STEROIDAL GLYCOLIPIDS AS HOST RESISTANCE STIMULATORS

Abstract: Described is a pharmaceutical composition for enhancing host resistance in an immunocompromised individual consisting essentially of a compound of the formula: where: R¹ is α or β- D -l-thiomannopyranose, α or β-L-l-thiofucopyranose; A is (CH₂) n where n is 5-7, or (CH₂) k X(CH₂) m where X is O, S, NH and k, m are independently 2-4 and k + m is 4-6; R² is C₁-C₈ alkyl or C₂-C₁₀ alkene; B where B is C₁-C₈ alkyl, C₁-C₈ alkoxy, NR³R⁴ where R³ and R⁴ are independently H, C₁-C₄ alkyl; CH(CH₃)D where D is OH, NH₂, NHR⁵ where R⁵ is C₁-C₁₀ alkyl or acetyl. or of a pharmaceutically acceptable salt thereof.

Description: This invention relates to steroidal derivatives of glycolipids, in which steroids are bridged via a medium length hydrocarbon chain, to 1-thio-D-mannopyranoses or 1-thio-L-fucopyranoses as the carbohydrates, and to the use of such compounds for the preparation of a pharmaceutical composition for enhancing host resistance in an immunocompromised individual. The search for new immunostimulator agents for augmenting host defenses to combat infection, cancer and congenital immunodeficiency disorders is an increasingly important area of pharmaceutical endeavor. For example, see Surgery , Vol. 92 , No. 2, pp. 138-145 (1982); Infection , Vol. 12 (1984) No. 117/157; and ibid., 270/82. Glycolipids are known in the pharmaceutical arts, e.g. M. M. Ponpipom et al ., in "Liposomes Technology Vol. III, Targeted Drug Delivery and Biological Interactions", ed. by G. Gregoriadis, CRC Critical Reviews, Ch. 7, pp. 95-115. Steroidal glycosidic compounds are known in the art as being useful immunological adjuvants. For example see, US-A- 4 259 324; US-A- 4 229 441; US-A- 4 189 471 (all three patents being assigned to Merck & Co., Inc.); Carbohydrate Res . 67 , pp. 55-63 (1978) by J. C. Chabala and T. Y. Shen; J. Med. Chem. 23 , p. 1184-1188 (1980) by M. M. Ponpipom et al .; Can. J. Chem. 58 , pp. 214-220 (1980) by M. M. Ponpipom et al . EP-A- 0007277 and EP-A- 0012083. Glycosides are also known in the art for exhibiting pharmacological effects. For example, see US-A- 4 228 274; Chem. Pharm. Bull. Jap., 12 , 528-532 (1964); and Proc. Nat'l Acad. Sci. USA, Vol. 78, No. 12, pp. 7294-7298 (1981). Another reference, J. Med. Chem., 15 , pp. 1284-1287 (1972), describes synthesis of epimeric 20- and 22-azacholesterols as potential therapeutic mediators for hyperfunctioning adrenal glands. However, the above disclosures do not specifically describe glycolipids bearing steroidal substituents for use as host resistance enhancing agents, i.e., immunostimulators. There is a continuing need and demand for safer and more effective agents in enhancing resistance to opportunistic bacterial and fungal invading agents in immunocompromised hosts. This invention describes the use of a compound of the formula: where: R¹ is α or β- D -1-thiomannopyranoside, α or β-L-1-thiofucopyranoside; A is (CH₂) n where n is 5-7, or (CH₂) k X(CH₂) m where X is O, S, NH and k, m are independently 2-4 and k + m is 4-6; R² is C₁-C₈ alkyl or C₂-C₁₀ linear or branched alkenyl; where B is C₁-C₈ alkyl, C₁-C₈ alkoxy, NR³R⁴ where R³ and R⁴ are independently H, C₁-C₄ alkyl; CH(CH₃)D where D is OH, NH₂, NHR⁵ where R⁵ is C₁-C₁₀ alkyl or acetyl, or of a pharmaceutically acceptable salt thereof, for the preperation of a pharmaceutical composition for enhancing host resistance in an immunocompromised individual. Preferred is the use of a compound which is present in an amount effective to exert an immunostimulant effect, in which compound R² of the above Formula I is the cholesterol 17-side chain or the stigmasterol 17-side chain, C(=o)B is C(=o)NH₂, C(=o)OCH₃ or C(=o)CH₃ and CH(CH₃)D is CH₃-CHOH-, CH₃CH(NHCOCH₃)-or CH₃CH(NH₂)-. Preferably the following compounds are used 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-D-mannopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-L-fucopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-L-fucopyranoside; 2-(2-(5-Cholesten-3β-yloxy)ethoxy)ethyl-1-thio-β-D-mannopyranoside; 6-(Stigmasta-5,22-dien-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(Pregn-5-en-20-one-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbomethoxy-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbamido-androst-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(Pregn-5-en-20-ol-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20R-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; or 6-(20R-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside. The above described pharmaceutical compositions stimulate resistance in an immunocomprised animal or human host to bacterial or fungal infection. Further provided is a compound of the following formula: where: R¹ is α or β- D -1-thiomannopyranoside, α or β-L-1-thiofucopyranoside; A is (CH₂) n where n is 5-7, or (CH₂) k X(CH₂) m where X is O, S, or NH and k, m are independently 2-4 and k + m is 4-6; R² is C₁₋₈ alkyl or C₂₋₁₀ linear or branched alkenyl; where B is C₁-C₈ alkyl, C₁-C₈ alkoxy, NR³R⁴ where R³ and R⁴ are independently H, C₁-C₄ alkyl; CH(CH₃)D where D is OH, NH₂, NHR⁵ where R⁵ is C₁-C₁₀ alkyl or acetyl; with the exception of 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-D-mannopyranoside; and 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-L-fucopyranoside. The following compounds are preferred: 6-(Pregn-5-en-20-one-3β-yloxy)hezyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbomethoxy-androst-5-en-3β-ylozy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbamido-androst-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(Pregn-5-en-20-ol-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20R-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; or 6-(20R-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-L-fucopyranoside; 2-(2-(5-Cholesten-3β-yloxy)ethoxy)ethyl-1-thio-β-D-mannopyranoside; 6-(Stigmasta-5,22-dien-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside. A further object of this invention is a pharmaceutical composition for enhancing host resistance in an immunocompromised individual which consists of a compound as described above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor. The use of the glycolipid compositions as described herein provides very high levels of protection against opportunistic infections in immunocompromised animals and humans. These compositions may be used prophylactically to protect immunosuppressed animals or patients against infection by opportunistic organisms. In human medicine, these are surgery patients, burn victims, cancer patients receiving chemotherapy, aplastic anemics, diabetics, and military recruits. In animal health, the primary potential use includes major segments of the worldwide economic animal populations during stressful shipping, mixing, and early life adaptation periods. By the term "adjuvant" as used herein is meant a material which can be employed to potentiate the antibody response of specific antigenic materials. The terms "antigen and antigenic material" which are also used interchangeably herein include one or more non-viable immunogenic or desensitizing (anti-allergic) agents of bacterial, viral or other origin, which when administered, produce a specific immunological response on the part of the host. The antigen component can consist of a dried powder, an aqueous solution, or an aqueous suspension, including mixtures of the same containing a nonviable immunogenic or desensitizing agent or agents. By the term "immunostimulant" as used herein is meant a material which can be employed to potentiate non-specific immune response on the part of the host. The compounds used and claimed in the present invention are not specific antigens per se . Rather are they only immunostimulants for producing a generalized and nonspecific immunological response on the part of the host, and can be used in pharmacutical compositions for intravenous, subcutaneous or intraperitoneal administration which compositions further include acceptable salts, carriers diluents, or vehicles. Referring to the above formula I the compounds include: R¹ is alpha- or beta-D-1-thio-mannopyranose, or alpha- or beta-L-1-thiofucopyranose. A preferred R¹ substituent is where the carbohydrate is β-D-mannopyranose. R¹ is attached via spacer arm chain A to the steroid ring at the beta 3-position. The spacer is composed of (CH₂) n where n is 5-7 and preferably 6. Alternately, the spacer arm can be comprised of a chain of the formula (CH₂) k X(CH₂) m where X is oxygen, sulfur, or NH preferably oxygen; k and m are independently 2-4, preferably 2; and the sum of k and m is 4-6, preferably being 4. Representative examples of A include n-pentylene, n-hexylene, n-heptylene, CH₂CH₂-O-CH₂CH₂, CH₂CH₂-S-CH₂CH₂, CH₂CH₂CH₂-O-CH₂CH₂, CH₂CH₂-O-CH₂CH₂CH₂, or CH₂CH₂CH₂-S-CH₂CH₂CH₂. A preferred A is n-hexylene. R² is the steroidal 17-substituent preferably being in the 17-beta position of the steroid ring. R² can be C₁-C₈ alkyl including linear and branched alkyl and can be methyl, ethyl, propyl, isopropyl, isobutyl, or isopentyl. Preferred is where the alkyl chain is 2,6-dimethylhexyl, being the well-known 17-beta cholesterol side chain. R² further can be C₂-C₁₀ alkenyl, including linear or branched alkenyls including, vinyl, propenyl, isopropenyl, n-butenyl, isobutenyl, isopentenyl, or allyl. Preferred is the alkenyl: 2,6-dimethyl-3-ethyl-hex-4-enyl, being the 17-stigmasterol side chain. R² can further be where B is: a) C₁-C₈ alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, tert -butyl, pentyl, hexyl, heptyl, octyl, or iso-octyl. Preferred is methyl. b) C₁-C₈ alkoxy for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, or hexyloxy. Preferred is methoxy. c) NR³R⁴, where R³ and R⁴ are independently selected from hydrogen, C₁-C₄ alkyl, including NH₂, NHCH₃, NHCH₂CH₃, NMe₂, or NEt₂. Preferred is amino. d) CHCH₃(D), where D is OH, NH₂, NHR⁵ where R⁵ is C₁-C₁₀ alkyl, including methyl, ethyl, propyl, isopropyl or acetyl. Preferred is where D is OH or NH₂. Representative examples include: 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-D-mannopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-L-fucopyranoside; 6-(2-(5-Cholesten-3β-yloxy)ethoxy)ethyl-1-thio-β-D-mannopyranoside; 6-(Stigmasta-5,22-dien-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(Pregn-5-en-20-one-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbomethoxy-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbamido-androst-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(Pregn-5-en-20-ol-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20R-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; or 6-(20R-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside. Preferred is the compound 6-(5-cholesten-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside. The compounds used and claimed in the present invention can be prepared by reacting a per-O-acetyl-1-thio-glycopyranose, wherein the glycopyranose is L-fucose or D-mannose with a steroidal aglycone halide such as 6-(5-cholesten-3β-yloxy)hexyl iodide. Methods for making the per-O-acetylated thioglycopyranose are well known in the art and in general the procedure involves the reaction of a 2-acetobromoglycose in the thiourea followed by treatment of the thiouronium salt with potassium metabisulfite which is described by M.N Ponpipom et al. Can J. Chem 58, 214 (1980). Methods for producing the 6-(5-cholesten-3β-yloxy)hexyl iodide are also well known in the art and generally involve the reaction sequence of steroidal tosylate with an alcohol which is adequately described by J. C. Chabala and T. Y. Shen, Carbo Res ., 67, 55 (1978). The corresponding steroids where stigmasterol, pregnenol, or androstanol are involved are formed by analogous procedures. Generally equimolar amounts of the per-O-acetylated thioglycopyranose and the steroidal hexyl iodide may be condensed in an inert, nonpolar solvent such as a halogenated solvent, e.g. dichloromethane or chloroform in the presence of a base such as e.g. triethylamine, 1,5-diazabicyclo[5.4.0]undec-5-ene or 1,5-diazabicyclo[4.3.0]non-5-ene. The reaction may be carried out from about 10° to about 30°C under an inert atmosphere. Depending upon the base employed the reaction may take from about 0.5 hour to about a few days. Thus, when employing the above diazabicyclo compounds, the reaction is usually completed in from about 0.5 to about 3 hours, while when employing triethylamine the reaction is usually completed in about 1-3 days. Following the reaction the solution is washed with water and dried if the solvent was a halogenated solvent or if the solvent was tetrahydrofuran, the solution is evaporated to dryness and the residue is partitioned between dichloromethane and water. The dried solution is concentrated to a syrup which is put on a silica gel column and eluted with chloroform followed by 1-2% ethanol in chloroform. The desired fractions are pooled and evaporated to give the blocked product 6-(5-cholesten-3β-yloxy)hexyl per-O-acetyl-1-thio-glycopyranoside which is deblocked by basic ion exchange treatment or sodium methoxide in methanol to give the desired final product. In general the steroid used has, as the A portion, the terminally halogenated alkoxyl group for example 6-iodohexyloxy. Further, "A" can also consist of a terminally halogenated alkoxy-alkoxy group e.g. iodoethoxyethoxy in the 3-position of the steroidal ring. The compounds can also alternatively be synthesized by first forming the steroidal aglycone glucopyranoside structure, in which the 17-substituent on the steroid ring is chemically blocked or is a precursor to a final product. After the condensation to form the aglycone steroidal glucopyranoside, subsequent chemistry can be carried out on the 17-group by, for example, deblocking, to form the hydroxy, reduction to form an amine, esterification to form an ester group, or de-esterification to form a carboxylic acid which can be followed by conversion to an amide or to a substituted amide or to a number carboxyl derivatives starting out originally with the ester function. The compositions of the present invention can conveniently be prepared in an aqueous phase in a parenterally acceptable liquid. For example, the aqueous phase can be in the form of a vaccine in which the immunostimulant is dispersed in a balanced salt solution, physiological saline solution, phosphate buffered saline solution, tissue culture fluids or other media in which the organism may have been grown. The aqueous phase may also contain preservatives and or substances conventionally incorporated in vaccine preparations. The compounds used and claimed are used in an amount which is deemed to be immunostimulatory to the host in inducing a generalized immune host response. In general, this amount of material would be anywhere from 2 to 120 mg/kg of host body weight and preferably 10 to 60 mg/kg of host body weight. Preferred is where the dosage is in the range of 20 to 40 mg of described compound herein to host weight. A further characteristic is in that the compounds which are present for their immunostimulatory response preferably are in their noncrystalline form. For reasons which are not yet known or clear, when the materials are present in the crystal form they appear to be relatively inactive in producing an immunological response generalized to the same degree as the materials would have produced in the amorphous form. The crystallinity of the sample can easily be determined by X-ray diffraction analysis which should indicate the absence of a peak height pattern but simply background noise indicating an amorphous material. Also a subject of the invention is a composition as described herein, containing a compound of the formula II, contained in a suitable carrier which may or may not have additional material such as diluents and other materials which may be deemed necessary under the circumstances. However, it is understood that the immunostimulatory preparation does not in fact include a specific antigen as a composition component. The new compounds disclosed and claimed in the present invention include those of the following formula: The descriptions and discussion of the symbols as given above or indicated are exactly the same as those described for the compounds. Representative examples include: 6-(Pregn-5-en-20-one-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbomethoxy-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbamido-androst-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(Pregn-5-en-20-ol-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20R-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; or 6-(20R-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside. A preferred compound is 6-(pregn-5-en-20-one-3β-yloxy) hexyl-1-thio-β-D-mannopyranoside. The following examples exhibit the subject invention as contemplated by us. EXAMPLE 1 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-D-mannopyranoside Prepared from 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranoside and cholest-5-en-3β-yl-6-iodohexyl ether as described in the literature [Chabala, J. C. and Shen, T. Y., Carbohydr. Res. , 67 (1978) 55-63]. Step A: Cholest-5-en-3β-yl-6-hydroxyhexyl ether By use of the procedure described in the literature [Kosower, E. M. and Weinstein, S., J. Am. Chem. Soc. , 78 (1956) 4347-4354; Davis, M., J. Chem. Soc. , (1962) 178-181] cholesteryl p-toluenesulfonate and 1,6-hexanediol were condensed in boiling dioxane to give cholest-5-en-3β-yl-6-hydroxyhexyl ether in 52% yield as colorless plates (from hexane), m.p. 75.9-81°C. Step B: Cholest-5-en-3β-yl-6-(p-toluenesulfonyloxy)hexyl ether A solution of cholest-5-en-3β-yl-6-hydroxyhexyl ether (32 g, 66 mmol) in dry benzene (1.3 ℓ) was treated with p-toluenesulfonic anhydride (24 g, 72.6 mmol) and 2,4,6-trimethylpyridine (11.6 ml, 8.8 g, 72 mmol), and stirred at room temperature under a dry nitrogen atmosphere for 1 hour. The mixture was filtered through a pad of Florisil® and concentrated to a waxy solid (33 g, 77%). Step C: Cholest-5-en-3β-yl-6-iodohexyl ether A solution of cholest-5-en-3β-yl-6-(p-toluenesulfonyloxy)hexyl ether (33 g, 51 mmol) and sodium iodide (16 g, 0.106 mol) in acetone (250 ml) was refluxed for 4 hours. The solvent was removed under reduced pressure, filtered, and the collected salts washed well with ether. The filtrate was evaporated and residual yellow oil boiled in hexanes (400 ml). The solution was decanted, concentrated to 200 ml, and stored in the refrigerator for two days. The product was filtered and the mother liquors concentrated to give a total yield of 30 g (97%), m.p. 103.5-104.5°C. Step D : 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-D-mannopyranoside To a solution of 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranoside (287 mg, 0.79 mmol) in dichloromethane (6 ml) was added cholest-5-en-3β-yl-6-iodohexyl ether (470 mg, 0.79 mmol) and triethylamine (0.11 ml, 0.79 mmol). After stirring under dry nitrogen atmosphere overnight at room temperature, the solvent was removed at reduced pressure and the residue chromatographed on silica gel eluted with 5-25% ethyl acetate in hexanes to give 6-(cholest-5-en-3β-yloxy)hexyl-2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranoside (0.36 g, 55% yield), m.p. 103-103.5°C. This product was dissolved in 1:1 (v/v) ethanol-tetrahydrofuran (10 ml) and treated with a suspension of Bio-Rad AG-1-X2 OH- ion-exchange resin (2.5-3 fold excess) in ethanol (5 ml). After stirring a room temperature for 45 minutes, the resin was filtered and washed with warm tetrahydrofuran (3 x 5 ml), and the combined filtrates concentrated to give 6-(5-cholesten-3β-yloxy)hexyl-1-thio-α-D-mannopyranoside (250 mg, 91% yield) as needles from warm tetrahydrofuran, m.p. (endothermic transitions) 64-64, 81-82, and 226-227°C. EXAMPLE 2 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside A solution of the sodium salt of 1-thio-β-D-mannopyranoside [prepared by the procedure of Tejima, S. et al ., Chem. Pharm. Bull. Jap. , 12 (1964) 528-532] (2.0 g, 9.1 mmol) in water (8 ml) was added to a solution of cholest-5-en-3β-yl-6-iodohexyl ether (6.0 g, 10.0 mmol) in tetrahydrofuran (40 ml) under nitrogen atmosphere. After stirring at room temperature for 24 hours, the solvent was removed by rotoevaporation and the resultant solid mass was purified by flash column chromatography [Still, W. C. et al ., J. Org. Chem. , 43 (1978) 2923-2925] on silica gel eluted with chloroform to 5%-10% methanol/chloroform. The eluent solvent was removed by rotoevaporation to give 6-(5-cholesten-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside as a white powder (6.2 g). The reaction product was chromatographed by thin layer chromatography (TLC) on Analtech Silica Gel GHLF 250 micron plates in 10% methanol/chloroform. The resulting R f value is given below in the Table 1. EXAMPLE 3 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-L-fucopyranoside Employing the procedure substantially as described in Example 2, but substituting for the sodium salt of 1-thio-β-D-mannopyranose, an equivalent amount of the sodium salt of 1-thio-2-L-fucopyranose, this compound is prepared. EXAMPLE 4 6-(5-Cholosten-3β-yloxy)hexyl-1-thio-β-L-fucopyrano-side The title compound was prepared from 2,3,4,6-O-tetra-acetyl-1-thio-β-L-fucopyranose and cholest-5-en-3β-yl-6-iodohexyl ether as described in Ponpipom, M. M. et al ., Can. J. Chem. , 58 (1980) 214-220. EXAMPLE 5 2-(2-(5-Cholesten-3β-yloxy)ethoxy)ethyl-1-thio-β-D-mannopyranoside Employing the procedure substantially as described in Example 1, but substituting for 1,6-hexanediol, used in the preparation of cholest-5-en-3-yl-6-iodohexyl ether thereof, an equivalent amount of diethylene glycol, there was prepared in sequence: Step A : 2-(2-(5-Cholesten-3β-yloxy)ethoxy)ethanol Step B: 2-(5-Cholesten-3β-yloxy)ethyl-2-(p-tolyl sulfonyloxy)ethyl ether Step C : 2-(5-Cholesten-3β-yloxy)ethyl-2-iodoethyl ether Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3-yl-6-iodohexyl ether, an equivalent amount of 2-(5-cholesten-3-yloxy)ethyl-2-iodoethyl ether, there was produced 2-(2-(5-Cholesten-3β-yloxy)ethyl)ethyl 1-thio-β-D-mannopyranoside (Step D). TLC data and R f values are given in the above Table. EXAMPLE 6 6-(stigmasta-5,22-dien-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Employing the procedure substantially as described in Example 1, but substituting for cholest-5-en-3β-yl, used in the preparation of cholest-5-en-3β-yl-6-iodohexyl ether, an equivalent amount of stigmasta-5,22-dien-3β-yl-p-toluenesulfonate, there was prepared in sequence: Step A : Stigmasta-5,22-dien-3β-yl-6-hydroxyhexyl ether Step B : Stigmasta-5,22-dien-3β-yl-6-(p-tolylsulfonyloxy)hexyl ether Step C : Stigmasta-5,22-dien-3β-yl-6-iodohexyl ether Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl-6-iodohexyl ether, an equivalent amount of stigmasta-5,22-dien-3β-yl-6-iodohexyl ether, there was prepared 6-(stigmasta-5,22-dien-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside (Step D). TLC data and R f values are given in the above Table. EXAMPLE 7 6-(Pregn-5-en-20-one-3β-yloxy)hexyl-1-thio-βD-mannopyranoside Employing the procedure substantially as described in the literature [see Example 1], but substituting for cholesteryl-p-toluenesulfonate used in the preparation of cholest-5-en-3β-yl-6-iodohexyl ether, an equivalent amount of 5-pregnen-20-one-3β-yl-p-toluenesulfonate, there was prepared in sequence: Step A : Pregn-5-en-20-one-3β-yl-6-hydroxyhexyl ether Step B : Pregn-5-en-20-one-3β-yl-6-(p-tolylsulfonyloxy)hexyl ether Step C : Pregn-5-3n-20-one-3β-yl-6-iodohexyl ether Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl-6-iodohexyl ether, an equivalent amount of pregn-5-en-20-one-3β-yl-6-iodohexyl ether, there was prepared 6-(pregn-5-en-20-one-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside (Step D). TLC data and R f values are given in the above Table. EXAMPLE 8 6-(17β-Carbomethoxy-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Employing the procedure substantially as described in the literature [see Example 1], but substituting for cholesteryl p-toluenesulfonate used in the preparation of cholest-5-en-3β-yl-6-iodohexyl ether, an equivalent amount of 17β-carbomethoxy-androst-5-en-3β-yl-p-toluenesulfonate, there was prepared in sequence: Step A : 17β-Carbomethoxy-androst-5-en-3β-yl-6-hydroxyhexyl ether Step B : 17β-Carbomethoxy-androst-5-en-3β-yl-6-(p-tolylsulfonyloxy)hexyl ether Step C : 17β-Carbomothoxy-androst-5-en-3β-yl-6-iodohexyl ether Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl-6-iodohexyl ether, an equivalent amount of 17β-carbomethoxy-androst-5-en-3β-yl-6-iodohexyl ether, there was prepared 6-(17β-carbomethoxy-androst-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside (Step D). TLC data and R f values are given in the above Table. EXAMPLE 9 6-(17β-Carbamido-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Step A : 6-(17β-Carboxyl-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside A solution of 6-(17β-carbomethoxy-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside (550 mg) and potassium hydroxide (85%, 110 mg) in methanol (1.4 ml) and water (0.3 ml) was refluxed for 29 hours under a nitrogen atmosphere. After cooling, 6N hydrochloric acid (3 ml) was added and the suspension filtered. The white solid was successively washed with water (5 X) and dried to give the carboxylic acid (316 mg). The 200 MHz NMR spectrum in chloroform-d and the infra-red spectrum of the peracetylated derivative was in accord with the desired structure. Step B : 6-(17β-Carbamido-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside A solution of 6-(17β-carboxyl-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside (425 mg) in chloroform (2 ml) and toluene (2 ml) at 0°C was treated with pyridine (0.5 ml) and oxalyl chloride (0.5 ml). After stirring at room temperature for 2 hours, the solution was added to a solution of chloroform saturated with ammonia gas. After stirring at room temperature for 2 hours, chloroform (150 ml) was added and the solution successively washed with water (3 X) and dried over anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the product as a slightly orange powder. The 200 MHz NMR spectrum in chloroform-d of the peracetylated derivative was in accord with the desired structure. TLC data and R f values given in the above Table. EXAMPLE 10 6-(Pregn-5-en-20-ol-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Sodium borohydride (60 mg) was added to a solution of 6-(pregn-5-en-20-one-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside (250 mg) in absolute ethanol (7 ml). After stirring at room temperature for 4 hours, the solution was cooled and glacial acetic acid (10 ml) was slowly added. The solution was added to chloroform (100 ml) and successively washed with water (3 X), 1N sodium bicarbonate (2 X), and water (1 X) and dried over anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the product as a fine white solid. The 200 MHz NMR spectrum of the peracetylated derivative was in accord with the desired structure. TLC data and R f values are given in the above Table. EXAMPLE 11 6-(20S-Acetamido-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Step A : Pregn-5-en-20-one-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether A solution of pregn-5-en-20-one-3β-yl-6-hydroxyhexyl ether (6.22 g) and p-toluenesulfonic acid (20 mg) in dihydropyran (100 ml) was stirred at room temperature for 18 hours. Solid sodium bicarbonate (1 g) was added and the mixture stirred for 30 minutes. The mixture was filtered through a pad of silica gel which was subsequently washed with 50% ethyl acetate in hexanes. The solvent was removed by rotoevaporation to give the product as a clear colorless oil. TLC data and R f values for compounds A-D are given in the above Table. Step B : 20R-and 20S-Amino-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether Employing the procedure substantially as described in the literature [Lu, M. T., et al ., J. Med. Chem. , 15 (1972) 1284], but substituting for 3β-acetoxy-pregn-5-en-20-one in the preparation of 3β-acetoxy-20-amino-pregn-5-ene, an equivalent amount of pregn-5-en-20-one-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether, there was prepared in sequence: 1) 20-Oximo-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether and 2) 20R,S-Amino-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether. This mixture of diastereomers was separated into its respective 20R- and 20S-amino compounds by HPLC on silica gel eluted with 15% methanol in chloroform. Step C : 20S-Acetamido-pregn-5-en-3β-yl-6-hydroxyhexyl ether A solution of 20S-amino-pregn-5-en-3β-yl-6-(tetrahydropyranyloxy)hexyl ether (23 g) in pyridine (50 ml) and acetic anhydride (30 ml) was stirred at room temperature for 6 hours. The solvent was removed by rotoevaporation at high vacuum to give 20S-acetamido-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether which was subsequently dissolved in tetrahydrofuran (50 ml) and methanol (100 ml). Dowex® 50W-8X (H+ form, 25 g) was added and the mixture stirred for 48 hours. The resin was filtered and the solvent removed by rotoevaporation to give 20S-acetamido-pregn-5-en-3β-yl-6-hydroxyhexyl ether. Step D : 20S-Acetamido-pregn-5-en-3β-yl-6-iodohexyl ether Employing the procedure substantially as described in the literature [see Example 1], but substituting for cholest-5-en-3β-yl 6-hydroxyhexyl ether in the preparation of cholest-5-en-3β-yl-6-iodohexyl ether, an equivalent amount of 20S-acetamido-pregn-5-en-3β-yl-6-hydroxyhexyl ether, there was prepared 20S-acetamido-pregn-5-en-3β-yl-6-(p-tolylsulfonyloxy)hexyl ether and 20S-acetamido-pregn-5-en-3β-yl-6-iodohexyl ether. Step E : 6-(20S-Acetamido-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl 6-iodohexyl ether, an equivalent amount of 20S-acetamido-pregn-5-en-3β-yl-6-iodohexyl ether, there was prepared 6-(20S-acetamido-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside. EXAMPLE 12 6-(20R-Acetamido-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Employing the procedure substantially as described in Example 10, Steps C through E, but substituting for 20S-acetamido-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether, an equivalent amount of 20R-acetamido-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether, there was prepared in sequence: Step C : 20R-Acetamido-pregn-5-en-3β-yl-6-hydroxyhexyl ether Step D : 20R-Acetamido-pregn-5-en-3β-yl-6-iodohexyl ether Step E : 6-(20R-Acetamido-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside TLC data and R f values for compounds C-E are given in the above Table. EXAMPLE 13 6-(20R-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Step A : N-(2,2,2-trichloro-ethoxycarbonyl)-20R-amino-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether To a solution of 20R-amino-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether [see Example 11, Step B] (1.2 g) in pyridine (5 ml) under a dry nitrogen atmosphere was added 2,2,2-trichloro-ethoxycarbonyl chloride (1 ml). After stirring at room temperature for 6 hours, chloroform (100 ml) was added and the solution was washed successively with 1N hydrochloric acid (3 X), 1N sodium bicarbonate solution (2 X). The solution was dried over anhydrous sodium sulfate and the solvent removed by rotoevaporation to give the product. TLC data and R f values for compounds A-E are given in the above Table. Step B : N-(2,2,2-trichloro-ethoxycarbonyl)-20R-amino-pregn-5-en-3β-yl-6-hydroxyhexyl ether A solution of N-(2,2,2-trichloro-ethoxycarbonyl)-20R-amino-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether (1.6 g) in methanol (10 ml) containing Dowex® 50W-8X (H+ form, 3 g) was stirred at room temperature for 34 hours. Ethyl acetate (100 ml) was added, the mixture filtered, and the solution washed successively with 1N sodium bicarbonate solution (3 X) and water (2 X). After drying over anhydrous sodium sulfate, the solvent was removed by rotoevaporation to give the product. Step C : N-(2,2,2-Trichloro-ethoxycarbonyl)-20R-amino-pregn-5-en-3β-yl-6-iodohexyl ether Employing the procedure substantially as described in the literature [see Example 1], but substituting for cholest-5-en-3β-yl-6-hydroxyhexyl ether in the preparation of cholest-5-en-3β-yl-6-iodohexyl ether, an equivalent amount of N-(2,2,2-trichloro-ethoxycarbonyl)-20R-amino-pregn-5-en-3β-yl-6-hydroxyhexyl ether, there was prepared this compound. Step D : 6-(N-(2,2,2-Trichloro-ethoxycarbonyl)-20R-amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Employing the procedure substantially as described in Example 2, but substituting for cholest-5-en-3β-yl-6-iodohexyl ether, an equivalent amount of N-(2,2,2-trichloro-ethoxycarbonyl)-20R-amino-pregn-5-en-3β-yl-6-iodohexyl ether, there was prepared this compound. Step E : 6-(20R-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside To a solution of 6-(N-(2,2,2-trichloroethoxycarbonyl)-20R-amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside (2.7 g) in glacial acetic acid (10 ml) was added in portions zinc dust (3.4 g) over a 70 hour period. Tetrahydrofuran (100 ml) and methanol (20 ml) were added and the mixture was filtered. The solvent was removed by rotoevaporation and the residue dissolved in methanol (50 ml) to which was added solid sodium bicarbonate (5 g). After stirring for 15 minutes, the mixture was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 10%-20% methanol in chloroform to give this compound. EXAMPLE 14 6-(20S-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Employing the procedure substantially as described in Example 13, but substituting for 20R-amino-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether, an equivalent amount of 20S-amino-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether, there was prepared in sequence: Step A : N-(2,2,2-trichloro-ethoxycarbonyl)-20S-amino-pregn-5-en-3β-yl-6-(2-tetrahydropyranyloxy)hexyl ether Step B : N-(2,2,2-Trichloro-ethoxycarbonyl)-20S-amino-pregn-5-en-3β-yl-6-hydroxyhexyl ether Step C : N-(2,2,2-Trichloro-ethoxycarbonyl)-20S-amino-pregn-5-en-3β-yl-6-iodohexyl ether Step D : 6-(N-(2,2,2-Trichloro-ethoxycarbonyl)-20S-amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside Step E : 6-(20S-amino-pregn-5-en-3β-yloxy)hexyl 1-thio-β-D-mannopyranoside EXAMPLE 15 In vivo Stimulation of Host Resistance Pseudomonas aeruginosa in vivo Protection Studies . Groups of 15-20 CF1 femal mice (Charles River Breeding, Cambridge, MA) weighing 22-28 gm were injected intraperitoneally (i.p.) with cyclophosphamide (Cytoxan; CY) at 250 mg per kg body weight. One to two hours later they were typically injected again with the test material by the route specified. Four days later, the mice were divided into groups of five, each of which were injected i.p. with a different dilution of a suspension of Pseudomonas aeruginosa (Immunotype 1). The number of survivors was determined periodically and an estimate was made of the number of CFU of Pseudomonas organisms necessary to cause 50% lethality by the cumulative method of L. J. Reed and H Muench ( Am. J. Hygiene 27 (1938) 493-497). A protective index (P.I.) was defined as the LD₅₀ for the mice receiving cyclophosphamide and the test compound divided by the LD₅₀ for the mice recieving cyclophosphamide alone. All control mice were injected with aqueous vehicle in the same route and schedule as the test animals. MATERIALS . All compounds for dosing were suspended in a sterile medium referred to as "aqueous vehicle" which contains 0.9% sodium chloride 0.5% carboxymethyl cellulose, 0.4% Tween® 80, and 0.9% benzyl alcohol unless otherwise stated. Test materials were evaluated via subcutaneous (s.c.), i.p., intramuscular (i.m.), orally (p.o.). and intravenous (i.v.) routes of administration. The initial test dose was 40 mg per kg per mouse, with each active compound subsequently titrated below this level. INFECTION OF ANIMALS . All bacteria were inoculated i.p. to induce infection in the in vivo experiments. Candida albicans , however, was administrated i.v. Bacteria cultures were harvested in the log phase, washed with phosphate buffered saline (PBS, and resuspended in PBS containing 10% glycerol for freezing at -70°C in 1 ml aliquots. The number of cell free units (cfu's) was determined before and after freezing. Frozen cultures were routinely thawed and diluted in sterile PBS just prior to inoculation. Viable cell counts were routinely done on thawed cultures the day of challenge to determine the number of cfu's. Candida albicans was stored in distilled water at room temperature. Viable cell counts were determined the day of testing. The testing and results of 6-(5-cholesten-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside (Example 2) against various organisms is shown in Table 2. The results of other claimed or used compounds of the invention tested for protection against Pseudomonas aeruginosa infection are shown in Table 3.

Claims: Use of a compound of the formula: where: R¹ is α or β- D -1-thiomannopyranoside, α or β-L-1-thiofucopyranoside; A is (CH₂) n where n is 5-7, or (CH₂) k X(CH₂) m where X is O or S or NH and k and m are independently 2-4 and the sum of k and m is 4-6; R² is C₁-C₈ alkyl or C₂-C₁₀ linear or branched alkenyl; where B is C₁-C₈ alkyl, C₁-C₈ alkoxy, NR³R⁴ where R³ and R⁴ are independently H, C₁-C₄ alkyl; CH(CH₃)D where D is OH, NH₂, NHR⁵ where R is C₁-C₁₀ alkyl or acetyl, or of a pharmaceutically acceptable salt thereof, for the preperation of a pharmaceutical composition for enhancing host resistance in an immunocompromised individual. The use according to Claim 1 characterized in that said compound is present in an amount effective to exert an immunostimulant effect. The use according to Claim 1 characterized in that R² of the formula is the cholesterol 17-side chain. The use according to Claim 1 characterized in that R² of the formula is the stigmasterol 17-side chain. The use according to Claim 1 characterized in that is The use according to Claim 1 characterized in that CH(CH₃)D is CH₃-CHOH-, CH₃CH(NHCOCH₃)-, or CH₃CH(NH₂)-. The use according to Claim 1 characterized in that said compound is selected from: 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-D-mannopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-L-fucopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-L-fucopyranoside; 2-(2-(5-Cholesten-3β-yloxy)ethoxy)ethyl-1-thio-β-D-mannopyranoside; 6-(Stigmasta-5,22-dien-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(Pregn-5-en-20-one-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbomethoxy-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbamido-androst-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(Pregn-5-en-20-ol-3β-yloxy)heiyl-1-thio-β-D-mannopyranoside; 6-(20S-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20R-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; or 6-(20R-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside. A compound of the formula: where: R¹ is α or β- D -1-thiomannopyranoside, α or β-L-1-thiofucopyranoside; A is (CH₂) n where n is 5-7, or (CH₂) k X(CH₂) m where X is O, S or NH and k and m are independently 2-4 and the sum of k and m is 4-6; R² is C₁-C₈ alkyl or C₂-C₁₀ linear or branched alkenyl; where B is C₁-C₈ alkyl, C₁-C₈ alkoxy, NR³R⁴ where R³ and R⁴ are independently H, C₁-C₄ alkyl; CH(CH₃)D where D is OH, NH₂, NHR⁵ where R⁵ is C₁-C₁₀ alkyl or acetyl; with the exception of 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-D-mannopyranoside; and 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-L-fuco-pyranoside. The compound of Claim 8 selected from: 6-(Pregn-5-en-20-one-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbomethoxy-androst-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(17β-Carbamido-androst-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(Pregn-5-en-20-ol-3β-ylozy)hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20R-Acetamido-pregn-5-en-3β-yloxy)-hexyl-1-thio-β-D-mannopyranoside; 6-(20S-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; or 6-(20R-Amino-pregn-5-en-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside; 6-(5-Cholesten-3β-yloxy)hexyl-1-thio-α-L-fuco-pyranoside; 2-(2-(5-Cholesten-3β-yloxy)ethoxy)ethyl-1-thio-β-D-mannopyranoside; 6-(Stigmasta-5,22-dien-3β-yloxy)hexyl-1-thio-β-D-mannopyranoside. A pharmaceutical composition for enhancing host resistance in an immunocompromised individual consisting of a compound of Claims 8 or 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.

Inventors: DURETTE, PHILIPPE L., HAGMANN, WILLIAM K., PONPIPOM, MITREE M.
Applicants: MERCK & CO. INC.
Application year: 1986
Main classification: A61K31
IPC codes: C07J41, C07J31