USE OF ALKYLATED IMINOSUGARS TO TREAT MULTIDRUG RESISTANCE

Abstract: The present invention relates to the field of cancer chemotherapy. More particularly, the present invention relates to a compound for improving the effectiveness of cancer chemotherapy by preventing, reducing, or reversing the development of cellular resistance to chemotherapeutic agents, i.e., the phenomenon known as "multidrug resistance" (MDR), during the course of therapy. This is achieved by administering to patients N-alkyl-1,5-dideoxy-1,5-imino-D-glucitol or galactitol compounds ("iminosugars") in conjunction with chemotherapeutic drugs.

Description: USE OF ALKYLATED IMINOSUGARS TO TREAT MULΗDRUG RESISTANCE BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to the field of cancer chemotherapy. More particularly, the present invention relates to a compound for improving the effectiveness of cancer chemotherapy by preventing, reducing, or reversing the development of cellular resistance to chemotherapeutic agents, i.e., the phenomenon known as "multidruq resistance" (MDR) , during the course of therapy. This is achieved by administering to patients N- alkyl-1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol compounds ("iminosugars") in conjunction with chemotherapeutic drugs. Description of Related Art Multidruq Resistance (MDR) Multidrug resistance, the phenomenon whereby primary exposure of tumor cells to a single chemotherapeutic drug results in cellular resistance to multiple drugs, is believed to be the basis for tumor cell survival (Bradley et al. (1988) Biochim. Biophys . Acta 948:87-128). MDR is manifested as a simultaneously acquired cellular resistance to several cytotoxic substances, which can be surprisingly structurally and functionally unrelated, and is often observed after prolonged exposure of cells to anticancer drugs of the "multidrug resistance group." The latter includes such different compounds as actinomycin D, itomycin C, anthracyclines, colchicine, rhodamine, ethidium bromide, doxorubicin, epipodophyllotoxins, paclitaxel, taxol, reserpine, and the vinca alkaloids. Exposure of cells to one of these drugs can lead not only to specific resistance to this drug, but also to non-specific cross-resistance to all the other drugs of the MDR group. Study of this phenomenon has focused on a number of different possible biological mechanisms. Volm et al . ((1993) Cancer 71:2981-2987) and Bradley et al . ((1994) Cancer Metastasis Rev. 13:223-233) have investigated the overexpression of P-gp, a plasma membrane glycoprotein believed to rapidly efflux MDR-type drugs, thus protecting cells from damage by preventing these drugs from reaching their intracellular targets. Doige et al . ((1993) Biochim . Biophys . Acta 1146:65-72) and Wadkins et al. ((1993) Biochim. Biophys . Acta 1153 :225-236) have studied the role of lipids in MDR. While differences in the glycerolipid and sphingomyelin compositions of MDR and drug-sensitive cells have been observed (Holleran et al. (1986) Cancer Chemother. Pharmacol . 17:11-15; Ra u et al. (1984) Cancer Treat . Rep . 68:637-641; May et al. (1988) Int . J. Cancer 42:728-733 ; Welsh et al . (1994) Arch. Biochem. Biophys . 315:41-47; Wright et al . (1985) Biochem . Biophys . Res . Commun . 133:539-545), and the ganglioside composition of MDR and drug-sensitive cells has been investigated, no clear picture as to the basis of drug resistance emerged from these studies. More recently, Lavie et al . ((1996) J. Biol . Chem . 271:19530-10536) demonstrated a correlation between the cellular content of glycosphingolipids and MDR. These workers demonstrated that tamoxifen, verapamil, and cyclosporin A, agents that reverse multidrug resistance, as well as l-phenyl-2-palmitoylamino-3-morpholino-l-propanol, an inhibitor of glucosylceramide synthesis, decrease glucosylceramide levels in an MDR human breast cancer cell line that accumulates high levels of glucosylceramide compared with the parental wild-type, drug-sensitive cell line (Lavie et al . (1997) J " . Biol . Chem. 272:1682-1687). They concluded that high cellular levels of glucosylceramide are correlated with MDR, and that glycolipids are therefore a target for the action of MDR- reversing agents . 1, 5-dideoxy-l, 5-imino-D-qlucitol and galactitol Compounds l,5-dideoxy-l,5-imino-D-glucitol (also known as 1-deoxynojirimycin, DNJ) and its JV-alkyl derivatives are known inhibitors of the N-linked oligosaccharide processing enzymes α-glucosidase I and II (Saunier et al., J. Biol . Chem . (1982) 257:14155-14161 (1982); Elbein, Ann . Rev. Biochem . (1987) 56:497-534). As glucose analogs, they were also predicted to have the potential to inhibit glucose transport, glucosyltransferases, and/or glycolipid synthesis (Newbrun et al . , Arch . Oral Biol . (1983) 28: 516- 536; Wang et al . , Tetrahedron Lett. (1993) 34:403-406). Their inhibitory activity against glucosidases has led to the development of these compounds as anti-hyperglycemic agents and antiviral agents. See, for example, PCT International Publication WO 87/03903 and U.S. Patents 4,065,562; 4,182,767; 4,533,668; 4,639,436; 4,849,430; 4,957,926; 5,011,829; and 5,030,638. J7-butyl DNJ is an inhibitor of HIV replication in vi tro (Fleet et al . (1988) FEBS Lett . 237:128-132; Karpas et al . (1988) Proc . Natl . Acad. Sci . USA 85:9229-9233). This compound has been clinically evaluated as a potential AIDS therapeutic (Jacob et al. (1992) in .Natural Products as Antiviral Agents , C. K. Chu et al., Eds., pp. 137-152, Plenum Publishing Co., N.Y.) , and has been found to exhibit little cytotoxicity in vi tro (Platt et al. (1992) Eur. J. Biochem. 208:187-193). Platt et al. ((1994) J. Biol . Chem. 269:8362- 8365) have demonstrated that certain W-alkylated derivatives of DNJ inhibit the glucosyltransferase- catalyzed biosynthesis of glucosylceramide, resulting in the inhibition of biosynthesis of all glucosylceramide- based glycosphingolipids . Glycolipids constitute an important class of glycoconjugates found in the membranes, and particularly the plasma membrane, of eukaryotic cells. These authors speculated that these JV-alkylated derivatives specifically inhibit UDP-glucose-N- acylsphingoεine glucosyltransferase (EC 2.4.1.80). This transferase generates glucosylceramde (GlcCer) , the precursor for the more complex glycosphingolipids and gangliosides. Platt et al . also demonstrated that 2V-butyl DNJ inhibited glycolipid expression at the cell surface. The authors suggested that N-alkylated DNJs would be useful in treating lysosomal glycolipid storage disorders such as Gaucher's disease. In a subsequent paper, Platt et al . showed that the galactose analogue of N-butyl DNJ, i.e., W-butyl- deoxygalactonojirimycin (N-butyl DGJ) , is a more selective inhibitor of glycolipid biosynthesis, only weakly inhibiting the N-linked oligosaccharide processing enzymes α-glucosidases I and II, and not inhibiting lysosomal β- glucocerebrosidase (which is required for the cleavage of GlcCer to glucose and ceramide) . N-butyl DGJ was shown to be comparable to N-butyl DNJ as an inhibitor of UDP- glucose-IV-acylsphingosine glucosyltransferase and in preventing lysosomal glycolipid storage in an in vitro model of Gaucher's disease. In 1997, Platt et al. { Science 276:428-431) reported the prevention of glycosphingolipid lysosomal storage in a mouse model of Tay-Sachs disease using J7-butyl DNJ. This disease is characterized by a deficiency in the A isoenzyme of β-hexosaminidase, which degrades G M2 ganglioside. A deficiency of this enzyme in humans results in accumulation of G M2 ganglioside in brain cell lysosomes, leading to severe neurological degeneration. The authors noted that this compound is water soluble and noncytotoxic over a broad range of concentrations in vitro and in vivo . Oral administration to healthy mice resulted in glycosphingolipid depletion in multiple organs without causing any overt pathological side effects. In Tay-Sachs mice, no toxicity to N-butyl DNJ was observed based on visible inspection and observation of the animals, and of organ weights at autopsy. While spleen and thymus tissues were 50% acellular, no immunocompromization was apparent. The authors concluded that in this in vivo mammalian model, oral treatment with N-butyl DNJ is well tolerated, and effectively inhibits glycosphingolipid biosynthesis and subsequent accumulation in brain cell lysosomes. Treatment of MDR Many chemosensitizers have been reported to antagonize MDR in in vi tro systems, and some have been shown to be effective in vivo when coadministered with appropriate chemotherapeutic agents to nude mice bearing multidrug-resistant tumors. Unfortunately, success in the laboratory has not necessarily translated to success in the clinic. Dose-limiting side effects of first-generation MDR modulators have been observed. Low therapeutic indices and failure to achieve therapeutic blood levels have also been problematic (Dalton et al. (1995) Cancer 75:815-20; Tsuro et al. (1981) Cancer Res . 41:1967-72; Ries et al. (1991) Med . Oncol . Tumor Pharmacother . 9:39-42; Chabner (1991) J. Clin . Oncol . 9:4-6; Raderer et al . (1993) Cancer 72:3553- 63; Mulder et al . (1996) J. Exp . Ther. Oncol . 1:19-28; Fischer et al . (1995) Hematol. Oncol . Clin . North Am . 9:363-82; Wishart et al . (1994) J. Clin . Oncol . 9:1771-77). In addition, patient dosing is sometimes complicated by pharmacokinetic drug interactions, resulting in increased plasma concentrations or decreased elimination of cytotoxic drugs, resulting in increased toxicity (Egorin et al . (1996) Proc . Am . Soc . Clin . Oncol . 15:473; Beketic- Oreskovic et al . (1995) J. Natl . Cancer Inst . 1593-602.88) . Most of the results from MDR-reversal trials have been disappointing, except for those for some hematological cancers (Chabner (1991) J. Clin . Oncol . 9:4-6; Raderer et al. (1993) Cancer 72:3553-63; Mulder et al . (1996) J. Exp . Ther. Oncol . 1:19-28; Fischer et al . (1995) tfeaiatol. Oncol . Clin . North Am. 9:363-82). Thus, a common, major obstacle to cure with chemotherapeutic agents is the survival and continued proliferation of cells that are resistant to further treatment . MDR is therefore a formidable impediment to successful chemotherapy. The art continues to seek agents that can be used to prevent or reduce this phenomenon during cancer chemotherapy. The use of N-substituted- imino-D-glucitol or galactitol derivatives in conjunction with chemotherapeutic agents for preventing or reducing the extent of MDR during chemotherapy has not, as far as the present inventor is aware, been previously disclosed or suggested. SUMMARY OF THE INVENTION In response to the need of the healing arts for agents that can be used to avoid the deleterious consequences of MDR during chemotherapy, the present inventor has surprisingly discovered that certain iminosugar glucosylceramide synthase inhibitors are effective for this purpose. These inhibitors can be used to prevent, reduce, or reverse MDR often observed during treatment of cancer patients with chemical anti-cancer agents. As noted above, first-generation MDR modulators exhibit a number of disadvantageous side effects . In addition, drugs such as Verapamil, tamoxifen, cyclosporin A, and l-phenyl-2-palmitoylamino-3-morpholino-l-propanol exhibit other, well known pharmacologic effects which may be undersirable in certain patients. In contrast, the iminosugars of the present invention possess beneficial advantages in treating MDR including, but not limited to, mechanistic specificity, lack of drug-drug interactions, and minimal or no effect on elimination of cytotoxic chemotherapeutic drugs. Accordingly, in one aspect, the present invention provides a compound for preventing, reducing, or reversing multidrug resistance in a patient undergoing treatment with a chemotherapeutic agent, comprising an anti- ultidrug resistance effective amount of an N- subs tituted- 1 , 5-dideoxy-l, 5-imino-D-glucitol or galactitol compound, or pharmaceutically acceptable salt thereof, of Formula I: wherein R is selected from arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C 2 to C 20 , and W, X, Y and Z are each independently selected from hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl, Preferred compounds are those wherein R is n-butyl or n- hexyl. The N- substituted- 1 , 5-dideoxy- 5 1, 5-imino-D-glucitol or galactitol compound, or combinations thereof, can be administered in accordance with a variety of different regimens, including prior to administration of the chemotherapeutic agent; both prior to 10 . and simultaneously with administration of the chemotherapeutic agent; prior to, simultaneously with, and subsequently to administration of the chemotherapeutic agent; simultaneously with administration of the chemotherapeutic agent; prior to and subsequently to 15 administration of the chemotherapeutic agent; or daily throughout the entire course of treatment with the chemotherapeutic agent . In the preferred method about 1,000 mg/day to about 3,000 mg/day of N- (n-butyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or 2.0. galactitol or N- (n-hexyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, or a pharmaceutically acceptable salt thereof, daily throughout the course of administration of a chemotherapeutic agent selected from an anthracycline, an alkaloid, an anti-microtubule drug, a topoisomerase II 5 inhibitor, and a DNA damaging agent. Administration of the JJ-alkylated iminosugar can commence about 14 days prior to administration of the chemothera-peutic agent. In another aspect, the present invention provides a pharmaceutical composition, comprising an anti-multidrug resistance effective amount of at least one .N-substituted- 1, 5 -dideoxy- 1, 5-imino-D-glucitol or galactitol compound as above, an anti-tumor effective amount of at least one anti- tumor chemotherapeutic compound, and a pharmaceutically acceptable carrier. Further scope of the applicability of the present invention will become apparent from the detailed description and drawings provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION The following detailed description is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variations in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery. The contents of each of the references cited herein, including the contents of the references cited within these primary references, are herein incorporated by reference in their entirety. The present inventor has discovered that N- substituted-l, 5-dideoxy-l, 5-imino-D-glucitol and galactitol compounds used in conjunction with antineoplastic chemotherapeutic agents are effective in preventing the development of, reducing the extent of, or reversing MDR in patients receiving chemotherapy. The present invention thus provides pharmaceutical compositions for preventing or reducing MDR in humans and other mammals being treated with chemical antitumor compounds by administering one or more Itf-substituted-l , 5-dideoxy-l, 5 -imino-D-glucitol or galactitol compounds to patients. The i inosugar and chemotherapeutic drugs of this invention can be provided to cells, tissues, or organs in vitro or in vivo, or to a human or other mammalian patient, including domestic animals such as cats and dogs, either in separate pharmaceutically acceptable formulations, formulations containing more than one therapeutic agent, or by an assortment of single agent and multiple agent formulations. However administered, these drug combinations form an anti- MDR effective and chemotherapeutically effective amount of components. Administration of the present iminosugar and chemotherapeutic drugs to cells, tissues, or organs in vi tro can be used as model experimental systems in which to investigate the phenomenon of MDR, with the goal of optimizing in vivo treatment therefor. As used herein, the term "anti-MDR effective amount" refers to an amount of an N-substituted- l , 5- dideoxy-1, 5-imino-D-glucitol or galactitol compound, or combination thereof, effective in preventing the development of, reducing the extent of, or reversing multidrug resistance often observed in tumor cells of patients being treated with antineoplastic agents. Such effective amount is medically beneficial, and does not cause toxic effects that outweigh the advantages associated with the use of these N-substituted-1, 5-dideoxy-1, 5-imino- D-glucitol or galactitol compounds in overcoming the adverse effects of MDR. The ultimate result is enhanced effectiveness of the chemotherapy. Also as used herein, the term "multidrug resistance group" refers to those antineoplastic agents to which tumor cells develop resistance after exposure thereof to an anticancer chemotherapeutic compound, i.e., to which such tumor cells develop multidrug resistance, whether this be specific resistance to this particular anticancer chemotherapeutic compound, or non-specific cross-resistance to other chemotherapeutic compounds which may or may not be structurally and functionally related. W-substituted-l,5-dideoxy-1.5-imino-D-qlucose and Galactose Compounds W-substituted-l,5-dideoxy-l,5-imino-D-glucitol or galactitol compounds useful in the present invention are represented by formula I : The glucitol and galactitol stereoisomers encompassed by formula I differ in the orientation of the hydroxyl group on C-4 of the ring. Employing the convention of Fleet et al. ((1992) Glycobiology 2 : 199-210) , the ring in formula I lies flat in the plane of the page. A group attached to the ring via a bond depicted with a series of dashed lines is oriented below the plane of the ring; a group attached to the ring via a bond depicted with a solid, elongated triangle is oriented above the plane of the ring. The group attached to the ring at C-4 via the bond depicted by the squiggly line is either below the plane of the ring (glucitol derivatives) or above the plane of the ring (galactitol derivatives) . In formula I, R is selected from arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C 2 to C 20 , preferably C 4 to C 20 , more preferably C 4 to C 14 , more preferably C 4 to C 10 , more preferably C 4 to C 8 , and most preferably C 4 to C 6 in the principal chain, n-butyl and n-hexyl are preferred. R can also be C_ to C 20 alkyl, preferably C 2 to C 14 , more preferably C 6 to C 12 , more preferably C 4 to C 10 alkyl, containing 1 to 5 , more preferably 1 to 3 , most preferably 1 to 2, oxygen atoms, i.e., oxa derivatives. Preferred R oxa derivatives are 3-oxanonyl, 3-oxadecyl, 7-oxanonyl, and 7-oxadecyl. W, X, Y and Z are independently selected from hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl . As used herein, the term "alkyl" as used in "arylalkyl" and "cycloalkylalkyl," either unsubstituted or containing the various substituents defined herein, can contain from one to about six carbon atoms in the principal chain, and up to about 15 carbon atoms total. Such alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, and the like. Substituents of the substituted alkyl groups described herein can include, for example, groups selected from alkyl, cycloaklyl, alkenyl, alkynyl, aryl, heteroaryl, 0, S, N, P, or halogen (Cl, F, Br, or I) atoms. Optionally, these substituent alkyl, cycloalkyi, etc., groups can be substituted with 0, S, N, P, or halogen (Cl, F, Br, or I) atoms. These substituent alkyl, cycloakyl, etc., groups include, for example, lower alkoxy groups such as methoxy, ethoxy, and butoxy, and groups such as halo, nitro, amino, and keto. The alkenyl groups described herein, either unsubstituted or with the various substituents defined herein, are preferably lower alkenyl groups containing from about two to about six carbon atoms in the principal chain, and up to about 15 carbon atoms total . They can be substituted, straight, or branched chain, and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. The alkynyl groups described herein, either unsubstituted or with the various substituents defined herein, are preferably lower alkynyl groups containing from about two to about six carbon atoms in the principal chain, and up to about 15 carbon atoms total . They can be substituted, straight or branched chain, and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. The aryl moieties described herein, either unsubstituted or with various substituents defined herein, can contain from about 6 to about 15 carbon atoms, and include phenyl and naphthyl. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is a preferred aryl . The cycloalkyi moieties described herein, either unsubstituted or with various substituents defined herein, can contain from about 5 to about 15 atoms, and include cyclobutylbutyl, cyclohexylhexyl, and the like. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, and amido . The alkanoyl groups, either unsubstituted or substituted with the various substituents defined hereinabove for "alkyl" groups, and the trifluoroalkanoyl groups described herein, can contain from one to about six carbon atoms in the principal chain, and up to about 15 carbon atoms total, and include acetyl, propanoyl, butanoyl, and the like. The aroyl groups described herein, either unsubstituted or with various substituents defined herein, can contain from about 6 to about 15 carbon atoms, and include benzoyl . Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Benzoyl is a preferred aroyl. The carbon atoms, i.e., the methyl and methylene groups, constituting the principal backbone of the branched or straight chain alkyl groups having a chain length of C 2 to C 20 can also be substituted as variously described above . Representative N-substituted-imino-D-glucitol and galactitol compounds useful in the present invention include, but are not limited to: N- (n-ethyl- ) -1, 5-dideoxy- 1, 5 -imino-D-glucitol or galactitol; N- (n-propyl- ) -1, 5-dideoxy- 1 , 5 -imino-D-glucitol or galactitol; N- (n-butyl- ) -l, 5-dideoxy-l, 5-imino-D-glucitol or galactitol; N- (n-hexyl- ) -1 , 5- dideoxy- 1 ,5-imino-D-glucitol or galactitol; N- (n-heptyl- ) -l , 5-dideoxy- l, 5 -imino-D-glucitol or galactitol; N- (n-octyl-) -1, 5- dideoxy- l , 5 -imino-D-glucitol or galactitol; N- (n-octyl-) -1, 5- dideoxy- 1 , 5 -imino-D-glucitol or galactitol, tetrabutyrate; N- (n-nonyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (n-decyl-) -1, 5- dideoxy- 1 , 5 - imino-D-glucitol or galactitol, tetrabutyrate; N- (n-undecyl-) -1, 5-dideoxy- 1, 5 -imino-D-glucitol or galactitol, tetrabutyrate; N- (n-nonyl- ) -1 , 5 -dideoxy- 1 ,5-imino-D-glucitol or galactitol; N- (n-decyl- ) -1 , 5- dideoxy- 1 , 5 -imino-D-glucitol or galactitol; N- (n-undecyl-) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol; N- (n-dodecyl-) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol; N- (2-ethylhexyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol; N- (4-ethylhexyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol; N- (5-methylhexyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol; N- (3-propylhexyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol; N- (l-pentylpentylhexyl) -1, 5-dideoxy-1,5-imino-D-glucitol or galactitol; N- (l-butylbutyl) -1, 5-dideoxy-1, 5 -imino-D-glucitol or galactitol; N- (7-methyloctyl-) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol; N- (8-methylnonyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol; N- (9-methyldecyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol; N- (10-methylundecyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol; N- (6-cyclohexylhexyl-) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol; N- (4-cyclohexylbutyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol; N- (2-cyclohexylethyl) -1, 5-dideoxy-l,5-imino-D-glucitol or galactitol; N- (1-cyclohexylmethyl) -l, 5-dideoxy-1, 5-imino-D-glucitol or galactitol; N- (1-phenylmethyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol; N- (3 -phenylpropyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol; N- (3- (4 -methyl) -phenylpropyl) -1, 5-dideoxy- 1, 5-imino-D- glucitol or galactitol; N- (6-phenylhexyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol; N- (n-nonyl- ) -1 , 5- dideoxy- 1 ,5-imino-D-glucitol or galactitol, tetrabutyrate; N- (n-decyl- ) -1 , 5-dideoxy-l , 5 - imino-D-glucitol or galactitol, tetrabutyrate; N- (n-undecyl- ) -1 , 5 -dideoxy- l, 5 -imino-D-glucitol or galactitol, tetrabutyrate; N- (n-dodecyl- ) -1, 5-dideoxy- 1, 5 -imino-D-glucitol or galactitol, tetrabutyrate; N- (2-ethylhexyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (4-ethylhexyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (5-methylhexyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (3-propylhexyl) -l, 5-dideoxy-1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (l-pentylpentylhexyl) -1,5-dideoxy-1,5-imino-D-glucitol or galactitol, tetrabutyrate; N- (1-butylbutyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (7-methyloctyl-) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (8-methylnonyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (9-methyldecyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (10-methylundecyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (6-cyclohexylhexyl-) -l, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (4-cyclohexylbutyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (2-cyclohexylethyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (l-cyclohexylmethyl) -l, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (1-phenylmethyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (3-phenylpropyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (3- (4-methyl) -phenylpropyl) -1, 5-dideoxy-l , 5-imino-D- glucitol or galactitol, tetrabutyrate; and N- (6-phenylhexyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate. Pharmaceutically acceptable salts of any of the glucitol or galactitol compounds encompassed herein can also be used in the methods of the present invention. Preferred compounds are N- (n-butyl-) -1,5-dideoxy- 1, 5-imino-D-glucitol or galactitol and N- (n-hexyl-) -1, 5- dideoxy-1, 5-imino-D-glucitol or galactitol. The N-substituted-imino-D glucitol compounds useful in the present invention can be prepared by methods well known in the art as described in, for example, Fleet et al. (1988) FEBS Lett . 237:128-132, U.S. Patents Nos. 4,182,767, 4,639,436, and 5,003,072, as well as PCT International Publication WO 95/19172 and the references cited therein. Deoxynojirimycin (DNJ) can be obtained from Sigma Chemical Company (St. Louis; cat. no. D 3291). JJ-substituted-imino-D-galactitol compounds can be prepared from deoxygalactonojirimycin (DGJ) , which can be obtained from Cambridge Research Biochemicalε (Northwich, Cheshire, U.K.), as described in Platt et al. (1994) J. Biol . Chem . 269:27108-27114. Briefly, DGJ can be reductively N-alkylated in the presence of palladium black under hydrogen using the appropriate aldehyde by the method of Fleet et al. (1988) FEBS Lett . 237:128-132. The reaction mixture is filtered through Celite, and the solvent removed by evaporation under vacuum. The resulting W-alkylated analogues are then purified by ion-exchange chromatography (Dowex ® AG50-X12, H+ form) in 2M aquepus ammonia, and the solvent removed by evaporation. The compounds can then be lyophilized and analyzed by ID H NMR and by matrix-assisted laser desorption. Methods for introducing oxygen into alkyl side chains are disclosed in Tan et al., (1994) Glycobiology 4 (2) :141-149. Non-limiting illustrative preparative procedures are presented below in Examples 1-5. In treating MDR, the medical practitioner can use the N-substituted-imino-D-glucitol or galactitol compounds of this invention in the form of pharmaceutically acceptable salts. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention can be derived, when possible, from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric, sulfonic, and sulfuric acids, and organic acids such as acetic, adipic, alginic, aspartic, benzoic, benzenesulfonic, bisulfatic, butyric, camphoric, camphorsulfonic, citric, digluconic, cyclopentane- propionic, dodecylsulfatic, ethanesulfonic, gluconic, glycolic, glucoheptanoic, glycerophosphatic, hemisulfatic, heptanoic, hexanoic, fumaric, 2-hydroxy-ethanesulfonic, lactic, maleic, malic, methanesulfonic, nicotinic, 2- naphthalenesulfonic, oxalic, palmitic, pectinic, persulfatic, 3-phenylpropionic, picric, pivalic, propionic, succinic, tartaric, thiocyanic, toluenesulfonic, tosylic, mesylic, and undecanoic. The chloride salt is particularly preferred for medical purposes. The present W-substituted-1, 5-dideoxy-l, 5-imino- D-glucitol or galactitol compounds have basic nitrogen atoms, and can be used in the form of a pharmaceutically acceptable salt thereof. The basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates such as dimethyl, diethyl, dibuytl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides such as benzyl and phenethyl bromides, and others. Water- or oil-soluble or diεpersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid. Other compounds of this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium, or magnesium, or with organic bases or basic quaternary ammonium salts. Compounds of this invention can be acids or bases. As such, they can be used to form salts with one another. This type of salt can then be provided to the patient in a pharmaceutically acceptable formulation or as a pure single salt. Chemotherapeutic Agents As indicated below, there are a large number of antineoplastic agents available in medical use, in clinical evaluation, and in pre-clinical development, that can be employed in the treatment of tumor cell growth in conjunction with the .N-substituted-imino-D-glucitol or galactitol compounds of the present invention. Such antineoplastic agents fall into a number of major categories, including antibiotics (such as actinomycin D) , antimetabolites, anthracyclines, alkaloids, alkylating agents, anti-microtubule agents (such as the vinca alkaloids and taxol) , anti-tumor enzymes, hormonal agents, immunological agents, interferon-type agents, platinum- containing agents, topoiεomerase inhibitors, DNA damaging agents (agents that cause breaks, such as single εtrand breakε, in DNA), and a category of miscellaneous agents. An example of a compound of this laεt category is carbetimer, which is an antineoplastic agent having significant cytotoxic activity in clonogenic asεays (Kisner et al. (1983) Proc. ASCO 2) and in nude mice bearing a variety of human tumors (Ardalan et al. (1986) Cancer Res . 46) . Antineoplastic Compounds 17-Beta-Estradiol Aclarubicin Aldesleukin Allopurinol Altretamine Amifoεtine Amεacrine Anaεtrozole Aεparaginase Azidopine BCG vaccine BCNU Bicalutamide Bleomycin Sulfate Busulfan Carboplatin Carmuεtine Chlorambucil Ciεplatin Cladribine Clodronate disodium Cyc1ophosphamide Cytarabine Cytarabine ocfoεfate Dacarbazine Dactinomycin Daunorubicin Hydrochloride Dexrazoxane Diethylstilbestrol Docetaxel Doxorubicin Hydrochloride Dronabinol Eflornithine Erythropoietin Estramustine Phosphate Sodium Etidronate Disodium Etoposide Etoposide phoεphate Fadrozole Filgraεtim Fluaεterone Fludarabine Phosphate Fluorouracil Fluoxymesterone Flutamide Fluxuridine Formeεtane Fotemustine Gallium Nitrate Gemcitabine Gemcitabine Hydrochloride Goserelin Acetate Granisetron Hydrochloride Hexadecylphoεphocholine Hydroxyurea Idarubicin Idarubicin Hydrochloride Ifosfamide Interferon alfa-2a Interferon alfa-2b Interferon, Toray (beta) Irinotecan Irinotecan Hydrochloride Lentinan Letrozole Leucovorin Calcium Leuprolide Acetate Levamiεole Lomustine Lonidamine Mechlorethamine Hydrochloride Medroxyprogesterone Acetate Megestrol Acetate Melphalan Mercaptopurine Methotrexate Sodium Mitolactol Mitomycin Mitotane Mitoxantrone Hydrochloride Nedaplatin Nilutamide Octreotide Acetate Ondanεetron Hydrochloride Oxaliplatin Paclitaxel Pamidronate Diεodium Pegaεparagase Pegaspargaεe Pentoεtatin Pilocarpine Pirarubicin Plicamycin Porfimer Sodium Procarbazine Hydrochloride Raltitrexed Romurtide Sargramostim Sizofilan Sobuzoxane Streptozocin 2-deoxy-2- ( ( (methylnitrosoamino) carbonyl) amino) -alpha (and beta) -D-glucopyranoεe Tamoxifen Citrate Tegafur + uracil TheraCyε BCG Live Thioguanine Thiotepa Topotecan Topotecan Hydrochloride Toremifene Tretinoin Vinblastine Hydrochloride Vincristine Sulfate Vinorelbine Vinorelbine Tartrate Zinostatin stimalamer Ambamuεtine Phenalon Ukrain Broxuridine EF-13 EF-27 Emitefur Liarozole Mitoguazone Pentostatin Virulizin Vorozole 9-aminocamptothecin AC Vaccine Technology AD-32 AG-337 ALRT-1057 Adenocarcinoma vaccine Anti-Her-2 MAb AS-101 Autolymphocyte therapy CGP-19835A Cancer therapy, Aquila Biopharmaceuticalε Crisnatol mesylate Dexaminoglutethimide Diaziquone Droloxifene Exemestane FGN-l Fenretinide GMK ICI-182780 JM-216 LGD-1069 Liεofylline M-Vax Marimaεtat Maxamine Neovastat Onconase PALA Peldeεine Piritrexim Porfiromycin Regreεεin SDZ-PSC-833 SnET2 Suramin Temoporfin Temozolomide Tiazofurin Tirapazamine 506U78 776C85 AGM-1470 ALRT-1550 Adenosine triphosphate Alanosine Aminopterin Amrubicin Annamycin Anti-Bcl2 oligonucleotides Antineoplaston A10 Antineoplaεton AS2-1 BCH-4556 BEC-2 BMS-182248-01 BPA Bisnafide budotitane CM-101 CTP-37 Calicheamicin cancer vaccines, Wiεtar Capecitabine Carboxypeptidaεe Carzeleεin cystemustine DA- 125 DHAC DPPE Decitabine Didemnin B Didox EB-1089 EL-530 EL-532 E09 ET-743 GBC-590 GL-331 Gd-Tex HN-66000 HP-228 Homoharringtonine IST-622 Idoxifene Ifoεfamide + methylene blue Interleukin-3 εynthokine KRN-5500 KRN-8602 L-Vax LY-231514 Ledoxantrone trihydrochloride Lobaplatin Lometrexol Lu-Tex MAK therapy MAK-BAb MGDF MS-209 Melanoma vaccine Metesind glucuronate Miproxifene phosphate NK-611 NKS01 Nemorubicin Nitrullyn NOAC O-Vax OC-TR ONO-4007 POLYDAN PPI-149 RF1010 RFS-2000 RII retinamide RMP-7 Rhizoxin S-l SKI-2053R SU101 Theradigm-melanoma VX-710 VX-853 YM-511 42/6 Antibody 5-FP AG-2034 AG-3340 Abiraterone acetate BTG Acemannan Adenocarcinoma vaccine Adenosine triphosphate Alnorin Antide Aphidicolin glycinate Asulacrine BAB-447 BBR-2778 BCH-4556 BIWB-1 Bizelesin Bryoεtatin-1 CEP-2563 CGP-41251 CGP-48664A CGP-55847 CI-994 CT-2584 Cancer vaccine, Genzyme Clomesone Cordecypin Criεnatol mesylate Cyclocreatine D-19575 D-21266 DX-8951f Diethylnorspermine Dolastatin-10 Edatrexate EM-800 FCE-28068 FK-317 Flavopiridol GF-120918 Intoplicine KT-6149 KW-2170 KW-2189 LU-103793 LU-79553 LY-309887 Lymphoma vaccine, Apollon MAC-DC MDAM ME-2906 Melanoma vaccine, UCLA MEN-10755 MGI - 114 MGV MKC-454 Methioninaεe Muc-1 vaccine NB-506 Norcantharidin OGT-719 OM-174 Oligonucleotide AML OncoLipin-2 PG-2 PR-350 Peptide G Pivaloyloxymethyl butyrate Quinocarmycin monocitrate S-16020-2 SDZ-62-434 SDZ-MKT-077 TAS-103 Theophylline TherAmide Theratope MUC-1 Titanocene dichloride Tularemia live vaccine Tumour vaccines, Medac UCN-01 XR-5000 ZD-9331 ZnPc A-007 C215FAb-SEA CAI Dilazep, chemoprotective Gosεypol HSP cancer vaccine Neuropeptideε, ICRT Perillyl alcohol Paracelεian TOP-53 TZT-1027 Methods for the preparation of many of the antineoplastic agents described above can be found in the literature. For example, methods for the preparation of doxorubicin are deεcribed in U.S. Patentε Nos. 3,590,028 and 4,012,448. Alternatively, certain agents are available commercially. Pharmaceutical Compositions The iminoεugar and chemotherapeutic compoundε employed in the methodε of the preεent invention can be adminiεtered for their therapeutic purpoεeε by any meanε that produce contact of theεe compounds with their site of action either in vitro or in vivo within the body. These compoundε can be formulated εeparately, or together in a single pharmaceutical composition, along with a pharmaceutically acceptable carrier, diluent, or excipient. The carrier, etc., can be a solid, a liquid, or both, and iε preferably formulated with the compound aε a unit-doεe composition, for example a tablet, which can contain from about 0.05% to about 95% by weight of the active compound (s) . Other pharmacologically active εubεtanceε can alεo be preεent. The pharmaceutical compoεitionε of the preεent invention can be prepared by any of the well known techniqueε of pharmacy, conεiεting essentially of appropriately admixing the components. The formulation of pharmaceuticals iε discusεed in, for example, Remington ' ε Pharmaceutical Sciences, 16th Edition, Arthur Oεol, Ed., Mack Publiεhing Co., Eaεton, Pennsylvania (1980), and Pharmaceutical Dosage Forms, H.A. Liberman and L. Lachman, Eds., Marcel Decker, New York, N.Y. (1980). The individual or combination pharmaceutical compositions of the present invention can be adminiεtered by any conventional means available for use in conjunction with pharmaceuticals. Pharmaceutical compoεitions according to the present invention include those εuitable for oral, buccal (e.g., εublingual) , parenteral (e.g., εubcutaneouε, intramuscular, intradermal, intrasternal, or intravenous injection, or infusion techniques) , rectal, transdermal, and topical administration, as well as by inhalation spray, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as deεired. Topical adminiεtration can involve the use of transdermal administration such aε tranεdermal patcheε or iontophoresis devices. For therapeutic purposeε, formulationε for parenteral adminiεtration, for example εterile injectable aqueouε or oleaginouε suspensionε, can be formulated according to the known art in the form of aqueouε or non- aqueouε isotonic sterile injection εolutionε or εuεpenεionε uεing εuitable diεperεing or wetting agentε and εuεpending agentε. The εterile injectable preparation can alεo be a εterile injectable εolution or εuεpenεion in a nontoxic, parenterally acceptable diluent or solvent, for example as a εolution in 1, 3-butanediol . These solutions and suεpensions can be prepared from εterile powderε or granuleε having one or more of the carrierε or diluents mentioned for use in the formulations for oral administration. Pharmaceutically acceptable vehicles for the compounds of the present invention include water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, Ringer's solution, seεame oil, benzyl alcohol, isotonic εodium chloride εolution, and/or variouε buffers. In addition, sterile, fixed oils are conventionally employed aε εolventε or εuεpending media. For thiε purpose, any bland fixed oil can be employed, including synthetic mono-or diglycerides . In addition, fatty acids such as oleic acid are useful in the preparation of injectables. Other adjuvantε and modes of administration are well and widely known in the pharmaceutical art. Injectable compositionε according to the preεent invention can contain from about 0.1% to about 5% w/w of a compound diεcloεed herein. Solid doεage forms for oral administration may include capsules, cachets, lozenges, tablets, or pillε, each containing a predetermined amount of at leaεt one compound of the preεent invention, or as powders, and granuleε. In εuch εolid doεage forms, the compounds of this invention are ordinarily combined with one or more adjuvantε appropriate to the indicated route of adminiεtration. If administered per os , the compounds can be admixed with lactose, sucroεe, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magneεium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient adminiεtration. Such capεuleε or tablets can contain a controlled-release formulation as can be provided in a disperεion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage formε can alεo compriεe buffering agentε εuch aε sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutionε, εuεpenεionε, syrups, and elixirε containing inert diluents commonly used in the art, such as water or other pharmaceutically acceptable non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and εuεpending agentε, and εweetening, flavoring, and perfuming agentε. Pharmaceutical compoεitionε εuitable for buccal (sub-lingual) administration include lozengeε compriεing a compound of the preεent invention in a flavored base, usually sucroεe, and acacia or tragacanth, and paεtilleε compriεing the compound in an inert baεe such as gelatin and glycerin or sucrose and acacia. Unit-dose suppoεitorieε for rectal adminiεtration of the compoundε diεcuεεed herein can be prepared by mixing the active agent with a εuitable non-irritating excipient εuch aε cocoa butter, synthetic mono-, di-, or triglycerides, fatty acidε, or polyethylene glycolε which are εolid at ordinary temperatureε but liquid at the rectal temperature, and which will therefore melt in the rectum and release the drug. Pharmaceutical compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paεte, gel, εpray, aerosol, or oil. Carriers that can be used include vaεeline, lanolin, polyethylene glycolε, alcoholε, and co binationε of two or more thereof . The active compound can be present at a concentration of from about 0.1% to about 15% w/w of the composition, for example, from about 0.5% to about 2%. Transdermal administration is also posεible. Pharmaceutical compositions suitable for transdermal administration can be presented aε diεcrete patcheε adapted to remain in intimate contact with the epidermiε of the recipient for a prolonged period of time. Such patcheε εuitable contain a compound of the preεent invention in an optionally buffered, aqueouε solution, dissolved and/or dispereεed in an adheεive, or diεperεed in a polymer. A εuitable concentration of the active compound iε in the range of from about 1% to about 35%, w/w, more preferably from about 3% to about 15%. As one particular posεibility, the compound can be delivered from the patch by electrotranεport or iontophoreεis, for example, as described in Pharmaceutical Research (1986) 3:318. Pharmaceutically acceptable carriers encompass all the foregoing and the like. In addition to the foregoing types of pharmaceutical compoεitionε, the iminoεugarε and chemotherapeutic compounds of the preεent invention can be administered in the form of delayed release or controlled releaεe pharmaceutical preparationε, i.e., pharmaceutical preparationε designed to delay and/or extend the time over which the active drug molecule (s) iε (are) delivered to the εite of action by manipulation of the doεage form. In both caεeε, release of the pharmaceutically active agent is εuch that a pharmaceutically effective amount thereof capable of achieving its intended effect is preεent in vitro or in vivo over an extended period of time. Encompaεεed within the scope of the present invention, therefore, are εuch preparations, wherein either drug is present separately, both drugs are preεent together, or wherein both drugε are preεent together in a εingle formulation, but wherein one or the other of the iminosugar or chemotherapeutic compound is present in delayed or controlled release form, and the other is not . Delayed and/or controlled release of the present iminosugar compounds is preferred due to their pharmacokinetic properties, i.e., the desirability of maintaining a constant blood serum level thereof over a prolonged period. This can be achieved by a number of different mechaniεmε, including, for example, pH εensitive release from the dosage form based on the changing pH of the small intestine, slow eroεion of a tablet or capεule, retention in the εtomach based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestinal tract, enzymatic release of the active drug from the dosage form, etc. Delayed delivery dosage formulations are disclosed in U.S. Patent 5,190,765. Slow release pharmaceutical compositions are also well known in the art. For example, U.S. Patent No. 4,524,060 discloεes a composition in the form of a non-compressed pellet having an enteric coat or a suεtained releaεe coat permeable to gaεtrointeεtinal juices. Other controlled release formulations are described in U.S. Patentε Nos. 4,880,830 and 5,068,112. In addition to the delayed release and controlled release dosage formulations discusεed above, there are doεage formε known in the art for delivering drugs continuously over time such aε those discloεed in U.S. Patentε Noε. 4,327,725, 4,612,008, 4,765,989, and 4,783,337 that compriεe a semipermeable wall surrounding a compartment . The compartment contains a drug formulation and a displacement member that pusheε the drug formulation from the doεage form when fluid iε imbibed by the doεage form through the semipermeable wall . Such dosage forms can deliver difficult to deliver drugs for their intended purpose. Another type of controlled release drug formulation or device is the gliadel wafer (Guilford Pharmaceutical) . This vehicle can be used for local administration, for example in a tumor bed, for example that in a brain tumor, of a chemotherapeutic agent such aε BCNU. In any caεe, the amount of active ingredient that can be combined with the carrier materialε to produce a single dosage form to be administered will vary depending upon the patient, the nature of the formulation, and the mode of administration. Certain of the pharmaceutical compounds of thiε invention which are adminiεtered in accordance with the methodε of the invention can εerve as prodrugs to other compounds of this invention. Prodrugs are drugs that can be chemically converted in vivo or in vitro by biological systems into an active derivative or derivatives. Prodrugs are adminiεtered in eεεentially the εame fashion as the other pharmaceutical compounds of the invention. Non- limiting examples are the esterε of the tf-substi-tuted-1, 5- dideoxy-1, 5-imino-D-glucitol or galactitol compounds of this invention. It should be noted that the pharmaceutical compositions of the present invention can contain individual iminosugarε, or combinationε thereof, in anti- MDR effective doεeε . Theεe iminoεugars can also be used in combination with anti-MDR effective amounts of other compounds useful aε anti-MDR agentε, εuch aε verapamil, tamoxifen, cycloεporin A, etc. In addition, the present invention encompasseε pharmaceutical compoεitions comprising at least one of the present N-substituted-1, 5- dideoxy-1, 5-imino-D-glucitol or galactitol compounds and at leaεt one anti-tumor chemotherapeutic compound. In εuch combined compoεitionε, the iminoεugar should be present in an anti-MDR effective amount, and the anti-tumor chemotherapeutic compound should be present in an anti- tumor effective amount. Specific dosages are discuεεed in detail below. Administration The iff-substituted-1, 5-dideoxy-l, 5-imino-D- glucitol or galactitol compounds and one or more antineoplastic agents can be administered either sequentially in separate formulationε, or εimultaneouεly in a εingle formulation. Either the iminoεugar or the antineoplaεtic agent, or both, can be uεed in combination with a lipoεome formulation to deliver the iminoεugar and/or antineoplaεtic agent to the target tumor while protecting more sensitive tisεue from the toxic effect of the antineoplastic agent. Administration can be effected by the route appropriate to the formulation of the pharmaceutical composition, discussed above. Administration by oral route is preferred in the case of the preεent iminosugars, but other routes are acceptable. Administration of anti-neoplaεtic chemotherapeutic agentε can be by any conventional route therefor, which includeε oral route, or intravenouε, intra-muεcular, or εubcutaneouε injection or infusion. Administration of phamaceutical compositions comprising both an iminosugar and an antineoplastic chemotherapeutic agent can thus be performed by any acceptable route compatible with both claεεeε of compoundε contained therein, such as the latter routeε. Combination formulationε can be in the form of a boluε, or in the form of aqueouε or non-aqueouε isotonic sterile injection solutionε or εuεpenεionε. These εolutions and εuspensionε can be prepared from εterile powderε or granuleε having one or more pharmaceutically acceptable carrierε, excipientε, or diluentε, or a binder εuch aε gelatin or hydroxypropyl-methyl cellulose, together with one or more of a lubricant, preεervative, surface-active agent, or dispersing agent. Dosages Imino Sugars To prevent, reduce, or reverse MDR during chemotherapy, the N-substituted-1, 5-dideoxy-1, 5-imino-D- glucitol and/or galactitol compounds of the preεent invention εhould be adminiεtered to humans, or domestic animals such as cats and dogs, in an anti-MDR effective amount. Functionally, an effective amount is an amount, by whatever route administered, that resultε in a blood εerum concentration in the range of from about 5 μM to about 500 μM, preferably from about 10 μM to about 250 μM, more preferably from about 15 μM to about 100 μM, and even more preferably from about 20 μM to about 60 μM. About 50 μM iε a preferred concentration. This can be achieved by administration of these compounds in an amount in the range of from about 10 mg/day to about 3,000 mg/day, more preferably from about 100 mg/day to about 3,000 mg/day, and moεt preferably from about 1,000 mg/day to about 3,000 mg/day. About 3,000 mg/day is a preferred dose. When administered in non-sustained release formulations, the total daily doεe of iminoεugarε indicated above can be adminiεtered in equal, one-third εubdoεes administered at eight hour intervals, e.g., about 1,000 mg every eight hourε . When a εuεtained-releaεe preparation is employed, the total daily dose can be administered at one time. In either case, the pharmaceutical compoεition should contain an amount of iminosugar effective to achieve a blood εerum level in the micromolar rangeε indicated above over successive 8 hour intervals. In a 24 week εtudy of the εafety and efficacy of N-butyl DNJ and zidovudine in patientε with HIV-l infection, Fiεchl et al . ((1994) J " . Acguired Immune Defic. Syndr. 7:139) noted that the major toxicity aεεociated with adminiεtration of 3,000 mg/day of Iff-butyl DNJ was diarrhea. These authors suggeεted that εuch diarrhea could be alleviated with a low complex carbohydrate diet and/or antidiarrheal medicationε. 2ff-alkylated glucitol and galactitol iminoεugarε each poεsess distinct advantages in the methods of the present invention. Iff-butyl DNJ does not inhibit the galactosyltranεferase that initiates the biosyntheεis of galactosylceramide (GalCer) -based glycosphingolipids (GalCer and sulfatide) , which are important constituents of myelin. Thus, Iff-butyl DNJ and related glucitol derivatives will not impair yelination and myelin stability in patients in which this is a concern. On the other hand, in patients in which inhibition of α-glucoεidase I and II or lysosomal β-glucocerebrosidaεe is undesirable, 2ff-alkyl galactitol iminosugarε may be preferred in view of the εpecificity of compoundε such as Jff-butyl DGJ in inhibiting glycoεphingolipid bioεyntheεiε (Platt et al. (1994) J. Biol . Chem. 269:27108-27114). In εome εituationε, it may be desirable to use a pharmaceutical composition comprising a combination of an iff-alkyl glucitol and an iff-alkyl galactitol iminosugar to avoid or ameliorate the effects of MDR during chemotherapy. Together, such iminosugarε εhould compriεe an anti-MDR effective amount. Chemotherapeutic Agents Guidelineε for drug εelection and doεage for the treatment of cancer can be found in Cancer: Principles & Practice of Oncology, 6th Edition, 1996, Vincent T. DeVita, Jr. et al., Edε . , J.B. Lippincott Company, Philadelphia. Due to εuppreεεion of MDR via the uεe of the iff-εubεtituted-1, 5-dideoxy-l , 5-imino-D-glucitol or galactitol compounds of the present invention, the medical practitioner will be able to administer conventional amountε of chemotherapeutic agentε, or perhaps even reduced amounts thereof, by employing the methodε and compositions discloεed herein. Such reduced amountε can be determined in patientε undergoing chemotherapy by routine monitoring of tumor antigens, such aε the CEA, PSA, or CA15-3 antigenε, in patient εerum, or in body tiεεues by other immunological methods; X-ray studies; radiographic imaging of tumors; CT, MRI, ultrasound, or PET scanning; biopsy; palpation; observation of the general εtate of the patient, performance statuε, etc., aε iε well known in the art. Thuε, patients can be monitored during chemotherapy in conjunction with the administration of iff-εubstituted- 1,5- dideoxy-1, 5-imino-D-glucitol and/or galactitol compounds and antineoplastic agents to determine the lowest effective doεeε of each. The doεeε deεcribed above can be administered to a patient in a single dose or in proportionate multiple εubdoses. In the latter case, dosage unit compoεitionε can contain εuch amountε of εubmultipleε thereof to make up the total doεe. Multiple subdoεeε can alεo be adminiεtered to increaεe the total dose should this be desired by the person prescribing the drug. Combination Pharmaceutical Compositions As noted above under "Pharmaceutical Compoεitionε, " the iminosugar and chemotherapeutic compounds employed in the methods of the present invention can be formulated in εingle pharmaceutical compositions comprising both classes of drugs. Such compoεitions should contain an iminosugar in an anti-MDR effective dosage amount and an anti-tumor chemotherapeutic compound in an anti-tumor effective doεage amount. An anti-MDR effective dosage amount of an iminosugar is an amount, by whatever route administered, that results in a blood serum concentration in the range of from about 5 μM to about 500 μM, preferably from about 10 μM to about 250 μM, more preferably from about 15 μM to about 100 μM, and even more preferably from about 20 μM to about 60 μM. About 50 μM iε a preferred concentration. When adminiεtered in a delayed or controlled releaεe formulation, thiε can be achieved by admin-iεtration of theεe compoundε in an amount in the range of from about 10 mg/day to about 3,000 mg/day, more preferably from about 100 mg/day to about 3,000 mg/day, and moεt preferably from about 1,000 mg/day to about 3,000 mg/day. About 3,000 mg/day iε a preferred dose. Non- controlled release formulationε εhould contain one-third of the total daily doεe, e.g., about 1,000 mg, and should be administered to the patient at eight hour intervalε. Doεages for antineoplastic agents are deεcribed in Cancer: Principles & Practice of Oncology, 6th Edition, 1996, Vincent T. DeVita, Jr. et al . , Edε . , J.B. Lippincott Company, Philadelphia, or are otherwiεe known in the art. When adminiεtered in a delayed or controlled releaεe form combination formulation containing an iminoεugar, both the antineoplastic agent and the iminosugar can be administered in their standard daily, single adminiεtration dose. When administered in a combination formulation containing an iminosugar in non-controlled release form, the antineoplastic agent can be preεent in an amount totalling one-third of the total daily doεe; εuch non-sustained release combination formulations εhould be adminiεtered to the patient at eight hour intervalε to achieve the desired, total daily doseε of both drugs. Alternatively, when an appropriate antineoplastic agent is given, the total daily dose of such antineoplastic agent can be present in controlled or non-controlled release form for once daily administration, and the iminosugar can be present in non- controlled release form equivalent to one-third of the total daily doεe, the two remaining one-third daily εubdoses of the iminoεugar being adminiεtered at subsequent eight hour intervals during the remainder of the day. Treatment Regimen The regimen for treating a patient undergoing chemotherapy with the compounds and/or compositions of the present invention is selected in accordance with a variety of factors, including the age, weight, sex, diet, and medical condition of the patient, the severity of the cancer, the route of administration, pharmacological conεiderationε such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular compoundε employed, and whether a drug delivery εystem is utilized. Typical chemotherapeutic regimens compriεe a course of six to eight cycles of treatment, each cycle typically involving administration of antineoplastic drugε over the courεe of three to four weeks . The iff-subεtituted-1, 5-dideoxy-l, 5-imino-D- glucitol or galactitol compoundε of the present invention can be administered daily to patients receiving chemotherapy in accordance with a number of different regimens. Fundamentally, these iminosugars should be administered in an anti-MDR effective amount for a period of time effective to exert their MDR preventing, reducing, or reverεing action on tumor cellε. Without wiεhing to be bound by any particular theory of this invention, the inventor hypothesizeε that thiε effect may be achieved by inhibition of UDP-glucoεe -iff-acyl - εphingoεine glucosyltransferase (EC 2.4.1.80) for a period of time sufficient to decrease the levels of glucosylceramide, and subsequently, more complex glycosphingolipidε and ganglioεideε, in the membraneε of cancerouε cellε. Baεed upon reεultε obtained in in vi tro systems and Tay-Sachs mice, adminiεtration can commence in a period in the range of from about 14 dayε to about three dayε prior to adminiεtration of the chemotherapeutic agent (ε), and can continue daily thereafter, up to and including administration of the chemotherapeutic agent. Administration of theεe iminoεugarε can be continued daily for a brief period, e.g., about one to about five dayε after adminiεtration of the chemotherapeutic agent, to alleviate or avoid potential MDR effectε during the period in which reεidual amounts of chemotherapeutic agents remain in tumor cells . Therefore, in general, the Jff-substituted-1, 5- dideoxy-1, 5-imino-D-glucitol or galactitol compounds of the present invention can be administered prior to administration of the chemotherapeutic agent. The iff-subεtituted-1, 5- ideoxy- 1, 5 -imino-D-glucitol or galactitol compoundε can also be administered both prior to and simultaneouεly with administration of the chemotherapeutic agent; or simultaneously with administration of the chemotherapeutic agent; or prior to, simultaneously with, and subsequently to administration of the chemotherapeutic agent; or prior to and subsequently to administration of the chemothera-peutic agent. More particularly, the present iff-substituted-1, 5- dideoxy-1, 5-imino-D-glucitol or galactitol compounds can be administered daily to the patient in a time period starting from about 14 days prior to adminiεtration of the chemotherapeutic agent. More preferably, theεe iminosugars can be adminiεtered daily to the patient in a time period εtarting from about 10 dayε prior to adminiεtration of the chemotherapeutic agent. In εome patientε, it may be neceεεary or deεirable to commence adminiεtration of these iminosugars about 7 dayε prior to administration of the chemotherapeutic agent. In other caseε, adminiεtration of theεe iminoεugarε can commence about 5 dayε, or even about 3 dayε, prior to adminiεtration of the chemotherapeutic agent. Aε indicated above, these iminosugarε can be further adminiεtered εimultaneously with the chemotherapeutic agent, and/or subεequently to administration of the chemotherapeutic agent, on a daily basis for a period in the range of from about one to about five days, preferably for about two days, after adminiεtration of each doεe of the chemotherapeutic agent. Administration of the iff-subεtituted-l, 5-dideoxy- 1,5-imino-D-glucitol or galactitol compounds of the present invention εhould be continued in conjunction with the preεcribed chemotherapeutic regimen aε outlined above until the cancer has been controlled or eradicated. The proven long-term safety associated with the administration of the iminosugars disclosed herein (note, for example, Fischl et al . ((1994) J. Acquired Immune Defic . Syndr. 7:139, in this regard) also permitε another regimen: the preεent iff-alkylated glucitol and galactitol derivatives can be administered on a daily basiε throughout the entire course of the patient's chemotherapy. Rather than adminiεtering theεe compounds only in anticipation of individual chemotherapy sessions aε described above, the practitioner can order continuouε daily administration thereof. In this regimen, and in a manner similar to that of the regimenε described above, administration of the present Iff-alkylated glucitol and galactitol derivatives can commence about 14 days, about 10 dayε, about 7 days, about 5 dayε, or about 3 dayε prior to administration of the initial dose of the chemotherapeutic drug, and continue on a daily basiε thereafter. As previously noted, patients undergoing treatment with the drug combinations disclosed herein can be routinely monitored by measuring serum antigen levels, by radiographic imaging of tumors, biopsy, palpation, etc., to determine the effectiveness of therapy. Continuous analysis of the data obtained by the foregoing methods permits modification of the treatment regimen during chemotherapy εo that optimal amounts of the Iff-alkyl-l,5-dideoxy-l,5-imino-D-glucitol and galactitol compounds of this invention and chemotherapeutic agent (s) are administered, and so that the duration of treatment can be determined as well. Thus, the treatment regimen/dosing εchedule can be rationally modified over the courεe of chemotherapy εo aε to achieve the loweεt doses of each of the Iff-substituted-1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol compounds of this invention and the chemotherapeutic agent (s), which together reεult in εatiεfactory anti-cancer effectiveness, and so that administration of these compounds is continued only so long as is necesεary to εuccessfully treat the cancer. The following non-limiting exampleε εerve to illuεtrate variouε aεpects of the preεent invention. Example 1 Preparation of 1,5- (butylimino) -1, 5-dideoxy-D-glucitol A εolution of 1, 5-dideoxy-l, 5-imino-D-glucitol (5.14 g, 0.0315 mole), butyraldehyde (3.35 ml, 0.0380 mole) and Pd black (1 g) in 200 ml methanol iε hydrogenated (60 pεi/29°C/21 hrs.). After filtering the resulting mixture, the filtrate is concentrated in vacuo to an oil. The title compound is crystallized from acetone, and recrystallized from methanol/acetone, m.p. ca. 132°C. The structure asεignment iε εupported by NMR, infrared spectra and elemental analysis. Analysis calcd. for C 10 H 21 NO 4 : C, 54.78; H, 9.65; N, 6.39. Found: C, 54.46; H, 9.33; N, 6.46. Example 2 Preparation of 1,5- (butylimino) -1, 5-dideoxy-D-glucitol, tetraacetate Acetic anhydride (1.08 g, 0.0106 mole) is added to the title compound of Example 1 (0.50 g, 0.0023 mole) in 5 ml pyridine and stirred for 17 days at room temperature. The product is evaporated under nitrogen gas. The resulting title compound is purified by silica gel chromatography. The structure asεignment iε supported by NMR, infrared spectra, and elemental analysis. Analyεiε calcd. for C 18 H 29 N0 8 : C, 55.80; H, 7.54; N, 3.62. Found: C, 55.42; H, 7.50; N, 3.72. Example 3 Preparation of 1,5- (butylimino) -1, 5-dideoxy-D-galactitol 30 mg (184 μmol) of deoxygalactonojirimycin are dissolved in 1 ml of 50 mM sodium acetate buffer, pH 5.0, to which 20 mg of palladium black is added. A hydrogen atmosphere is maintained in the reaction vessel, and 100 μl (1.1 mmol) of butyraldehyde are introduced. The reaction is stirred for 16 hr. at room temperature (ca. 20°C) . The reaction is stopped by filtration through a bed (1 g) of Celite (30-80 meεh) , and the reaction productε are εeparated by chromatography using a column containing 4 ml of packed Dowex ® AG50-X12 (H+ form) resin. The Iff-butyl DGJ iε eluted from the column with 2M ammonia, and itε molecular aεε and chemical εtructure determined by laεer deεorption maεε εpectrometry and ID X H NMR, reεpectively. Example 4 Preparation of 1,5- (propylimino) -1, 5-dideoxy-D-galactitol The εynthetic procedure and compound analyεiε of Example 3 can be repeated, except that propanoyl aldehyde can be εubεtituted for an equivalent amount of butyraldehyde for analogous preparation of Iff-propyl DGJ. Example 5 Preparation of 1,5- (hexylimino) -1, 5-dideoxy-D-galactitol The synthetic procedure and compound analyεiε of Example 3 can be repeated, except that caproaldehyde can be εubεtituted for an equivalent amount of butyraldehyde for analogouε preparation of Iff-hexyl DGJ. Iff-alkyl DGJ compoundε prepared as described in foregoing Examples 3-5 can be obtained in overall yields of 68-74% based on the starting DGJ, and in greater than 95% purity. The invention being thuε deεcribed, it will be obviouε that the εame can be varied in many ways . Such variationε are not to be regarded aε a departure from the εpirit and εcope of the preεent invention, and all εuch modificationε and equivalentε as would be obvious to one εkilled in the art are intended to be included within the εcope of the following claims.

Claims: CLAIMS 1. A compound for preventing, reducing, or reversing multidrug resistance in a patient undergoing treatment with a chemotherapeutic agent, comprising an anti -multidrug resistance effective amount of an N- substituted-1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol compound, or a pharmaceutically acceptable salt thereof, of Formula I: wherein R is selected from the group consisting of arylalkyl, cycloalkylalkyl, and branched or straight ]0 chain alkyl having a chain length of C 2 to C 20 , and W, X, Y and Z are independently selected from the group consisting of hydrogen, alkanoyl, aroyl, and trifluoroalkanoyl . 2. The compound of claim 1, wherein R is a 5 straight or branched chain alkyl group having a chain length of C 2 to C 20 , and W, X, Y, and Z are each hydrogen. 3. The compound of claim 2, wherein R is a straight chain alkyl group having a chain length of C 4 to C -,20 4. The compound of claim 3, wherein R is a straight chain alkyl group having a chain length of C 4 to C 14 . 5. The compound of claim 4, wherein R is a straight chain alkyl group having a chain length of C 4 to io • 6. The compound of claim 5, wherein R is a straight chain alkyl group having a chain length of C 4 to C β . 7. The compound of claim 6, wherein R is a straight chain alkyl group having a chain length of C 4 to C 6 - 8. The compound of claim 7, wherein R is n-butyl. 9. The compound of claim 7, wherein R is n-hexyl . 10. The compound of claim 1, wherein R is a straight or branched chain alkyl group having a chain length of C 2 to C 20 , and W, X, Y, and Z are each an alkanoyl group having a chain length of C x to C 20 . 11. The compound of claim 10, wherein R is a straight chain alkyl group having a chain length of C 4 to 2 o • 12. The compound of claim 1, wherein said N- sibstituted-1, 5-dideoxy-l , 5-imino-D-glucitol or galactitol compound is selected from the group consisting of: N- (n-ethyl- ) -1 , 5-dideoxy- 1 , 5-imino-D-glucitol or galactitol ; N- (n-propyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol ; N- (n-butyl-) -1 , 5-dideoxy-l, 5-imino-D-glucitol or galactitol ; N- (n-hexyl-) -1 , 5-dideoxy- 1, 5-imino-D-glucitol or galactitol ; N- (n-heptyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol ; N- (n-octyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol; N- (n-octyl- ) -1 , 5-dideoxy-1 , 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (n-nonyl- ) -1 , 5 -dideoxy- 1 , 5 -imino-D-glucitol or galactitol, tetrabutyrate; N- (n-decyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (n-undecyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (n-nonyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol ; N- (n-decyl- ) -1 , 5-dideoxy- 1 , 5 -imino-D-glucitol or galactitol ; N- (n-undecyl-) -1 , 5-dideoxy-1, 5 -imino-D-glucitol or galactitol; N- (n-dodecyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol; N- (2-ethylhexyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol ; N- (4-ethylhexyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol ; N- (5-methylhexyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol ; N- (3-propylhexyl) -1, 5 -dideoxy-1, 5-imino-D-glucitol or galactitol; N- (l-pentylpentylhexyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol ; N- (1-butylbutyl) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol; N- (7-methyloctyl-) -1, 5 -dideoxy-1, 5-imino-D-glucitol or galactitol; N- (8-methylnonyl) -1 , 5-dideoxy-1 , 5-imino-D-glucitol or galactitol ; N- (9-methyldecyl) -1, 5-dideoxy- 1, 5-imino-D-glucitol or galactitol ; N- (10-methylundecyl) -1, 5-dideoxy- 1, 5-imino-D-glucitol or galactitol ; N- (6-cyclohexylhexyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol ; N- (4-cyclohexylbutyl) -1, 5-dideoxy-1, 5 -imino-D-glucitol or galactitol; N- (2-cyclohexylethyl) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol ; N- (1-cyclohexylmethyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol ; N- (1-phenylmethyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol ; N- (3 -phenylpropyl) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol ; N- (3- (4 -methyl) -phenylpropyl) -1, 5-dideoxy- 1, 5 -imino-D- or glucitol galactitol; N- (6-phenylhexyl) -1 , 5-dideoxy- 1 , 5 -imino-D-glucitol or galactitol ; N- (n-nonyl) -1, 5-dideoxy-1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (n-decyl-) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (n-undecyl- ) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (n-dodecyl-) -1 , 5 -dideoxy- 1, 5 -imino-D-glucitol or galactitol, tetrabutyrate; N- (2-ethylhexyl) -1, 5 -dideoxy-1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (4-ethylhexyl) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (5 -methylhexyl) -1, 5 -dideoxy- 1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (3 -propylhexyl) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (l-pentylpentylhexyl) -1, 5-dideoxy- 1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (1-butylbutyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (7-methyloctyl-) -1, 5-dideoxy-1, 5 -imino-D-glucitol or galactitol, tetrabutyrate; N- (8-methylnonyl) -1, 5 -dideoxy- 1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (9-methyldecyl) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (10-methylundecyl) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (6-cyclohexylhexyl- ) -1, 5-dideoxy- 1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (4-cyclohexylbutyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (2-cyclohexylethyl) -1, 5 -dideoxy- 1, 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (1-cyclohexylmethyl) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol, tetrabutyrate,- N- (1-phenylmethyl) -1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol, tetrabutyrate; N- (3 -phenylpropyl) -1 , 5-dideoxy- 1 , 5 -imino-D-glucitol or galactitol, tetrabutyrate; N- (3- (4 -methyl) -phenylpropyl) -1 , 5-dideoxy- 1 , 5-imino-D- glucitol or galactitol, tetrabutyrate; and N- (6-phenylhexyl) -1 , 5 -dideoxy- 1 , 5 -imino-D-glucitol or galactitol, tetrabutyrate, or a pharmaceutically acceptable salt thereof. 13. The compound of claim 12, wherein said N- substituted-1 , 5 -dideoxy- 1 , 5-imino-D-glucitol or galactitol compound is selected from the group consisting of N- (n-butyl) -1, 5-dideoxy-l, 5-imino-D-glucitol or galactitol and N- (n-hexyl) -1 , 5-dideoxy- 1, 5-imino-D- glucitol or galactitol . 14. The compound of claim 1, wherein said chemotherapeutic agent is selected from the group consisting of an alkaloid, a topoisomerase II inhibitor, and a DNA damaging agent . 15. The compound of claim 14, wherein said alkaloid is a vinca alkaloid. 16. The compound of claim 15, wherein said vinca alkaloid is selected from the group consisting of vincristine, vinblastine, and vindesine . 17. The compound of claim 14, wherein said topoisomerase II inhibitor is selected from the group consisting of an anthracycline and an epipodophyllotoxin. 18. The compound of claim 17, wherein said anthracycline is selected from the group consisting of docorubicin, daunorubicin, idarubicin, and mitoxantrone. 19. The compound of claim 17, wherein said epipodophyllotoxin is selected from the group consisting of etoposide and tenoposide. 20. The compound of claim 14, wherein said DNA damaging agent is actinomycin D. 21. The compound of claim 1, wherein said effective amount of said N-substituted-1 , 5-dideoxy-l , 5-imino-D- glucitol or galactitol compound is an amount that results in a blood serum concentration in the range of from about 5 μM to about 500 μM by whatever route it is administered. 22. The compound of claim 21, wherein said effective amount of said N-substituted-1 , 5-dideoxy-l, 5- imino-D-glucitol or galactitol compound is an amount that results in a blood serum concentration in the range of from about 20 μM to about 60 μM by whatever route it is administered. 23. The compound of claim 22, wherein said effective amount of said N-substituted-1 , 5-dideoxy-l , 5- imino-D-glucitol or galactitol compound is an amount that results in a blood serum concentration of about 50 μM by whatever route it is administered. 24. A pharmaceutical composition, comprising an anti-multidrug resistance effective amount of at least one N-substituted-1 , 5-dideoxy-l , 5-imino-D-glucitol or galactitol compound of claim 1; an anti-tumor effective amount of at least one anti- tumor chemotherapeutic compound; and a pharmaceutically acceptable carrier. 25. The pharmaceutical composition of claim 24, wherein both said N-substituted-1, 5-dideoxy-l , 5-imino-D- glucitol or galactitol compound and said anti-tumor chemotherapeutic compound are in controlled release form. 26. The pharmaceutical composition of claim 24, wherein only said N-substituted-1 , 5-dideoxy-1, 5-imino-D- glucitol or galactitol compound is in controlled release form. 27. The use of an N-substituted-1 , 5-dideoxy-l, 5- imino-D-glucitol or galactitol compound, or a pharmaceutically acceptable salt thereof, of Formula I: wherein R is selected from the group consisting of arylalkyl, cycloalkylalkyl, and branched or straight chain alkyl having a chain length of C 2 to C 20 , and W, X, Y and Z are independently selected from the group consisting of hydrogen, alkanoyl , aroyl, and trifluoroalkanoyl , for manufacture of a mediciment for preventing, reducing, or reversing multidrug resistance in a patient undergoing treatment with a chemotherapeutic agent .

Inventors: JACOB GARY S, JACOB, GARY, S.
Applicants: JACOB GARY S, SEARLE & CO, G.D. SEARLE & CO., JACOB, GARY, S.
Application year: 1998
Main classification: C07D211
IPC codes: A61K31, A61K38, A61K45, A61P35, A61P43, C07D211