 65, A method of alleviating signs or symptoms associated with cystic fibrosis wherein said cell permeable antagonist is a derivative of myo-inositol 3,4,5,6-tetrakisphosphate. [67" claim-type="Currently amended] The method of claim 66, A method for alleviating signs or symptoms associated with cystic fibrosis, wherein said derivative is selected from the group consisting of 1-O-alkyl, 2-O-alkyl and 1,2-di-O-alkyl derivatives. [68" claim-type="Currently amended] The method of claim 67, A method for alleviating the signs or symptoms associated with cystic fibrosis wherein said alkyl is independently methyl or butyl. [69" claim-type="Currently amended] The method of claim 67, A method for alleviating signs or symptoms associated with cystic fibrosis wherein said alkyl derivative is 1,2-di-O-alkyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [70" claim-type="Currently amended] The method of claim 69, wherein A method for alleviating the signs or symptoms associated with cystic fibrosis wherein said alkyl is independently methyl or butyl. [71" claim-type="Currently amended] The method of claim 70, A method of alleviating signs or symptoms associated with cystic fibrosis wherein said alkyl derivative is 1,2-di-O-butyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [72" claim-type="Currently amended] The method of claim 67, Alleviates signs or symptoms associated with cystic fibrosis, wherein the alkyl derivative is 2-O-acyl-1-O-alkyl-myo-inositol (3,4,5,6) tetrakisphosphate octakis (acetoxymethyl) ester How to. [73" claim-type="Currently amended] The method of claim 72, A method for alleviating the signs or symptoms associated with cystic fibrosis wherein said acyl is butyryl. [74" claim-type="Currently amended] The method of claim 72, A method for alleviating the signs or symptoms associated with cystic fibrosis wherein said alkyl is independently methyl or butyl. [75" claim-type="Currently amended] The method of claim 74, wherein Alleviating signs or symptoms associated with cystic fibrosis, wherein said alkyl is 2-O-butyryl-1-O-methyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester Way. [76" claim-type="Currently amended] The method of claim 74, wherein Alleviates signs or symptoms associated with cystic fibrosis, wherein the alkyl derivative is 1-O-butyl-2-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester How to. [77" claim-type="Currently amended] The method of claim 67, Alleviating signs or symptoms associated with cystic fibrosis, wherein the alkyl derivative is 2-O-alkyl-1-O-acyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester Way. [78" claim-type="Currently amended] 78. The method of claim 77 wherein Signs or symptoms associated with cystic fibrosis wherein the alkyl derivative is 2-O-alkyl-1-O-butyryl-myo-inositol (3,4,5,6) tetrakisphosphate octakis (acetoxymethyl) ester How to mitigate. [79" claim-type="Currently amended] The method of claim 78, A method for alleviating the signs or symptoms associated with cystic fibrosis wherein said alkyl is independently methyl or butyl. [80" claim-type="Currently amended] The method of claim 66, A method of alleviating the signs or symptoms associated with cystic fibrosis wherein said derivative is a 1,2-di-O-alkylidene derivative. [81" claim-type="Currently amended] The method of claim 80, Signs associated with cystic fibrosis wherein the alkylidene derivative is D, L-1,2-di-cyclohexylidene-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester How to alleviate the symptoms. [82" claim-type="Currently amended] 62. The method of claim 61, And alleviating signs or symptoms associated with cystic fibrosis wherein said inositol polyphosphate is phosphatidylinositol 3,4,5-trisphosphate. [83" claim-type="Currently amended] 83. The method of claim 82, A method of alleviating signs or symptoms associated with cystic fibrosis wherein said cell permeable antagonist is a derivative of myo-inositol 3,4,5,6-tetrakisphosphate. [84" claim-type="Currently amended] 84. The method of claim 83, A method for alleviating signs or symptoms associated with cystic fibrosis wherein the derivative is 1,2-di-O-acyl-myo-inositol 1,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [85" claim-type="Currently amended] 85. The method of claim 84, A method for alleviating signs or symptoms associated with cystic fibrosis wherein the derivative is 1,2-di-O-butyryl-myo-inositol 1,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [86" claim-type="Currently amended] A cell permeable agent of inositol polyphosphate comprising inositol polyphosphate derivatives or mimics thereof. [87" claim-type="Currently amended] 87. The method of claim 86, And said inositol polyphosphate is myo-inositol 3,4,5,6-tetrakisphosphate. [88" claim-type="Currently amended] 88. The method of claim 87 wherein The cell permeable agent is a derivative of myo-inositol 3,4,5,6-tetrakisphosphate. [89" claim-type="Currently amended] 89. The method of claim 88 wherein And the derivative is D, L-1-O-butyryl-2-O-deoxy-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [90" claim-type="Currently amended] 88. The method of claim 87 wherein The cell permeable agent is a derivative of myo-inositol 1,3,4-triphosphate. [91" claim-type="Currently amended] 91. The method of claim 90, And the derivative is D, L-2,5,6-tri-O-acyl-myo-inositol 1,3,4-triphosphate hexakis (acetoxymethyl) ester. [92" claim-type="Currently amended] 92. The method of claim 91, And the derivative is D, L-2,5,6-tri-O-butyryl-myo-inositol 1,3,4-triphosphate hexakis (acetoxymethyl) ester. [93" claim-type="Currently amended] 87. The method of claim 86, And said inositol polyphosphate is phosphatidylinositol 3,4,5-triphosphate. [94" claim-type="Currently amended] 94. The method of claim 93, The cell permeable agent is a derivative of phosphatidylinositol 3,4,5-trisphosphate. [95" claim-type="Currently amended] 95. The method of claim 94, And the derivative is di-palmitoyl-D, L-O-acyl-phosphatidylinositol 3,4,5-triphosphate heptakis (acetoxymethyl) ester. [96" claim-type="Currently amended] 97. The method of claim 95, And the derivative is sn-di-O-palmitoyl-D, L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester. [97" claim-type="Currently amended] 95. The method of claim 94, And the derivative is sn-di-O-octanoyl-D, L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester. [98" claim-type="Currently amended] 87. A method of inhibiting the secretion of goat ions from a cell comprising contacting the cell permeable agent of claim 86 with the cell. [99" claim-type="Currently amended] 99. The method of claim 98, And said inositol polyphosphate inhibits the secretion of chlorine ions, which is myo-inositol 3,4,5,6-tetrakisphosphate. [100" claim-type="Currently amended] The method of claim 99, wherein And wherein said cell permeable agent inhibits the secretion of chlorine ions that is a derivative of myo-inositol 3,4,5,6-tetrakisphosphate. [101" claim-type="Currently amended] 101. The method of claim 100, A method of inhibiting the secretion of chlorine ions wherein the derivative is 1,2-di-O-acyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [102" claim-type="Currently amended] 102. The method of claim 101, wherein A method of inhibiting the secretion of chlorine ions wherein the derivative is 1,2-di-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [103" claim-type="Currently amended] 102. The method of claim 101, wherein A method for inhibiting the secretion of chlorine ions, wherein the derivative is 1,2-di-O-butyryl-scyllo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [104" claim-type="Currently amended] 101. The method of claim 100, A method of inhibiting the secretion of chlorine ions wherein the derivative is D, L-1-O-butyryl-2-O-deoxy-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester . [105" claim-type="Currently amended] The method of claim 99, wherein And wherein said cell permeable agent inhibits the secretion of chlorine ions that are derivatives of myo-inositol 1,3,4-trisphosphate. [106" claim-type="Currently amended] 105. The method of claim 105, A method of inhibiting the secretion of chlorine ions, wherein the derivative is D, L-2,5,6-tri-O-acyl-myo-inositol 1,3,4-trisphosphate hexakis (acetoxymethyl) ester. [107" claim-type="Currently amended] 107. The method of claim 106, A method of inhibiting the secretion of chlorine ions wherein the derivative is D, L-2,5,6-tri-O-butyryl-myo-inositol 1,3,4-trisphosphate hexakis (acetoxymethyl) ester. [108" claim-type="Currently amended] 99. The method of claim 98, And said inositol polyphosphate inhibits the secretion of chlorine ions, which is phosphatidylinositol 3,4,5-trisphosphate. [109" claim-type="Currently amended] 109. The method of claim 108, And wherein said cell permeable agent inhibits the secretion of chlorine ions which are derivatives of phosphatidylinositol 3,4,5-trisphosphate. [110" claim-type="Currently amended] 109. The method of claim 109, The derivative is a di-palmitoyl-D, L-O-acyl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) esters to inhibit the secretion of chloride ions. [111" claim-type="Currently amended] 112. The method of claim 110, A method of inhibiting the secretion of chlorine ions, wherein the derivative is sn-di-O-palmitoyl-D, L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester . [112" claim-type="Currently amended] 109. The method of claim 109, A method of inhibiting the secretion of chlorine ions, wherein the derivative is sn-di-O-octanoyl-D, L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester . [113" claim-type="Currently amended] 87. A method of inhibiting the secretion of chloride ions in a subject comprising administering to the subject a cell permeable agent as defined in claim 86. [114" claim-type="Currently amended] 113. The method of claim 113, And said inositol polyphosphate inhibits the secretion of chlorine ions, which is myo-inositol 3,4,5,6-tetrakisphosphate. [115" claim-type="Currently amended] 119. The method of claim 114, wherein And wherein said cell permeable agent inhibits the secretion of chlorine ions that is a derivative of myo-inositol 3,4,5,6-tetrakisphosphate. [116" claim-type="Currently amended] 116. The method of claim 115, A method of inhibiting the secretion of chlorine ions wherein the derivative is 1,2-di-O-acyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [117" claim-type="Currently amended] 116. The method of claim 116 wherein A method of inhibiting the secretion of chlorine ions wherein the derivative is 1,2-di-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [118" claim-type="Currently amended] 116. The method of claim 116 wherein A method for inhibiting the secretion of chlorine ions, wherein the derivative is 1,2-di-O-butyryl-scyllo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [119" claim-type="Currently amended] 116. The method of claim 115, A method of inhibiting the secretion of chlorine ions wherein the derivative is D, L-1-O-butyryl-2-O-deoxy-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester . [120" claim-type="Currently amended] 119. The method of claim 114, wherein And wherein said cell permeable agent inhibits the secretion of chlorine ions that are derivatives of myo-inositol 1,3,4-trisphosphate. [121" claim-type="Currently amended] 121. The method of claim 120, A method of inhibiting the secretion of chlorine ions, wherein the derivative is D, L-2,5,6-tri-O-acyl-myo-inositol 1,3,4-trisphosphate hexakis (acetoxymethyl) ester. [122" claim-type="Currently amended] 124. The secretion of chlorine ions according to claim 121, wherein the derivative is D, L-2,5,6-tri-O-butyryl-myo-inositol 1,3,4-trisphosphate hexakis (acetoxymethyl) ester How to inhibit. [123" claim-type="Currently amended] 113. The method of claim 113, And said inositol polyphosphate inhibits the secretion of chlorine ions, which is phosphatidylinositol 3,4,5-trisphosphate. [124" claim-type="Currently amended] 123. The method of claim 123, wherein And wherein said cell permeable agent inhibits the secretion of chlorine ions which are derivatives of phosphatidylinositol 3,4,5-trisphosphate. [125" claim-type="Currently amended] 124. The method of claim 124 wherein The derivative is a di-palmitoyl-D, L-O-acyl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) esters to inhibit the secretion of chloride ions. [126" claim-type="Currently amended] 126. The method of claim 125, A method of inhibiting the secretion of chlorine ions, wherein the derivative is sn-di-O-palmitoyl-D, L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester . [127" claim-type="Currently amended] 124. The method of claim 124 wherein A method of inhibiting the secretion of chlorine ions, wherein the derivative is sn-di-O-octanoyl-D, L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester . [128" claim-type="Currently amended] 87. A method of alleviating signs or symptoms associated with secretory diarrhea in a subject comprising administering the cell permeable agent of claim 86 to the subject. [129" claim-type="Currently amended] 129. The method of claim 128, And alleviating signs or symptoms associated with secretory diarrhea wherein said inositol polyphosphate is myo-inositol 3,4,5,6-tetrakisphosphate. [130" claim-type="Currently amended] 129. The method of claim 129 wherein A method of alleviating signs or symptoms associated with secretory diarrhea wherein said cell permeable agent is a derivative of myo-inositol 3,4,5,6-tetrakisphosphate. [131" claim-type="Currently amended] 131. The method of claim 130, A method for alleviating signs or symptoms associated with secretory diarrhea wherein said derivative is 1,2-di-O-acyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [132" claim-type="Currently amended] 131. The method of claim 131 wherein A method for alleviating signs or symptoms associated with secretory diarrhea wherein said derivative is 1,2-di-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [133" claim-type="Currently amended] 131. The method of claim 131 wherein A method for alleviating signs or symptoms associated with secretory diarrhea wherein said derivative is 1,2-di-O-butyryl-scyllo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [134" claim-type="Currently amended] 131. The method of claim 130, Signs or symptoms associated with secretory diarrhea wherein the derivative is D, L-1-O-butyryl-2-O-deoxy-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester How to alleviate. [135" claim-type="Currently amended] 129. The method of claim 129 wherein A method for alleviating signs or symptoms associated with secretory diarrhea wherein the agent is a derivative of myo-inositol 1,3,4-trisphosphate. [136" claim-type="Currently amended] 137. The method of claim 135, Alleviate signs or symptoms associated with secretory diarrhea, wherein the derivative is D, L-2,5,6-tri-O-acyl-myo-inositol 1,3,4-trisphosphate hexakis (acetoxymethyl) ester Way. [137" claim-type="Currently amended] 138. The method of claim 136, Alleviates signs or symptoms associated with secretory diarrhea, wherein the derivative is D, L-2,5,6-tri-O-butyryl-myo-inositol 1,3,4-trisphosphate hexakis (acetoxymethyl) ester How to. [138" claim-type="Currently amended] 129. The method of claim 128, And alleviating signs or symptoms associated with secretory diarrhea wherein said inositol polyphosphate is phosphatidylinositol 3,4,5-trisphosphate. [139" claim-type="Currently amended] 138. The method of claim 138, wherein A method for alleviating signs or symptoms associated with secretory diarrhea wherein said cell permeable agent is a derivative of phosphatidylinositol 3,4,5-trisphosphate. [140" claim-type="Currently amended] 140. The method of claim 139, wherein A method for alleviating signs or symptoms associated with secretory diarrhea, wherein said derivative is di-palmitoyl-D, L-O-acyl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester. [141" claim-type="Currently amended] 141. The method of claim 140, Alleviates signs or symptoms associated with secretory diarrhea, wherein the derivative is sn-di-palmitoyl-D, L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester How to. [142" claim-type="Currently amended] 140. The method of claim 139, wherein Signs or symptoms associated with secretory diarrhea wherein the derivative is sn-di-O-octanoyl-D, L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester How to alleviate. [143" claim-type="Currently amended] 87. A method of alleviating the signs or symptoms associated with brain expansion in a subject comprising administering the cell permeable agent of claim 86 to the subject. [144" claim-type="Currently amended] 143. The method of claim 143 wherein And said inositol polyphosphate is a myo-inositol 3,4,5,6-tetrakisphosphate. [145" claim-type="Currently amended] 145. The method of claim 144 wherein And said cell permeable agent is a derivative of myo-inositol 3,4,5,6-tetrakisphosphate. [146" claim-type="Currently amended] 145. The method of claim 145, And said derivative is 1,2-di-O-acyl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [147" claim-type="Currently amended] 146. The method of claim 146 wherein And said derivative is 1,2-di-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [148" claim-type="Currently amended] 146. The method of claim 146 wherein And the derivative is 1,2-di-O-butyryl-scyllo-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester. [149" claim-type="Currently amended] 145. The method of claim 145, Signs or symptoms associated with brain expansion, wherein the derivative is D, L-1-O-butyryl-2-O-deoxy-inositol 3,4,5,6-tetrakisphosphate octakis (acetoxymethyl) ester How to mitigate. [150" claim-type="Currently amended] 145. The method of claim 144 wherein And said cell permeable agent is a derivative of myo-inositol 1,3,4-trisphosphate. [151" claim-type="Currently amended] 151. The method of claim 150, A method for alleviating signs or symptoms associated with brain expansion, wherein the derivative is D, L-2,5,6-tri-O-acyl-myo-inositol 1,3,4-trisphosphate hexakis (acetoxymethyl) ester . [152" claim-type="Currently amended] 151. The method of claim 151, Alleviate signs or symptoms associated with brain expansion, wherein the derivative is D, L-2,5,6-tri-O-butyryl-myo-inositol 1,3,4-trisphosphate hexakis (acetoxymethyl) ester Way. [153" claim-type="Currently amended] 143. The method of claim 143 wherein And said inositol polyphosphate is a phosphatidylinositol 3,4,5-trisphosphate. [154" claim-type="Currently amended] 153. The method of claim 153, Said agent is a derivative of phosphatidylinositol 3,4,5-trisphosphate. [155" claim-type="Currently amended] 154. The method of claim 154, wherein And said derivative is di-palmitoyl-D, L-O-acyl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester. [156" claim-type="Currently amended] 162. The method of claim 155, wherein Signs or symptoms associated with brain expansion, wherein the derivative is sn-di-O-palmitoyl-D, L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester How to mitigate. [157" claim-type="Currently amended] 154. The method of claim 154, wherein Signs or symptoms associated with brain expansion, wherein the derivative is sn-di-O-octanoyl-D, L-6-O-butyryl-phosphatidylinositol 3,4,5-trisphosphate heptakis (acetoxymethyl) ester How to mitigate.
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公开号 | 申请日 | 公开日 | 申请人 | 专利标题
法律状态:
1996-09-20|Priority to US71712296A 1996-09-20|Priority to US8/717,122 1997-09-10|Priority to US8/926,831 1997-09-19|Application filed by 린다 에스. 스티븐슨, 더 리전트 오브 더 유니버시티 오브 캘리포니아 2000-07-25|Publication of KR20000048499A
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申请号 | 申请日 | 专利标题 US71712296A| true| 1996-09-20|1996-09-20| US8/717,122|1996-09-20| US8/926,831|1997-09-10| 相关专利
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