Substituted liposaccharides useful in the treatment and prevention of endotoxemia

Abstract

Compounds of formula (I) - in the formula R1 is a group of formula (a), (b), (c), (d), (e), (f), (g) or (h), where J, K and Q are independently C1-C15 alkyl, L is O, NH or CH2, M is O or NH and G is NH, O, S, SO or SO2; R2 is a C5-C15 alkyl; R3 is an acyl group of C5-C15 or a group of formula (i), (j), (k), (l) or (m), where E is NH, O, S, SO or SO2, A, B and D are independently C1-C15 alkyl; R4 is an alkyl group of C4-C20 or a group of formula (n), where U and V are independently C2-C15 alkyl and W is hydrogen or an alkyl group of C1-C5; RA is R5 or R5–O–CH2, R5 is hydrogen or a group of the general formula –J', –J'–OH, –J'–O–K', –J'–O–K'–OH or –J'–O–PO(OH)2, where J' and K' are alkyl groups having 1-5 carbon atoms;R6 is hydroxyl, halogen, C1-C5 alkoxy or C1-C5 acyloxy; A1 and A2 are independently OH, a group of formula (o), or a group of formula (p), (q) or (r) in which Z is a C1-C10 alkyl group - and pharmaceutically acceptable salts thereof, which are useful for the prevention and treatment of endotoxemia (e.g. sepsis, septicemia and various forms of septic shock). The preparation of the above compounds is also described. à;

Description

The invention relates to compounds which are useful for the prophylactic or therapeutic treatment of the effects of endotoxins, including sepsis, septicemia, endotoxemia and various forms of septic shock. More particularly, the invention relates to lipid-A analogs which are useful as inhibitors of endotoxemia. The incidence of Gram-negative bacteremia in the United States is estimated to be approximately 100,000-300,000 cases / year, with a mortality rate of 30-60%. Antibiotics are commonly used as primary chemotherapy for this disease; however, their bactericidal effect can result in bacterial lysis and the concomitant release of endotoxin, a lipopolysaccharide (LPS) residue from the bacterial outer membrane. The released LPS induces a number of pathophysiological events in mammals (collectively referred to as Gram-negative endotoxemia or sepsis syndrome). These include fever, generalized inflammation, disseminated intravascular coagulation (DIC), hypotension, acute renal failure, acute respiratory distress syndrome (ARDS), hepatocellular damage, and heart failure. Although endotoxin induces septic shock, it has little or no direct toxic effect on tissues; on the contrary, it triggers an immunobiological response that leads to a cascade of cytokines, such as tumor necrosis factor (TNF), interleukin-1, interleukin-6, and interleukin-8, and other biological mediators, such as nitric oxide, as well as a series of secondary mediators (such as prostaglandins, leukotrienes, interferons, platelet-activating factor, endorphins, and colony-stimulating factors). The development of pathophysiological concentrations of the above cytokines and inflammatory mediators affects vasomotor tone, microvascular permeability, and leukocyte and platelet aggregation, causing a syndrome called systemic inflammatory response syndrome (SIRS) and septic shock. The bacterial lipopolysaccharide molecule has three main regions: a long-chain polysaccharide (O antigen), a core region, and a lipid-A region. The entire lipopolysaccharide molecule, as well as its individual components, have toxic effects as described above. However, most of the above toxic effects are attributed to the lipid-A portion. Structurally, lipid-A consists of a diphosphorylated disaccharide acylated with long-chain fatty acids. Treatments for endotoxin-related diseases are generally directed at controlling the inflammatory response. Such therapies include corticosteroid therapy, which is used to attenuate endotoxin-mediated cell membrane damage and reduce the production of certain biological mediators; administration of antibodies that neutralize bacterial LPS; treatment with antihypertensive agents or naloxone, which is likely to block the hypotensive effects associated with the sepsis syndrome; and treatment with nonsteroidal anti-inflammatory drugs, which aim to completely inhibit cyclooxygenases and thereby reduce the production of certain secondary mediators, such as prostaglandins and thromboxane. However, none of the above known therapies have resulted in a significant reduction in morbidity and mortality from sepsis and septic shock syndrome. Therefore, there is a long-standing need for agents that can satisfactorily treat the above disease. In USSN 07 / 935,050, filed August 25, 1992 (the contents of which are incorporated herein by reference), Christ et al. disclose disaccharide compounds useful in the treatment of endotoxemia, such as the compound of formula B531. Lipopolysaccharide compounds are also described, for example, by Macher et al. (GB 2179945), Meyers et al. (GB 2220211), Shiba et al. (EP 172581), Anderson et al. (US 4495346) and Shiba et al. (US 5066794). The invention relates to novel lipopolysaccharide analogues for the treatment of sepsis, septic shock, endotoxemia and related disorders. The compounds of the invention have advantageous properties for therapeutic use, such as increased pharmacological selectivity, efficacy and, in particular, increased long-lasting effects. One representative of the compounds of the invention is compound 1 of formula (1-1). The invention further relates to the use of the above compounds for the treatment and prevention of disorders mediated by LPS. Such disorders include, for example, sepsis, septicemia (including endotoxemia), endotoxemia resulting from Gram-negative bacteremia [with associated symptoms such as fever, generalized inflammation, disseminated intravascular coagulation, hypotension, acute respiratory distress syndrome, adult respiratory distress syndrome (ARDS), hepatocellular damage and / or heart failure], and various forms of septic shock (e.g. endotoxic shock). Thus, the compounds of the invention can be used for the prophylactic or therapeutic treatment of localized or systemic inflammatory responses to infections caused by various types of organisms (including Gram-negative bacteria), and for the prevention and treatment of diseases associated with the translocation of Gram-negative bacteria or endotoxin from the intestines. The above disorders are collectively referred to as systemic inflammatory response syndrome or SIRS [for a detailed discussion of the above terms, see Boné et al., Chest 101, 1644-1655 (1992)]. The terms used in this specification are interpreted as follows unless expressly defined otherwise. Alkyl groups are aliphatic, organic groups that have a branched or straight carbon chain and a given In this case, they may be substituted with one or more halogen atoms at any position of the alkyl chain. Alkyl groups are understood to include groups having one free valence, such as the -CH2-CH3 group, and alkylene groups having two free valences, such as the -CH2-CH2- group. It is understood by those skilled in the art that one or two free valences are used interchangeably to describe chemically stable compounds. In the description, prodrugs are understood as compounds which have a lower intrinsic activity than the drug itself, but which, upon administration to a biological system, yield a drug substance either by spontaneous chemical reaction or by enzyme-catalyzed or metabolic reaction. Various prodrugs, such as acyl esters, carbonates, phosphates and methanes, may be mentioned by way of example. The above groups are mentioned by way of example only, without any intention of limitation, of various prodrugs known to those skilled in the art. The above prodrugs of the compounds of general formula (I) are within the scope of the invention. A pharmaceutically acceptable salt is understood to mean a salt of a compound of formula (I) which is formed by reacting the compounds of the invention with an organic or inorganic acid or base. The compounds of formula (I) may be used in both the unionized and salt forms. In practice, the use of the salt form is equivalent to the use of the base form, and both forms are within the scope of the invention. Geometrical isomers are understood to mean trans or cis isomers, which are known to those skilled in the art. All geometric isomers are within the scope of the invention. The compounds of the invention may also contain asymmetric carbon atoms and therefore may exist as stereoisomers, both enantiomers and diastereomers. The invention includes all stereoisomers and mixtures thereof. In the preparation examples described herein, the most preferred isomer is prepared. It goes without saying that asymmetric carbon atoms other than the sugar residue may also be present in the compounds of formula (I), for example in side chains. In this case, all diastereomers thus formed are within the scope of the invention. The figures are briefly described below. Figure 1 shows the inhibition of TNF-α release by Compound 1, illustrating the inhibition of LPS-mediated induction of tumor necrosis factor (TNF) by the compound of the invention in human whole blood. Figure 2 shows the general scheme used to determine the antagonistic potency of an agent in whole blood after incubation for various times. Figure 3 shows the TNF-α inhibitory effect of the test compound of the invention over time, demonstrating that Compound 1 has a longer-lasting effect as an LPS antagonist than Compound B531. These data represent the average of 7 independent experiments, each experiment being performed in triplicate. The invention is described in detail below. New lipopolysaccharides The invention relates, on the one hand, to a novel use of substituted lipopolysaccharides, which include compounds of general formula (I) - in the formula R1 is a group of general formula (a), (b), (c), (d), (e), (f), (g) or (h), where J, K and Q independently represent a straight or branched alkyl group having 1-15 carbon atoms, L is O, NH or CH2, M is O or NH and G is NH, O, S, SO or SO2; R2 represents a straight or branched alkyl group having 5 to 15 carbon atoms; R3 represents a straight or branched acyl group having 5-15 carbon atoms, or a group of general formula (i), (j), (k), (1) or (m), where E is NH, O, S, SO or SO2, A, B and D are independently a straight or branched alkyl group having 1 to 15 carbon atoms; R4 represents a straight or branched alkyl group having 4 to 20 carbon atoms, or a group of the general formula (n), where U and V independently represent a straight or branched alkyl group having 2-15 carbon atoms and W represents a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms; R represents R5 or R5-O-CH2, R5 is hydrogen or -J', -J'-OH, -J'-O-K', -J'-O-K'-OH or -J'-O-PO(OH)2 group, where J' and K' are independently a straight or branched alkyl group having 1-5 carbon atoms; R6 represents a hydroxyl group, a halogen atom, a C1-C5 alkoxy group or a C1-C5 acyloxy group; A1 and A2 independently represent OH, a group of formula (o), or a group of formula (p) or (r), in which Z represents a straight or branched alkyl group having 1 to 10 carbon atoms -; and pharmaceutically acceptable salts thereof. Embodiments of the compounds of formula (I) above include the following, or combinations thereof: R2 is a straight or branched alkyl group having 8 to 15 carbon atoms; R2 represents a straight or branched alkyl group having 9-12 carbon atoms; R2 is a straight or branched alkyl group having 10 carbon atoms; HU 221 342 B1 A1 and A2 independently represent OH or -O-PO(OH)2; R6 represents a hydroxyl group; R5 represents a straight or branched alkyl group having 1 to 5 carbon atoms; R1 is a group of formula (a), (b), (e) or (h), where J, K, and Q are independently a straight or branched alkyl group having 1 to 15 carbon atoms; R3 is a group of formula (i) or (j), wherein A, B and D independently represent a straight or branched C1-C15 alkyl group; the double bonds in R3 are in the cis configuration; the double bonds in R3 are in the trans configuration; R4 represents a straight or branched alkyl group having 4 to 20 carbon atoms, or a group of the general formula (n) in which U represents a straight or branched alkyl group having 2-5 carbon atoms, V represents a straight or branched alkyl group having 5-12 carbon atoms and W represents a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms; RA means R5; and RA means R5-O-CH2-. In further embodiments A1 and A2 independently represent OH or -O-PO(OH)2; R1 is a group of general formula (a), (b), (e) or (h) in which J, K, and Q are independently a straight or branched alkyl group having 1 to 15 carbon atoms; R2 represents a straight or branched alkyl group having 8 to 15 carbon atoms; R3 represents a group of general formula (i) or (j) in which A, B and D are independently a straight or branched alkyl group having 1 to 15 carbon atoms; R4 means a group of general formula (n), where U represents a straight or branched alkyl group having 2-5 carbon atoms, V represents a straight or branched alkyl group having 5-12 carbon atoms and W represents a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms; and R5 is a straight or branched alkyl group having 1 to 5 carbon atoms; and R6 represents a hydroxyl group. In another embodiment A1 and A2 independently represent -O-PO(OH)2; R1 represents a group of formula (a), (b), (e) or (h), wherein J and Q independently represent a straight or branched alkyl group having 1-5 carbon atoms and K is a straight or branched alkyl group having 8 to 15 carbon atoms; R2 represents a straight or branched alkyl group having 8 to 15 carbon atoms; R3 means a group of general formula (i) in which The meaning is straight or branched chain, C5-12 alkyl group and B means straight or branched carbon chain, C6-12 alkyl group; R4 means a group of general formula (n) in which U represents a straight or branched alkyl group having 2-5 carbon atoms, V means straight or branched carbon chain, C5-12 alkyl group and W represents a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms; and R5 is a straight or branched alkyl group having 1 to 5 carbon atoms; and R6 represents a hydroxyl group. In another embodiment, A1 and A2 are -O-PO(OH)2; R1 is a group of general formula (b), (e) or (h) in which J and Q independently represent a straight or branched carbon chain alkyl group having 1-3 carbon atoms and K is a straight or branched alkyl group having 10-12 carbon atoms; R2 represents a straight or branched alkyl group having 9-12 carbon atoms; R3 means a group of general formula (i) in which A represents a straight or branched chain alkyl group of 8-12 carbon atoms and B means straight or branched carbon chain, C6-10 alkyl group; R4 means a group of general formula (n) in which U represents a straight or branched alkyl group having 2-4 carbon atoms, V represents a straight or branched alkyl group having 5-12 carbon atoms and W represents a hydrogen atom, a straight or branched carbon chain alkyl group having 1-3 carbon atoms; and R5 is a straight or branched alkyl group having 1-3 carbon atoms; and R6 represents a hydroxyl group. In a further embodiment, A1 and A2 are -O-PO(OH)2; R1 is a group of formula (s); R2 is -(CH2)9CH3; R3 is a group of formula (t); R4 is a group of formula (u); R5 is -CH3 and R6 is hydroxyl. The invention also includes compounds in which R1 and R3 contain a sulfonyl group, i.e. compounds in which the carbonyl group in the above side chains is replaced by an SO2 group. These compounds are prepared by reacting the appropriately substituted sugar alcohol with a suitable HU 221 342 Bl is reacted with alkylsulfonyl chloride. Thus, R1 and R3 may also be a group of the general formula (x), (y), (w), (z), (aa), (bb), (cc) or (dd), in which A, B, D, E, J, K, L, Q and M have the meanings given above. The invention also includes compounds in which the unsaturation in the R3 side chain is not a double or triple carbon-carbon bond, but an optionally substituted aromatic group, i.e. compounds in which R3 is a group of general formula (ee), (ff) or (gg), where E is NH, O, S, SO or SO2, A independently represents a straight or branched alkylene group having 1-15 carbon atoms, D is a straight or branched alkyl group having 1-15 carbon atoms, F is Η, -OT, NT'T2, -CO2T or a phenyl group, where T, T1 and T2 independently represent a hydrogen atom or an alkyl group having 1-5 carbon atoms B means straight or branched carbon chain, Alkyl group with 1-15 carbon atoms. Generally, compounds are preferred in which R1 is a group of general formula (b), (e) or (h) in which J, K and Q are independently a straight or branched alkyl group having 1 to 15 carbon atoms; R2 represents a straight or branched alkyl group having 8 to 12 carbon atoms; R3 represents a group of general formula (i) or (j) in which A, B and D are independently a straight or branched alkyl group having 1 to 15 carbon atoms; R4 means a group of general formula (n) in which U means straight or branched carbon chain, C2-5 alkyl group, V represents a straight or branched alkyl group having 4-10 carbon atoms and W represents a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms; R5 is a hydrogen atom, a group of the general formula -J' or -J'OH, in which J' is a straight or branched carbon chain, C1-5 alkyl group; R6 represents a hydroxyl group, a halogen atom or an acyloxy group having 1-5 carbon atoms; A1 and A2 independently represent OH or a group of formula (o); and pharmaceutically acceptable salts thereof. Most preferred are those compounds of general formula (I) in which R1 is a group of general formula (b) or (h) in which J is a straight or branched chain alkyl group having 1-5 carbon atoms and K. represents a straight or branched alkyl group having 9-14 carbon atoms; R2 represents a straight or branched alkyl group having 8 to 12 carbon atoms; R3 means a group of general formula (i) in which A represents a straight or branched alkyl group having 6 to 12 carbon atoms and B means straight or branched carbon chain, C4-C8 alkyl group; R4 means a group of general formula (n) in which U represents a straight or branched alkyl group having 2-4 carbon atoms, V means straight or branched carbon chain, C5-C9 alkyl group and W represents a hydrogen atom or a straight or branched alkyl group having 1 to 3 carbon atoms; R5 represents a straight or branched alkyl group having 1 to 3 carbon atoms; R6 represents a hydroxyl group; A1 and A2 are a group of formula (o); and pharmaceutically acceptable salts thereof. The invention also relates to processes for the preparation of compounds of formula (I). General synthetic processes are described herein which are suitable for the preparation of variously substituted compounds of the invention. The preparation of one of the compounds of the invention, compound 1, is described below. Most of the starting materials and reactants are well known to those skilled in the art. Certain of the starting materials and reactants described in the following preparation process are described in detail by Christ et al. in U.S. Patent No. 5,530,113, filed 07 / 935,050, the contents of which are incorporated herein by reference. One method for preparing the compounds of the invention is described below. Although the preparation of compound 1 is described in this example, other analogs of the invention can be prepared using suitable starting materials. Therefore, this preparation method is actually a general preparation method. For example, by using appropriate alkylating agents in reaction step 22, structurally different analogs can be prepared in terms of the meaning of the R1 substituent. The introduction of the groups indicated for R2 can be ensured in reaction step 15 by using a suitable alkylating agent. In addition, in reaction step 25, by replacing the reactant described herein with a suitable reactant, analogs can be prepared that contain a different group for R3. Analogs without Ra oxygenated side chains can be prepared by minor modifications of the synthetic procedure described below, which are well known to those skilled in the art. For example, to prepare compounds of formula (I) in which RA is methyl, this leaving group in the tosylate product of step 8 can be replaced by an iodine atom in the Finklestein reaction. The iodine compound can be dehalogenated by treatment with zinc metal, HU 221 342 Β1 thus we obtain a compound containing a methyl group in the RA value. An example of the synthesis of the R4 side chain is given below. Various changes in this side chain can be achieved by replacing the original starting material with a suitable starting material, for example, the length or branching of the side chain can be influenced by using the appropriate starting material. Thus, the use of appropriate tosylates in reaction step 6 leads to compounds of general formula (I) containing different R4 groups (reaction scheme 1). The synthesis shown in Scheme 2 provides general routes for the preparation of compounds of the invention (see the working examples for details of the preparation procedure). Although we believe that Process 1 of Scheme 2 is advantageous for the preparation of the compounds of the invention due to various factors, including, for example, the use of cheaper starting materials, higher yields, and less toxic chemicals, Process 2 (Schemes 3-6) described below can also be used to prepare the compounds of the invention. Most of the reactants and starting materials are well known to those skilled in the art. Certain reactants and starting materials for Process 2 of the invention are described in detail by Christ et al. in US 07 / 935,050, the contents of which are incorporated herein by reference. Although the preparation of Compound 1 is described in this example, other analogs of the invention can be prepared using appropriate starting materials. Therefore, the synthesis is a truly general process. For example, using a different alkylating agent to prepare the intermediate of formula U can produce structurally different analogs at the R1 substituent. The group represented by R2 in the preparation of the intermediate of formula O can be controlled by using the appropriate alkylating agent. Additionally, by substituting an appropriate compound for intermediate E in the preparation of intermediate G, analogs with different R3 values ​​can be prepared. The preparation of the R4 side chain is illustrated below (Scheme 3). The preparation of variations of the above side chain can be achieved by replacing the starting material with other suitable starting materials. For example, the length or branching of the above side chain can be controlled by using a suitable starting material. (Details of the synthesis are described in the working examples.) The preparation of the “left-hand” part of the molecule can be carried out according to Scheme 4. The preparation of the "right-hand" part of compound 1 can be carried out by the procedure of Scheme 5. These two parts of the molecule are then coupled using the process of Scheme 6 to produce Compound 1. The invention also relates to pharmaceutical compositions containing the compounds of general formula (I) according to the invention. The lipid A analogs of the invention may be administered at doses that provide adequate inhibition of LPS activation of target cells; these doses are generally preferably in the range of 0.01-50 mg / patient, more preferably 0.05-25 mg / patient, and most preferably 1-12 mg / patient. The above doses are most preferably administered as a continuous infusion over 3 days. Parenteral administration includes subcutaneous, intravenous, intramuscular and intraarterial injections using various infusion techniques. Intraarterial and intravenous injections are administered through a catheter. For certain indications, administration methods that provide rapid delivery to the tissue or organ to be treated are preferred, such as intravenous injections for the treatment of endotoxemia. Pharmaceutical compositions containing the active ingredient may be in a form suitable for any desired route of administration. The aqueous suspensions of the invention contain the active ingredient in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; and dispersing or wetting agents such as naturally occurring phosphatidone (e.g. lecithin), condensation products of alkylene oxides with fatty acids (e.g. poly(oxyethylene) stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g. heptadeca(ethyleneoxy)cetanol), condensation products of ethylene oxide with partial esters of fatty acids and hexyl anhydride (e.g. poly(oxyethylene) sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate. The pharmaceutical compositions of the invention are preferably in the form of sterile injectable preparations, for example sterile injectable aqueous or oleaginous suspensions. These suspensions may be prepared by methods known to those skilled in the art using suitable dispersing or wetting agents and suspending agents, as described above. The sterile injectable preparations may be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example solutions in 1,3-butanediol, or may be lyophilized powders. Acceptable carriers and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose, any sterile, fixed oil may be employed, such as synthetic mono- or diglycerides.Additionally, fatty acids, such as oleic acid, can be used to prepare injectable compositions. Preparations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, bacteriostats and solutes such as: HU 221 342 Bl which render the preparation isotonic with the blood of the patient to be treated; suitable preparations are also aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The preparations may be presented in unit doses or in sealed containers containing multiple doses, such as ampoules or tubes, and may be stored in a freeze-dried (lyophilized) state, to which only the sterile liquid carrier, such as water for injection, need be added immediately before use. Freshly prepared injection solutions and suspensions may be prepared from the sterile powders described above. It will be understood, however, that the specific dosage level useful for treating a particular patient will vary depending on a variety of factors, including the activity of the compound being administered; the age, weight, general health, and sex of the patient being treated; the time and route of administration; the rate of clearance; and other medications previously administered; and the severity of the disease being treated. The compounds of the invention and their preparation and use are illustrated in more detail by the following examples. These examples are presented without any intention of limitation. It is understood that modifications that are obvious to those skilled in the art also fall within the scope of the invention. The compounds of the invention are identified by compound number as shown in Table 1. EN 221 342 B1 Table 1. Compounds of general formula (I) oaaaaaaaaaaa Oá oooooooooonnnaa a1 aaaaaaau U υ u υ uuu ω U n QC oooooooo X aaaaaaaaaauu X u υ u υ ou <_> o υ CO X uaa s— ua X u X u X nanan z-^ -e X uaa ÍN aaa X ua X u X u x_z uu υ auuo rt aaaa OS aa á' aaaooooououuo '^zx»z X oooaaauaaa X υ U uu υ X o XX o* CN uoo u XÍN Xu a” aaaa uuu xz naaaaaaaaaaau υ uuu υ uou <_> ZX z—X z—x ZX z—XZ“X z-í? zx Z-Í' Z^xaanaaaa X aaauuauou UU uu υ U υ aaaaaa X aaa V u zx u υ uuouu 0£ il II X II II II || II II II aauaaaa X aaa υ υ t_> υ uu υ O o υ Z·*·.Z—X oz^ z“x Z-? zx oz—X z-2? z-? aaaaa X* aaauu U uu υ u υ uoooooooouu υ uuu υ uaaaaaaaaaaaaa 4 Z— 4 o Z-x.4 uX zu Qí zX zx zX Z^xz^x z-? aaaa £ aaaa á a υ u υ ouou U uuu x_z ana rí a rí na Π a rí aau rí auu © o © X u © rí auu υ o íN ÍN υ oao zx ín a © a ÍN υ au ö auou •^Z a υ ÍN aaa υ ooooo X uuoooa* uuaauua X uuoo X oaa υ u ÍN auuuao ÍN uuu CN uooo υ oaa PL o υ u υ ouu Å ouour\ o <N ín ÍN ÍN ÍN ÍN ÍN a a a a a a a a a a a < o o o o. o o o o o o o < o o o o o o o ó o o ö CL CL CL CL CL CL CL CL CL CL CL o o o o o o o o o o o —H CM co ^r kC>or Cs or ^4 s* “. HU 221 342 Β1 Chemical shooting Unless otherwise noted, all reactions were carried out under inert atmosphere. The intermediates and final products had the expected structures based on their spectral analysis (e.g., nuclear magnetic resonance, spectroscopy, and / or mass spectroscopy). The course of the reactions was monitored by thin-layer chromatography on silica gel. Preparative chromatography was performed on silica gel unless otherwise noted. Preparation of compound 1 by method 1 Sensitive reactions were performed under nitrogen atmosphere and in dry equipment, using anhydrous sodium sulfate as a drying agent unless otherwise noted. All products showed appropriate nuclear magnetic resonance spectra. Purification of compound (1) kg of material was chromatographed on silica gel and eluted with a gradient of hexane and ethyl acetate (100%→33% hexane). The pure fractions were combined and distilled at 97-100 °C, 19.35 Pa. 4513 g of purified material was obtained. Preparation of compound of formula (2) (Scheme 7) To an ice-cold solution of 4500 g (22.2 mol) of ester (1) in 12.6 l of tetrahydrofuran was added 27 mol of sodium hydroxide in 10.8 l of water. The mixture was stirred briefly and then 2.5 l of concentrated hydrochloric acid was added. The phases were separated and the aqueous phase was re-extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated. The product slowly crystallized. 2983 g of the title compound was obtained as a white powder. Purification of compound of formula (2) To a solution of 15.8 mol of the acid of formula (2) in 33 L of acetonitrile was added 16.7 mol of dicyclohexylamine. The solution was heated to 60 °C and allowed to cool overnight. The crystals were collected and washed twice with solvent and recrystallized from acetonitrile. The above salt was added to a suspension of 12 kg of Amberlite IR-120 Plus (previously washed with methanol) in 24 L of ethyl acetate and 24 L of water. The mixture was stirred for several hours and the organic phase was separated. The aqueous phase was re-extracted with 12 L of ethyl acetate and the combined organic phases were dried over anhydrous sodium sulfate and concentrated. 2997 g of a white solid were obtained. Preparation of compound of formula (3) (Scheme 8) To a warm (about 67 °C) solution of lithium aluminum hydride (1.1 mol / l) in tetrahydrofuran is slowly added a solution of 1 kg of the acid (2) in 4 l of tetrahydrofuran. The solution is allowed to cool overnight. The solution is slowly added to 5 l of aqueous hydrochloric acid (1.1 mol / l). The mixture is extracted with 12 l of toluene. The organic phase is washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent is removed in vacuo. The resulting syrup is distilled at 103 °C. 914 g of the title compound are obtained as a pale yellow oil. Preparation of compound of formula (4) (Scheme 9) To a solution of 913.8 g of diol of formula (3) in 3 L of pyridine at 0 °C was added 3 L of triethylamine, followed by a solution of 1 kg of tosyl chloride in 1.5 L of pyridine and 1.5 L of triethylamine. The mixture was allowed to warm overnight and then poured into a cold solution of 16 M aqueous hydrochloric acid and 8 L of methylene chloride. The organic phase was separated and the aqueous phase was extracted with further methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The residue was chromatographed twice on silica gel and eluted with a hexane / ethyl acetate gradient (9:1→1:6). 642 g of the title tosylate was obtained. Preparation of compound of formula (5) (Scheme 10) 8.68 mol 60% sodium hydride dispersion in oil To a suspension of 1.15 L of dimethylformamide and 1.1 L of tetrahydrofuran was slowly added 1.139 kg of the tosylate of formula (4) and 7.7 kg of methyl iodide in 1.15 L of dimethylformamide and 1.1 L of tetrahydrofuran. The mixture was stirred overnight, then diluted with 3 L of dimethylformamide and slowly added to a saturated aqueous ammonium chloride solution. The mixture was extracted with 8 L of hexane, the extract was dried over anhydrous sodium sulfate, and the solvent was removed. An orange / yellow oil was obtained. The oil was chromatographed on silica gel and eluted with a hexane / ethyl acetate gradient (100:0→6:1). 940 g of the title compound were obtained as a pale yellow oil. Preparation of compound (7) (Scheme 11) To a suspension of 1019 g of amino sugar (6) in 5 L of methanol was added 1080 ml of 25% sodium methylate solution (5 mol) in methanol, followed by 610 ml of ethyl trifluoroacetate. The mixture was stirred overnight, the solvent was removed in vacuo, and the residue was triturated with isopropanol. The mixture was filtered and the residue was washed with additional isopropanol. 1369 g of the title product was obtained. Preparation of compound (8) (Scheme 12) To a suspension of 1300 g of hydroxy sugar (7) in 4 l of pyridine was added 79 g of dimethylaminopyridine and then 2713 ml of acetic anhydride. The mixture was stirred overnight. The solvent was removed in vacuo. 5 x 500 ml of toluene were added and the solvent was removed again in vacuo. The resulting solid was chromatographed on silica gel, eluting with 1 / 1 hexane / ethyl acetate. 1479 g of the title compound was obtained as a white solid. Preparation of compound (9) (Scheme 13) To a solution of 1479 g of the acylated sugar (8) in 8 L of methylene chloride was added 764 mL of allyl alcohol, followed by the slow addition of 976 mL of tin tetrachloride. The mixture was stirred overnight and then slowly poured into 7.5 L of ice-cold water. The organic phase was separated and the aqueous phase was washed with additional methylene chloride. The combined organic phases were washed with aqueous sodium bicarbonate, dried, and concentrated in vacuo. The residue was chromatographed on 7.5 kg of silica gel, eluting with a hexane / ethyl acetate gradient (4 / 1 —>1 / 1) to give the title compound. HU 221 342 BI is obtained. 1327 g of the title compound are obtained as a pale yellow oil. Preparation of compound of formula (10) (Scheme 14) To an ice-cold solution of 1322 g of protected sugar of formula (9) in 8.5 L of methanol was added 437 ml of 25% methanolic sodium methylate solution over 1 hour. To the resulting mixture was added 1740 g of prewashed Amberlite IR.-120 Plus resin. The mixture was filtered, concentrated and the residue was chromatographed on silica gel, eluting with methanol. 907 g of the title product was obtained. Preparation of compound (11) (Scheme 15) The triol (10) was suspended in 7.5 L of acetone, 85 g of camphorsulfonic acid was added, and 965 mL of 2,2-dimethoxypropane was slowly added. The mixture was stirred overnight, and 51 mL of triethylamine was added. The solvent was removed in vacuo to give a brown solid, which was chromatographed on silica gel. Elution was carried out with a hexane / ethyl acetate gradient (3 / 1 —>2 / 1). 842 g of the title compound was obtained as an off-white gum. Preparation of compound (12) (Scheme 16) To a suspension of 82 g of 60% oily sodium hydride dispersion in 2.2 l of tetrahydrofuran and 580 ml of dimethylformamide, 351 g of tosylate (5) and then 400 g of free alcohol (11) in a mixture of 1360 ml of tetrahydrofuran and 360 ml of dimethylformamide were added. The mixture was stirred overnight, the mixture was cooled on ice, methanol and then 2 l of water were added. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried and concentrated. The resulting mixture was chromatographed on silica gel. Elution was carried out with a hexane / ethyl acetate gradient (19 / 1→1 / 1). 711 g of the title compound was obtained. Preparation of compound of formula (13) (Scheme 17) To a mixture of 48% aqueous hydrogen fluoride solution in 1500 ml acetonitrile in a Teflon flask was added a solution of 613 g of starting material of formula (12) in 750 ml acetonitrile and 750 ml methylene chloride. The mixture was stirred for 1 hour and then poured into 8 l of water. The mixture was extracted with 4x2 l of methylene chloride. The combined organic phases were washed with aqueous, saturated sodium bicarbonate solution, dried and concentrated in vacuo. The residue was chromatographed on silica gel. Elution was carried out with a methylene chloride / methanol gradient (39 / l->9 / l). 519 g of the title compound was obtained. Preparation of compound (14) (Scheme 18) To a solution of 577 g of diol (13) in 5 l of pyridine were added 339 g of tosyl chloride and 14.5 g of N,N-dimethylaminopyridine. The mixture was stirred at room temperature for 2 days and then poured into 14 l of cold 1 mol / l aqueous hydrochloric acid. The mixture was extracted with 2x5 l of methylene chloride. The combined organic phases were dried and concentrated. The residue was chromatographed on silica gel, eluting with a hexane / ethyl acetate gradient (6 / 1—>1 / 1). 632 g of the title compound were obtained as a yellow syrup, which slowly crystallized on standing. Preparation of compound (15) (Scheme 19) To a solution of 1825 ml of 25% sodium methoxide in methanol in 1365 ml of dimethylformamide at 85 °C was added 714 g of tosylate (14) in 1365 ml of dimethylformamide over 1.25 hours. The mixture was stirred for 30 minutes, cooled to 4 °C, and poured into an ice-cold mixture of 1 mol / l aqueous hydrochloric acid and 4.6 kg of ice. The mixture was stirred for 30 minutes and filtered. The filtrate was washed with 2 l of water, and the combined aqueous phases were extracted with 2 x 4 l of ethyl acetate. The combined organic phases were dried and concentrated. The residue was purified by chromatography on silica gel, eluting with a hexane / ethyl acetate gradient (3 / 1 -> 1 / 1), to give 549 g of the title compound as a pale yellow-white solid. Preparation of compound (16) (Scheme 20) The reaction was carried out under an argon atmosphere. To a solution of 139 g of potassium tert-butoxide in 440 ml of dimethyl sulfoxide was added a solution of 247 g of sugar (15) in 440 ml of anhydrous dimethyl sulfoxide. The mixture was heated at 85 °C for 1.5 hours, then 250 ml of water was added, and the mixture was kept at 85 °C overnight, then cooled in an ice bath. The mixture was poured into 3.5 l of brine and extracted with 3 x 750 ml of methylene chloride. The combined organic phases were dried and concentrated. 560 g of the title compound was obtained as a brown oil. Preparation of compound (17) (Scheme 21) To a mixture of 199 g of the free amine of formula (16) in 780 ml of tetrahydrofuran and 390 ml of saturated aqueous sodium bicarbonate solution, 157 g of Troc-Cl were added. After half an hour, the mixture was slowly poured into a mixture of 500 ml of 40% aqueous methylamine solution and 3 l of water. The mixture was extracted with χ 1750 ml of methylene chloride. The combined organic phases were dried and concentrated. The residue was chromatographed on silica gel. Elution was carried out with a hexane / ethyl acetate gradient (5 / 1—>1 / 1). 287 g (100%) of the title compound was obtained as a yellow-off-white solid. Preparation of compound (18) (Scheme 22) To a solution of hydroxy sugar (17) obtained in the previous step in methylene chloride, 155.6 g of tetrazole was added, followed by 182 ml of diallyl diisopropyl phosphoramidite. After half an hour, the mixture was poured into an ice-cold mixture of 455.6 g of Oxone® (potassium peroxymonosulfate), 1.25 l of water and 2.5 l of tetrahydrofuran. After 15 minutes, the mixture was poured into an ice-cold 10% aqueous sodium thiosulfate solution. After 15 minutes, the mixture was extracted with 2 l of methylene chloride. The organic phase was separated, the aqueous phase was re-extracted with methylene chloride, and the combined organic phases were dried, and the solvent was removed in vacuo. The residue was chromatographed on silica gel, eluting with a hexane / ethyl acetate gradient (6 / 1→2 / 1), yielding 205.7 g of the title compound as a pale yellow syrup. Preparation of compound of formula (19) (Scheme 23) To a solution of 400 ml of 48% aqueous hydrogen fluoride solution in 1.2 l of acetonitrile in a Teflon vessel, a solution of 138.8 g of sugar of formula (18) in 500 ml of methylene chloride was added. The mixture was stirred overnight. HU 221 342 Β1 is stirred, diluted with 3 l of water and extracted with 2.4 l of methylene chloride. The organic phase is washed with aqueous sodium bicarbonate solution, dried and the solvent is removed in vacuo. The residue is chromatographed on silica gel, eluting with a hexane / ethyl acetate gradient (2 / 1—>1 / 1) and then with a methylene chloride / methanol gradient (19 / 1—>9 / 1). 129.2 g of the title compound are obtained as a waxy, gummy substance. Preparation of compound of formula (21) (Reaction scheme 24) To an ice-cold solution of 450 g of 1-decanol in 685 ml of triethylamine and 1125 ml of methylene chloride is added 330 ml of mesyl chloride. The cooling bath is removed after 1.5 hours and the solvent is removed in vacuo. To the residue is added 2.5 l of 1 mol / l aqueous hydrochloric acid. The mixture is extracted 3x2 l with methylene chloride. The organic phases are combined, dried and the solvent is removed in vacuo. The residue is chromatographed on silica gel, eluting with a 1 / 1 hexane / ethyl acetate mixture. 651 g of the title product is obtained. Preparation of compound (22) (Scheme 25) To a suspension of 60% sodium hydride dispersion in mineral oil in 1 L of tetrahydrofuran and 470 mL of dimethylformamide was added a solution of alcohol (11) in 280 mL of dimethylformamide and 1 L of tetrahydrofuran over 1 hour. Then 470 g of mesylate (21) was added over 15 minutes. After 2 days, 400 mL of methanol, then 4 kg of ice and 4 L of water were added to the mixture. The mixture was extracted with 2x4 L of ethyl acetate. The combined organic phases were dried and the solvent was removed in vacuo. The residue was chromatographed on silica gel. Elution was carried out with a hexane / ethyl acetate gradient (39 / 1—>2 / 1). 618 g of the title compound are obtained. Preparation of compound of formula (23) (Scheme 26) A mixture of 520 g of sugar of formula (22), 5.2 L of glacial acetic acid and 1.3 L of water was stirred overnight. The solution was Pour into 7.5 l of water and filter. The filtrate is dried by azeotropic distillation with 3 x 500 ml of toluene under vacuum. 458 g of the title compound is obtained. Preparation of compound of formula (24) (Scheme 27) The reaction is carried out under an argon atmosphere. To a suspension of 295 g of potassium tert-butoxide in 1 L of dimethyl sulfoxide is added 340 g of sugar of formula (23) 1.5 L of a solution of dimethyl sulfoxide. The mixture is heated at 85 °C for 1.25 h, then 1.4 L of 3 mol / L aqueous potassium hydroxide solution is added and the mixture is stirred at 85 °C overnight. The mixture is cooled to room temperature and poured into a mixture of 3.5 L of brine and 3.5 L of water. The mixture is extracted three times with methylene chloride, dried and the solvent is removed in vacuo. The residue is chromatographed on silica gel, eluting with a gradient of methylene chloride / methanol (19 / 1—>4 / 1). 740 g of the title product are obtained. Preparation of compound (25) (Scheme 28) A solution of 740 g of amino sugar (24) in 338 g of benzophenoneimine was heated at 45°C overnight. The mixture was chromatographed on silica gel and eluted with a hexane / ethyl acetate gradient (39 / 1→1 / 1). 371 g of the title product are obtained as a pale yellow solid. Preparation of compound of formula (26) (Scheme 29) To a solution of 366 g of diol sugar of formula (25) in 1.3 l of dimethylformamide, 118 g of imidazole and then 117 g of tert-butyldimethylsilyl chloride were added. After 5 minutes, the mixture was poured into 1.4 l of saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The organic phases were combined, the solvent was removed in vacuo, and the residue was chromatographed on silica gel. Elution was carried out with a hexane / ethyl acetate gradient (49 / 1—>4 / 1). 446 g of the title compound was obtained as a syrup. Preparation of compound (27) (Scheme 30) To a solution of 437 g of alcohol (26) in 3 L of toluene, 225 ml of pyridine were added and the solution was cooled in an ice bath. 531 ml of 1.9 mol / l phosgene in toluene were added and the mixture was stirred for 10 minutes. 469 ml of allyl alcohol were then added. After 40 minutes, 2.3 L of saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic phase was separated, dried and the solvent was removed in vacuo. The residue was chromatographed on silica gel, eluting with a hexane / ethyl acetate gradient (49 / 1 -> 4 / 1). 441 g of the title compound was obtained as a yellow syrup. Preparation of compound (28) (Scheme 31) To a solution of 431 g of sugar (27) in 200 ml of tetrahydrofuran, 330 ml of glacial acetic acid and 110 ml of water were added. The reaction mixture was stirred for 3 hours, cooled on ice and 6.6 1 1 mol / 1 aqueous sodium hydroxide solution was added. The mixture was extracted with 2x21 methylene chloride. The combined organic phases were dried and the solvent was removed in vacuo. The residue was chromatographed on silica gel, eluting with a methylene chloride / methanol gradient (19 / 1—>4 / 1). 309 g of the title amine was obtained in the form of a syrup. Preparation of compound (29) (Scheme 32) To an ice-cold solution of 309 g of amino sugar (28) in 3 L of methylene chloride, 435 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) were added, followed after 10 min by 275 g of carboxylic acid. After 10 min, the mixture was extracted with saturated aqueous sodium bicarbonate solution. The organic phase was separated, the aqueous phase was re-extracted with methylene chloride, the combined organic phases were dried, and the solvent was removed in vacuo. The residue was chromatographed on silica gel, eluting with a hexane / ethyl acetate gradient (19 / 1—>3 / 1). 338 g of the title compound were obtained as a pale yellow syrup. Preparation of compound (30) (Scheme 33) To a solution of 48% aqueous hydrogen fluoride in 293 ml of acetonitrile was added 4.6 g of silica gel, followed by the addition of 146.7 g of sugar (29) dissolved in 147 ml of methylene chloride. After 0.5 h, the mixture was diluted with 975 ml of water and extracted with methylene chloride. The organic phase was separated and the aqueous phase was re-extracted with methylene chloride. The combined organic phases were washed with aqueous sodium bicarbonate, dried, and the solvent was removed in vacuo. The residue was 11 HU 221 342 B1 residue is chromatographed on silica gel, elution is carried out with a hexane / ethyl acetate gradient (5 / 1→0 / 1). 110.4 g of the title product are obtained as an off-white, waxy solid. Preparation of compound of formula (31) (Scheme 34) To a solution of 129 g of the sugar of formula (19) in 500 g of trichloroacetonitrile was added 240 g of potassium carbonate. The mixture was stirred for 1.5 hours and filtered through diatomaceous earth. The filter pad was washed with methylene chloride and the filtrates were combined and the solvent was removed in vacuo. The residue was chromatographed on silica gel, eluting with a hexane / ethyl acetate gradient (1 / 1->0 / 1). 145.7 g of the title product was obtained as a yellow gum. Preparation of compound of formula (33) (Scheme 35) 145.7 g of sugar (31) and 109.2 g of sugar (32) were azeotropically dried by evaporation from 3 × 200 ml of toluene. A solution of the two sugars in 750 ml of methylene chloride was added to an ice-cold solution of 62.7 g of silver triflate in 130 ml of methylene chloride. The mixture was warmed to room temperature and stirred overnight. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution and sodium thiosulfate solution. The organic phase was separated and the aqueous phase was washed with methylene chloride. The combined organic phases were dried and the solvent was removed in vacuo. The residue was chromatographed twice on silica gel, eluting with a hexane / ethyl acetate gradient (5 / 1—>1 / 1). 189.56 g of the title product are obtained as a sticky foam. Preparation of compound of formula (34) (Scheme 36) To a solution of 188.7 g of disaccharide (33) in 590 ml of tetrahydrofuran was added 457.6 g of zinc powder, followed by 395 ml of glacial acetic acid. After 0.5 h, the mixture was filtered through diatomaceous earth and the filter pad was washed with tetrahydrofuran. The organic phases were combined and the solvent was removed in vacuo. The residue was azeotropically dried by distillation with 4 x 250 ml of benzene. 223.1 g of the title product are obtained as a pink, gummy substance. Preparation of compound of formula (35) (Scheme 37) To a solution of 223.1 g of sugar of formula (34) in 1.3 l of tetrahydrofuran is added a solution of 37.5 g of sodium bicarbonate in 250 ml of water. Then 67.4 g of cis-11-octadecenoyl chloride. After 10 minutes, the mixture is extracted twice with ethyl acetate. The combined organic phases are dried and the solvent is removed in vacuo. The residue is chromatographed on silica gel, eluting with a hexane / ethyl acetate gradient (2 / 1→0 / 1). 160.2 g of the title product are obtained as a pale yellow wax. Preparation of compound of formula (36) (Scheme 38) A solution of 161.3 g of the sugar of formula (35) in 215 ml of methylene chloride was added to a solution of 150 ml of 48% hydrogen fluoride and 474 ml of acetonitrile in a Teflon vessel. After 4 hours, the mixture was poured into 500 ml of water. The mixture was extracted twice with methylene chloride. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried, and the solvent was removed in vacuo. The residue was chromatographed on silica gel, eluting with a gradient of methylene chloride / ethyl acetate / methanol (500 / 500 / 20—>500 / 500 / 160). The title compound was obtained as a yellow, waxy gum. Preparation of compound of formula (37) (Scheme 39) 719 mg of sugar (36) are dissolved in methylene chloride and 1.4 g of sodium sulfate are added. 189 μΐ diallyl diisopropyl phosphoramidite and 162 mg of tetrazole are added to the solution, stirred for 10 minutes and then cooled to -78 °C. A solution of 192 mg of m-chloroperoxybenzoic acid in 4 ml of methylene chloride is added dropwise. The mixture is washed with aqueous sodium thiosulfate solution and then with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residue is purified by chromatography. 660 mg of the title product is obtained. Preparation of compound 1 (sodium salt) (Scheme 40) To a solution of 166 mg of tetrakis(triphenylphosphine)palladium(0) in 2 ml of 10 / 1 tetrahydrofuran / acetic acid was added a solution of 660 mg of intermediate (38) in 3 ml of the above solvent. After 30 min, additional tetrakis(triphenylphosphine)palladium(0) was added. After another 1.5 h, toluene was added to the mixture and the solvent was removed in vacuo. The mixture was purified by chromatography on diethylaminoethylcellulose. The purified mixture was dissolved in 0.1 N aqueous sodium hydroxide solution, filtered through a sterile filter with a 0.45 μm pore size, and purified by high-pressure liquid chromatography (HPLC) on a YMC-Pack ODS-AP column. 130 mg of compound 1 was obtained. The analytical data of compound 1 are as follows: Η-NMR (CD3OD) δ: 5.3 (1H, m); 4.6 (1, m); 4.0 (m, m); 3.9 (1H, d); 3.7 (1H, t); 3.6 (1H, t); 3.4 (3H, s); 3.3 (3H, t); 2.6 (2H, t); 2.3 (2H, m); 2.0 (2H, m); 1.7-1.2 (m, m); 0.9 (6H, t). 3IP-NMR (CD3OD) δ: 4.71, 398. Preparation of compound 1 by method 2 Example 1 Preparation of intermediate B g To a suspension of intermediate A (prepared according to the method of Christ et al., EP-A 9239057.5) in 150 ml of dichloromethane and 29.2 g of 48% HBF4, 165 ml of TMSCHN2 (TMS: trimethylsilyl) as a 2 mol / l solution in hexane were added while cooling in an ice bath. The mixture was stirred until the reaction was almost complete according to TLC, then 20 ml of methanol and then 10 ml of acetic acid were added to the reaction mixture. An aqueous sodium bicarbonate solution was added to the mixture and extracted with methylene chloride. The mixture was dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The residue was purified by chromatography. 14.9 g of the title intermediate B are obtained. Example 2 Preparation of intermediate product of formula C To a cold (0 °C) solution of 14.9 g of intermediate B in 100 ml of methylene chloride, slowly add 12 HU 221 342 Bl 140 ml of diisobutylaluminum hydride in hexane at a concentration of 1 mol / l were added until the reaction was complete according to TLC analysis. The reaction mixture was diluted with 100 ml of 1N aqueous hydrochloric acid solution, then 50 ml of concentrated hydrochloric acid solution was added. The phases were separated and the aqueous phase was re-extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel. 12.06 g of the title intermediate C were obtained. Example 3 Preparation of intermediate of formula D To a solution of 10.64 g of intermediate C in 40 ml of methylene chloride were added 15.75 ml of triethylamine, 11.86 g of p-toluenesulfonyl chloride and 690 mg of dimethylaminopyridine. The resulting suspension was stirred until the reaction was complete according to thin layer chromatography analysis, then diluted with water and extracted with methylene chloride. After chromatography on silica gel, 18.7 g of intermediate D was obtained. Example 4 Preparation of the intermediate of formula E To a solution of 18.7 g of intermediate D in 200 ml of acetone was added 24.6 g of sodium iodide. The reaction mixture was refluxed for 1.5 h, the solvent was removed in vacuo, and the residue was partitioned between water and hexane. The organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed. Chromatographic purification on silica gel gave 15.4 g of intermediate E as a colorless liquid. Example 5 Preparation of intermediate product of formula F This compound is prepared according to the method of Christ et al. (EP-A 92309057.5). Example 6 Preparation of intermediate product of formula G To a solution of 18.6 g of intermediate A and 15.4 g of intermediate E in hexane was added 23.9 g of silver oxide and the mixture was refluxed overnight. The mixture was cooled, filtered through diatomaceous earth, the solvent was removed and the residue was chromatographed on silica gel. 21 g of intermediate G was obtained as a colorless syrup. Example 7 Preparation of intermediate H g To a cold (0 °C) solution of intermediate G in methylene chloride, 3.5 ml of 48% tetrafluoroboric acid was added dropwise. After 5 minutes, the mixture was washed with aqueous sodium bicarbonate solution and brine. The mixture was concentrated in vacuo and chromatographed on silica gel. 18.7 g of intermediate H are obtained in the form of a colorless syrup. Example 8 Preparation of intermediate of formula I To a solution of 17.6 g of intermediate H in 105 ml of pure methyl iodide was added 83 g of silver oxide. The mixture was stirred overnight, then diluted with hexane and filtered through diatomaceous earth. The mixture was concentrated in vacuo and the residue was dissolved in 40 ml of methylene chloride. The mixture was cooled to 0 °C, 2.44 g of imidazole and 4.7 ml of tert-butyldimethylsilyl chloride were added. The reaction mixture was stirred overnight and 150 ml of sodium bicarbonate solution was added. The organic phase was dried over anhydrous sodium sulfate and chromatographed on silica gel. 10.5 g of intermediate of formula I are obtained in the form of a colorless syrup. Example 9 Preparation of intermediate of formula J 100 ml of intermediate I was dissolved in methylene chloride, 7.4 ml of diallyl diisopropyl phosphoramidite were added, followed by 6.37 g of tetrazole. The mixture was cooled and stirred for 20 minutes. A suspension of 24.2 mmol of meta-chloroperoxybenzoic acid in 50 ml of methylene chloride was added over 15 minutes, while maintaining the temperature of the reaction mixture below -60 °C. Sodium bicarbonate solution was added and the organic phase was separated, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. Chromatographic purification on silica gel gave 14 g of intermediate J as a colorless syrup. Example 10 Preparation of intermediate with formula K To a suspension of 39.5 g of di(thiophenyl)tin - prepared according to the method of Christ et al. (EP-A 92309057.5) in 235 ml of methylene chloride is added 12 ml of thiophenol. Triethylamine is added dropwise over 15 minutes. A portion of the resulting "tin reagent" mixture (150 ml) is added dropwise over 15 minutes to a solution of 12.9 g of intermediate J in 25 ml of methylene chloride. The remaining tin reagent is added to the reaction mixture over 30 minutes to complete the reaction. The reaction mixture is diluted with ethyl acetate and washed with 1N aqueous sodium hydroxide solution and brine. The organic phase is dried over anhydrous sodium sulfate, the solvent is removed, and the residue is purified by chromatography. 11.1 g of the title intermediate K were obtained as a yellow syrup. Example 11 Preparation of intermediate product of formula L To a cold solution of 11.1 g of intermediate K and 7.1 ml of pyridine in 10 ml of methylene chloride was added 2.9 ml of trichloroethyl chloroformate and the mixture was stirred overnight. Aqueous sodium bicarbonate solution was added to the reaction mixture and the organic phase was concentrated. HU 221 342 Β1 is separated, dried over anhydrous sodium sulfate, and the solvent is removed in vacuo. Chromatographic purification affords 12.96 g of intermediate L as a pale yellow solid. Example 12 Preparation of intermediates of formula M 12.96 g of intermediate L was dissolved in methylene chloride. To the resulting solution was added 6 ml / 1 of acetonitrile-hydrogen fluoride solution and the mixture was stirred for 4 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture, the organic phase was separated, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. Chromatographic purification gave 10.9 g of the title intermediate M as an amber syrup. Example 13 Preparation of intermediate product of formula N To a solution of 9.5 g of intermediate M in 50 ml of trichloroacetonitrile was added 15 g of potassium carbonate and the mixture was stirred for 10 minutes. The mixture was filtered through diatomaceous earth and the solvent was removed in vacuo. Chromatographic purification gave 14.5 g of the title intermediate N which was used immediately in Example 19. Example 14 Preparation of intermediate of formula O 160 g of intermediate F with 475 ml of hexane and To a solution of 474 ml of iododecane was added 723 g of silver oxide. The mixture was heated at 70 °C in the dark for 2 h and filtered through diatomaceous earth. The solution was concentrated in vacuo and the residue was purified by chromatography. The title intermediate 221 of formula O was obtained as a colorless oil. Example 15 Preparation of intermediate P To a solution of intermediate O in 90 ml of methylene chloride and 90 ml of acetonitrile, 9 ml of a 48% aqueous solution of hydrogen fluoride in 81 ml of acetonitrile was added. The mixture was stirred for 30 minutes, then 350 ml of aqueous sodium bicarbonate solution was added. The mixture was extracted with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, the solvent was removed in vacuo, and the residue was chromatographed. 30 g of intermediate P were obtained as a yellow oil. Example 16 Preparation of intermediate Q from g intermediate P and 10.2 g imidazole To a cold (0 °C) solution of 500 ml of methylene chloride was added 10.85 g of (tert-butyl)dimethylsilyl chloride. The reaction mixture was stirred for 1.5 hours and then poured into 400 ml of saturated aqueous ammonium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate, the solvent was removed in vacuo and the residue was chromatographed. 34.5 g of intermediate Q was obtained as a colorless syrup. Example 17 Preparation of intermediate with formula R 32.2 g of intermediate Q and 184 ml of pyridine To a cold (0 °C) solution of 213 ml of toluene is added a 1.94 mol / l solution of phosgene in toluene. After 20 minutes, 31 ml of allyl alcohol is added to the reaction mixture and the mixture is stirred for 30 minutes. An aqueous solution of sodium bicarbonate is added to the reaction mixture, the organic phase is separated, dried over anhydrous sodium sulfate and the solvent is removed in vacuo. Chromatographic purification gives 36.9 g of intermediate R as a colorless syrup. Example 18 Preparation of intermediate with formula S To a solution of 2.4 ml of 48% aqueous hydrogen fluoride in 48 ml of acetonitrile is added a solution of 20 g of intermediate R in 24 ml of methylene chloride and the mixture is stirred overnight. Aqueous sodium bicarbonate solution is added to the reaction mixture, the organic phase is separated, dried over anhydrous sodium sulphate and the solvent is removed in vacuo. After chromatographic purification, 11 g of intermediate S are obtained as a colourless syrup. Example 19 Preparation of intermediate with formula T 8.97 g of intermediate S and 14.5 g of intermediate N were dissolved in 20 ml of toluene and the mixture was dried by azeotropic removal of the solvent. This procedure was repeated three times. The dried mixture was then dissolved in 50 ml of methylene chloride and slowly added to a solution of 5.8 g of silver triflate in 50 ml of methylene chloride. The mixture was stirred for 10 minutes and then 250 ml of aqueous sodium bicarbonate solution and 250 ml of 10% aqueous sodium thiosulfate solution were added. The organic phase was separated, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. After chromatographic purification, 13 g of intermediate T were obtained as a pale yellow syrup. Example 20 Preparation of intermediate U To a 10 ml solution of intermediate AT in methylene chloride, 12 ml of 0.5 mol / l tin(II)-tris(benzenethiolate)-triethylamine complex in methylene chloride was slowly added. After 10 minutes, another equivalent of tin reagent was added to the reaction mixture. After 15 minutes, 250 ml of ethyl acetate was added to the reaction mixture and extracted with 250 ml of 1N aqueous sodium hydroxide solution. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. Toluene was added to the residue and the solvent was removed in vacuo. The resulting oil was used in the next reaction step without further purification. HU 221 342 B1 Example 21 Preparation of intermediate V mmol To a solution of intermediate U in 5 ml of methylene chloride cooled to 0 °C was added 997 mg of 3-ketotetradecanoic acid, prepared according to the method of Christ et al. (Patent Application EP-A 92309057.5), followed by the addition of 1.5 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and the mixture was stirred for approximately 30 minutes. The reaction mixture was diluted with 150 ml of methylene chloride, washed with 1N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate and the solvent was removed in vacuo. Chromatographic purification on silica gel and then chromatography on basic alumina gave 1.64 g of intermediate V. Example 22 Preparation of intermediate with formula W A solution of 1.45 g of intermediate V in 5 ml of glacial acetic acid was added to a suspension of 14 g of zinc / copper in 10 ml of acetic acid with vigorous stirring. The mixture was stirred for 15 min, then an additional 10 g of zinc / copper were added. After 15 min, the mixture was filtered through diatomaceous earth and the filter was washed with ethyl acetate. The combined washings were diluted with toluene and the solvent was removed in vacuo. The residue was purified by chromatography on a double layer of basic alumina and silica gel, and the intermediate W obtained was used without further purification. Example 23 Preparation of intermediate product of formula X 1.02 mmol of intermediate W and 575 mg of cisvacenoic acid were dissolved in 5 ml of toluene three times and the solvent was removed in vacuo. The dried residue was dissolved in 3 ml of methylene chloride, 780 mg of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added and the mixture was stirred for 3 hours. The reaction mixture was diluted with methylene chloride and chromatographed directly. 734 mg of intermediate X were obtained. Further chromatographic purification of the impure fractions yielded an additional 58 mg of product. Example 24 Preparation of intermediate with formula Y To a solution of 785 mg of intermediate X in 10 mL of methylene chloride was added 48% aqueous hydrogen fluoride in 15 mL of acetonitrile. The mixture was stirred for 90 min, diluted with 50 mL of methylene chloride, washed with water and then with aqueous sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate and chromatographed. 719 mg of intermediate Y was obtained. Example 25 Preparation of intermediate with formula Z 719 mg of intermediate Y are dissolved in methylene chloride and 1.4 g of sodium sulfate are added. After addition of 189 µl of diallyl diisopropyl phosphoramidite and 162 mg of tetrazole, the mixture is stirred for 10 minutes and then cooled to -78 °C. A solution of 192 mg of m-chloroperoxybenzoic acid in 4 ml of methylene chloride is added dropwise. The reaction mixture is washed with aqueous sodium thiosulfate solution and aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent is removed in vacuo. The residue is purified by chromatography. 660 mg of intermediate Z are obtained. Example 26 Preparation of compound 1 To a solution of 166 mg of tetrakis(triphenylphosphine)palladium(O) in 10:1 tetrahydrofuran / acetic acid was added 660 mg of intermediate Z in 3 ml of the above mixture. After 30 min, additional tetrakis(triphenylphosphine)palladium(O) was added. After a further 1.5 h, toluene was added to the reaction mixture and the solvent was removed in vacuo. The mixture was purified by chromatography on diethylaminoethylcellulose. The purified mixture was dissolved in 0.1 N aqueous sodium hydroxide solution, filtered through a 0.45 µm sterile filter and purified by high-pressure liquid chromatography on a YMC-Pack ODS-AP column. 130 mg of the title compound was obtained. The analytical data of the compounds and intermediates prepared as described above are presented below. Compound 1: Ή-NMR (CD 3 OD) δ: 5.3 (1H, m); 4.6 (1, m); 4.0 (m, m); 3.9 (1H, d); 3.7 (1H, t); 3.6 (1H, t); 3.4 (3H, s); 3.3 (3H, t); 2.6 (2H, t); 2.3 (2H, m); 2.0 (2H, m); 1.7-1.2 (m, m); 0.9 (6H, t). 3'P-NMR (CD 3 OD) δ: 4.71, 3.98. Mass spectra: Compound 1: (M+Na)+ = 1333 Compound of formula 2: (M+3 Na)+= 1363 Compound of formula 3: (M+3 Na)+= 1365 Compound of formula 5: (M+Na)+= 1303 Compound of formula 6: (M+Na)+= 1359 Compound of formula 7: (M+Na)+ = 1305 Compound of formula 8: (M+3 Na)+= 1393 Compound of formula 10: (M+Na)+ = 1425 Intermediate with formula G: Ή-NMR (CDCl 1 ) δ: d, (1H); 3.9-3.7 (m, multiple); 3.65 (t, 1H); 3.37 (s, 3H); 3.2 (m, 2H); 1.75 (q, 2H); 1.52 (s, 3H); 1.4 (s, 3H); 1.3 (wide m, multiple); 0.95 (s, 9H); 0.9 (t, 3H) and 0.2 (d, 6H). Intermediate with formula H: Ή-NMR (CDCl 1 ) δ: 4.58 (d, 1H); 4.09 (m, 2H); 3.9 (dd, 1H); 3.75 (dd, 1H); 3.7 (m, 1H); 3.5 (t, 1H); 3.37 (s, 3H); 3.23 (t, 1H); 3.05 (t, 1H); 1.8 (m, 2H); 1.68 (m, 1H); 1.5 (m, 1H); 1.3 (wide m, multiple); 0.95 (s, 9H); 0.9 (t, 3H); 0.2 (d, 6H). Intermediate of formula I: Ή-NMR (CDCl 3 ) δ: 4.52 (d, 1H); 4.05 (m, 2H); 3.75 (m, 1H); 3.67 (t, 1H); 3.5 (t, 1H); 3.45 (s, 3H); 3.35 (s, 3H); 3.25 (t, 1H); 3.05 (t, 1H); 1.8 (m, 2H); 1.65 (m, 1H); 1.5 (m, 1H); 1.3 (wide s, m); 0.95 (s, 9H); 0.2 (s, 6H). HU 221 342 Bl Intermediate with formula J: H-NMR (CDCl 3 ) δ: 5.95 (m, 2H); 5.35 (d, 1H); 5.22 (d, 1H); 4.6 (q, 2H); 4.5 (d, 1H); 4.32 (q, 1H); 3.9-3.75 (m, 3H); 3.7 (dd, 1H); 3.65 (dd, 1H); 3.45 (m, 1H); 3.38 (s, 3H); 3.33 (s, 3H); 3.27 (t, 1H); 3.2 (t, 1H); 1.9-1.75 (m, 3H); 1.5 (m, 1H); 1.3 (wide m, multiple); 0.95 (s, 9H); 0.9 (t, 3H); 0.2 (s, 6H). Intermediate product of formula L: •H-NMR (CDC13) δ: 5.95 (d, 1H); 5,4 (d, 2H); 5,25 Z(d, 2H); 4,95 (d, 1H); 4,7 (q, 2H); 4,55 (q, 2H); 4,32 (q, 1H); 3.9-3.75 (m, 3H); 3,7 (dd, 1H); 3,65 (dd, 1H); 3,55 (m, 1H); 3,4 (m, 1H); 3,4 (s, 3H); 3,3 (s, 3H); 3,25 (m, 1H); 1.75 (m, többszörös); 1,5-1,4 (m, 2H); 1,3 (széles s, többszörös); 0.95-0.9 (sleeves, 12H); 0,2 (d, 6H). Available price • H-NMR (CDClj δ: 5.95 (m, 2H); 5.75 (d, 1H); 5.4 (d, 1H); 5.25 (d, 2H); 4.75-4.65 (dd, 2H); 4.6 (q, 1H); 4.3 (q, 1H); 4.1 (m, 2H); 3.9 (m, 2H); 3.4 (s, 3H); 3H). O képletű köztitermék: 'H-NMR (CDClj) δ: 4.5 (d, 1H); 3.8 (dd, 1H); 3.78 (m, 2H); 3.6 (m, többszörös); 3.2 (m, 2H); 1.5 (s, 3H); 1.4 (s, 3H); 1.3 (széles s, többszörös); 0.95 (s, 9H); 0.9 (t, 3H); 0.18 (d, 6H). P képletű köztitermék: •H-NMR (CDClj) δ: 4.5 (d, 1H); 3.75 (dd, 2H); 3.6 (q, 2H); 3.5 (t, 1H); 3.3 (m, 1H); 3.2 (t, 1H); 3.0 (t, 1H); 1.6 (m, 2H); 1.25 (széles s, többszörös); 0.95 (s, 9H); 0.9 (t, 3H); 0.18 (d, 6H). Q képletű köztitermék: 'H-NMR (CDC13) δ: 4.5 (d, 1H); 3.82 (t, 2H); 3.7 (m, 2H); 3.6 (t, 1H); 3.3 (m, 1H); 3.2 (t, 1H); 3.05 (q, 2H); 1.6 (m, 2H); 1.3 (széles s, többszörös); 0.95 (s, 9H); 0.88 (s, 9H); 0.85 (t, 3H); 0.2 (d, 6H); 0.1 (d, 6H). R képletű köztitermék: 'H-NMR (CDClj) δ: 5,9 (m, 1H); 5.4-5.25 (dd, 2H); 4,75 (t, 1H); 4,6 (d, 2H); 4,45 (d, 1H); 3,75 (q, 1H); 3,7 (d, 2H); 3,53 (q, 1H); 3,38 (m, 1H); 3,25 (t, 1H); 3,15 (t, 1H); 1,5 (t, 2H); 1.25 (s, többszörös); 0.95 (s, 9H); 0.85 (m, 12H); 0,2 (s, 6H); 0.07 (s, 6H). S képletű köztitermék: •H-NMR (CDC13) δ: 5.9 (m, 1H); 5.4-5.25 (dd, 2H); 4.75 (t, 1H); 4.6 (d, 2H); 4.52 (d, 1H); 3.7 (m, többszörös); 3.65-3.6 (dd, 2H); 3.55 (q, 1H); 3.4 (m, 1H); 3.28 (t, 1H); 3.2 (t, 1H); 1.5 (t, 2H); 1.3 (s, multiple); 0.9 (s, 9H); 0.85 (t, 3H); 0.2 (s, 6H). Intermediate with formula T: •H-NMR (CDCl3) δ: 5.9 (m, 3H); 5.6 (d, 1H); 5.4-5.2 (m, 6H); 4.8 (d, 1H); 4.7-4.6 (m, 2H); 4.55 (q, 1H); 4.5 (d, 1H); 4.3 (q, 1H); 3.8-3.7 (m, multiple); 3.6 (dd, 1H); 3.5 (m, multiple); 3.35 (s, 3H); 3.2 (s, 3H); 3.15 (t, 1H); 1.7 (m, 2H); 1.5 (m, 2H); 1.3 (s, multiple); 0.95 (t, 6H); 0.2 (t, 6H). Intermediate of formula V: 1 H-NMR (CDCl 3 ) δ: 7.3 (d, 1H); 5.95 (m, 3H); 5.6 (d, 1H); 5.4-5.2 (m, 6H); 4.95 (d, 1H); 4.8 (d, 1H); 4.7-4.5 (m, multiple); 4.3 (q, 1H); 3.9-3.65 (m, multiple); 3.6 (m, multiple); 3.45 (t, 1H); 3.4 (t, 3H); 3.35 (s, 2H); 3.28 (3H); 2.5 (t, 2H); 1.8 (m, 2H); 1.6 (m, 2H); 1.45 (m, 2H); 1.3 (broad s, multiple); 0.95-0.8 (m, 18H); 0.15 (d, 6H). Intermediate product with formula X: 1 H-NMR (CDCl 3 ) δ: 7.3 (d, 1H); 5.95 (m, 4H); 5.4-5.2 (m, 8H); 4.95 (d, 1H); 4.8 (d, 1H); 4.7 (t, 1H); 4.6 (d, 1H); 4.55 (q, 1H); 4.3 (q, 1H); 4.1 (t, 1H); 3.9 (q, 1H); 3.8 (t, 1H); 3.7-3.5 (m, multiple); 3.45 (t, 1H); 3.35 (s, 3H); 3.3 (s, 2H); 3.28 (s, 3H); 2.5 (t, 2H); 2.2 (t, 1H); 2 (d, 1H); 1.7 (q, 2H); 1.6 (m, 2H); 1.3 (s, multiple); 0.95-0.8 (m, 21); 0.15 (d, 6H). Intermediate with formula Y: 1 H-NMR (CDCl 3 ) δ: 6.65 (d, 1H); 6.55 (d, 1H); 5.905 (m, 5H); 5.7 (m, 1H); 5.4-5.2 (m, 12H); 4.8 (m, 2H); 4.6 (d, 1H); 4.5 (m, 10H); 4.3 (q, 1H); 4.1 (m, 1H); 3.85-3.45 (m, multiple); 3.4 (s, 3H); 3.35 (s, 3H); 3.25 (s, 3H); 3.2 (t, 1H); 2.5 (dd, 2H); 2.2 (t, 2H); 2 (m, multiple); 1.7-1.2 (m, multiple); 0.9 (t, 12H). Biological examples Both bacterial LPS and bacterial lipid-A induce the production of tumor necrosis factor (TNF), IL-1β, IL-6 and IL-8, as well as other cytokines and cellular mediators in human whole blood and human macrophage cell lines. The production of pathophysiological amounts of the above cytokines plays an important role in the development of systemic inflammatory response syndrome and septic shock. The lipopolysaccharide analogs of the invention inhibit the production of cytokines mediated by LPS and / or lipid-A, as demonstrated by the following experiments. Example A Inhibition of LPS-induced cytokine production in vitro Human whole blood was prepared and assayed according to the method of Rose et al. [Rose et al., Infection and Immunity 63, 833-839 (1995)]. HL60 cells were cultured in RPMI medium supplemented with 10% fetal calf serum and antibiotics, and differentiation into macrophages was induced by treatment with 0.1 pmol / L 1,25-dihydroxycholecalciferol (vitamin D3; Biomol Research Laboratories, Plymouth Meeting, PA) and LPS-mediated IL-8 production was assayed. Briefly, bacterial LPS (e.g., from E. coli 0111:B4; Sigma Chemicals, St. Louis, MO) was added at a concentration of 10 ng / ml, or lipid-A (Daiichi Chemicals, Tokyo, Japan) was added as a 10-fold solution in Ca++- and Mg++-free Hank's balanced salt solution (CMF-HBSS; Gibco). In experiments in which analogs of the invention were tested, the analog was added directly to the LPS or lipid-A in CMF-HBSS. HU 221 342 was added to the reaction mixture before the addition of Β1 (e.g., at a concentration between 0 and 100 pmol / l, as a 10-fold aliquot). The reaction mixture was incubated for 3 hours, then plasma was prepared from whole blood or the culture supernatant was removed and assayed for the presence of induced cytokines using an ELISA assay kit (Genzyme, Cambridge MA) according to the manufacturer's instructions. However, any standard ELISA kit can be used for the above purpose. Experiments were performed at least twice, in triplicate. Lipid-A analogs inhibited LPS-induced TNF production in human whole blood in a concentration-dependent manner. Among the analogs tested, compound 1 was found to be the most potent. The results are shown in Figure 1. The IC50 of compound 1 on LPS-induced TNF production was approximately 1.5 nmol / l. Other analogs, such as compounds 2, 3, 4, 5, 6, 7, 8, 9 and 10, also inhibited LPS-induced TNF production. The IC50 values ​​of these compounds ranged from 1.5 nmol / l to 159 nmol / l. Compound 1 also inhibited LPS-induced IL-8 production in HL-60 (human macrophage-like) cells. Inhibition of IL-8 production in the presence of 1 nmol / L or more of Compound 1 was complete whether LPS or lipidA was used as antagonist. The compounds of the invention similarly inhibited the production of other cytokines induced by LPS in human whole blood even when the above cytokines were produced several hours after LPS administration, for example IL-1β and IL-6 require at least 4 hours to reach maximum concentrations, while IL-8 requires at least 10 hours after LPS administration to reach maximum levels. Using the above methods, the compounds of the invention were administered at concentrations between 0 and 10 pmol / l and LPS at a concentration of 10 ng / ml. The inhibition of the production of TNF, IL-Ιβ, IL-6 and IL-8 was measured as a function of time after LPS administration. The above inhibition of cytokine production was also found to be concentration-dependent, but in all cases the inhibition of cytokine synthesis was greater than 90% in the presence of concentrations of Compound 1 at 10 nmol / l or higher for 24 hours after LPS administration. Example B Persistence of compounds in human whole blood Although some of the compounds of the invention are not rapidly cleared from the circulation, their activity decreases over time, with a half-life of 1-3 hours. This rapid deactivation necessitates continuous dosing to maintain antagonist efficacy. The study of deactivation has led to the development of a method for determining the in vitro deactivation of compounds in human whole blood. The assay is performed by preincubating the lipid A antagonists with blood for various times, then adding LPS as described above, incubating the sample for 3 hours, and then determining the cytokines released. The scheme of the above assay is shown in Figure 2. Using the above assay, we have shown that B531 (described by Christ et al. in US 07 / 935050) is deactivated (i.e., loses its activity with increasing preincubation time). Figure 3 shows that compound 1 is also deactivated, but due to its higher activity and slower deactivation rate, it is still effective after 6 hours, while B531 is only effective immediately after administration. These data are the average of 7 independent experiments, each experiment was performed in triplicate. Example C Inhibition of TNF or IL-6 production in in vitro animal model systems The compounds of the invention inhibit LPS-induced TNF or IL-6 production in whole blood or macrophages isolated from guinea pigs, rats, and mice. Macrophages from Hartley-White guinea pigs (Elm Hill Breeders, Chelmsford, MA) and C57BL / 6 mice (Jackson Labs, Bar Harbor, ME) were isolated from the abdomens of animals that had undergone primary immunization. Primary immunization was performed by intraperitoneally injecting mice with 2 mg of Bacillus calmette guerin (BCG; RIBI Immunochemical Research, Inc., Hamilton, MT) in 10 mg / ml saline, while guinea pigs were injected with 2 mg of BCG in a 7 ml dose volume in mineral oil. Peritoneal macrophages were isolated from the abdomens of the animals 3 days after injection by standard methods.The cells were allowed to adhere to culture plates for 2-3 hours, then cultured in RPMI 1640 medium containing 10% fetal calf serum and LPS was added to a final concentration of 10 ng / ml as described above. To demonstrate the inhibitory effect, the compounds of the invention (concentrations between 0 and 100 pmol / l) were added to the culture medium immediately before the addition of LPS. After a 3-hour incubation period, guinea pig, mouse and rat TNF levels and / or IL-6 levels were determined either by ELISA or, in the case of TNF released from guinea pig macrophages, by cytolytic bioassay [Lymphokines 2, 235 (1981)]. In mouse peritoneal macrophages, compound 1 exerted an excellent inhibitory effect (IC50=16 nmol / l for IL-6 and 20 nmol / l for TNF); The IC50 value for TNF release in guinea pig macrophages was 0.3 nmol / l, while the IC50 value for TNF release in rat peritoneal macrophages was 11 nmol / l. Example D In vitro studies Mice primed with BCG [Vogel S. et al., J. Immunology 124, 2004-2009 (1980)] were used as an in vivo test system to demonstrate the inhibitory effect of lipid-A analogues on 1) LPS-induced TNF production and 2) LPS-induced lethality, as follows. week-old male C57BL / 6 mice (supra) were primed with 2 mg intravenously administered into the tail vein HU 221 342 B1 BCG. Ten days after injection, E. coli LPS (supra) in pyrogen-free 5% glucose solution (Otsuka Pharmaceuticals Inc., Tokyo, Japan) was administered intravenously into the tail vein of BCG-primed mice. LPS was administered at a dose of 1-3 pg / mouse to assay both TNF production and mortality. The test compound was administered as a component of the injected LPS solution at concentrations ranging from 3 to 300 pg / mouse. Plasma was prepared 1 hour after LPS injection and TNF was assayed by the ELISA method described above. Mortality due to septic shock was recorded 36 hours after LPS injection. The compounds of the invention effectively inhibited TNF production after LPS administration. Compounds 10 and 1 effectively inhibited TNF production in vivo in mice (ED50=5 and 10.6 pg / mouse, respectively). Compounds 2, 3, 4, 5, 6, 7, 8 and 9 also inhibited TNF production, with ED50 values ​​ranging from 10 to 200 pg / mouse for compounds 5 and 6, and compound 7 had an ED50 value >100. In parallel experiments in guinea pigs, these analogs also effectively inhibited LPS-induced TNF production in vivo (optimal ED50 values ​​ranged from 2.3 to 6.1 pg / guinea pig for compounds 1, 7, and 10). The lipid A analogs of the invention can be used as active pharmaceutical ingredients to treat or prevent any LPS-mediated inflammation or disorder. Such disorders include, but are not limited to, endotoxemia (or sepsis syndrome) resulting from Gram-negative bacteremia (with accompanying symptoms such as fever, generalized inflammation, disseminated intravascular coagulation, hypotension, acute renal failure, acute respiratory distress syndrome, hepatocellular damage, and / or heart failure); and LPS-mediated exacerbation of latent or active viral infections (e.g., infection with HIV-1, cytomegalovirus, herpes simplex virus, and influenza virus). The lipid-A analog is usually administered dissolved in a pharmaceutically acceptable formulation, for example, physiological saline solution optionally containing 5% glucose. When the lipid-A analog is used to treat viral infections, it may be administered in conjunction with appropriate virucidal agents. The lipid-A analog may be stored as a freeze-dried formulation. Lipid-A analogs are administered in doses that provide adequate inhibition of LPS activation in target cells; generally, this corresponds to a dose of 0.01-50 mg / patient / day, more preferably 0.05-25 mg / patient / day, most preferably 1-12 mg / patient / day. The drug should be administered by injection or infusion as soon as possible after SIRS is diagnosed, based on clinical predictors such as APACHE score [Knaus et al., Chest 100, 1619-1636 (1991) and Knaus et al., JAMA, 1233-1241 (1993)] or other clinical predictors. In addition, the injection or infusion should be administered as soon as possible after exposure to endotoxins or after diagnosis of systemic Gram-negative bacterial infection, especially if an even more rapid and early diagnostic indicator of systemic Gram-negative infection is available. Prophylactic indications for the active ingredients of the invention include their use in the event of a suspected endotoxin infection. This may occur when 1) there is an increased likelihood of systemic (blood) accumulation of endotoxins from systemic or localized Gram-negative bacterial infection (for example, during surgery); 2) increased likelihood that blood concentrations of endotoxin will increase. Under normal physiological conditions, only minimal amounts of endotoxin cross the intestinal endothelium into the visceral circulation. The endotoxin that has crossed is then usually cleared from the body by the liver (and possibly other cells or organs). Blood endotoxin concentrations may increase if the rate of endotoxin clearance by the liver (or other endotoxin-secreting cells or organs) is reduced. Increased intestinal translocation may occur as a result of intestinal ischemia, hypoxia, trauma, or other injury to the integrity of the intestinal lining (or intoxication by drugs or alcohol). Blood endotoxin levels increase when liver function is impaired by disease (cirrhosis), injury (surgery or trauma), or temporary removal (such as during liver transplantation); 3) the body is exposed to endogenous endotoxins that result in an inflammatory response, either acutely or chronically; this may be by inhalation or other means of endotoxin uptake. An example of SIRS-inducing endotoxin uptake is corn dust fever [Schwartz et al., Am. J. Physiol. 267, 609-617 (1994)], which occurs in workers in the grain industry, e.g., in the Midwest of the United States. Such workers may be treated prophylactically, e.g., by daily inhalation of an aerosolized formulation of the invention prior to work, e.g., in the field or at grain elevators. For most other prophylactic and therapeutic applications, intravenous infusion or bolus injection is used. Injection is preferred, but pharmacokinetic requirements may necessitate the use of infusion in some cases. Treatment should be initiated as soon as possible after diagnosis of SIRS and continued for at least 3 days or until the risk of mortality is reduced to an acceptable level.

Claims

PATENT CLAIMS I. Compounds of general formula (I) - in the formula R1 is a group of general formula (a), (b), (c), (d), (e), (f), (g) or (h), where J, K and Q are independently straight or branched alkyl groups of 1-15 carbon atoms, L is O, NH or CH2, HU 221 342 Bl M is O or NH and G is NH, O, S, SO or SO2; R2 is a straight or branched alkyl group of 5-15 carbon atoms R3 is a straight or branched acyl group of 5-15 carbon atoms, or a group of general formula (i), (j), (k), (1) or (m), where E is NH, O, S, SO or SO2, A, B and D are independently straight or branched alkyl groups of 1-15 carbon atoms;R4 is a straight or branched alkyl group having 4 to 20 carbon atoms, or a group of the general formula (n), where U and V are independently a straight or branched alkyl group having 2 to 15 carbon atoms and W is a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms; RA is R5 or R5-O-CH2, R5 is a hydrogen atom or a group of the general formula -J', -J'-OH, -J'-O-K', -J'-O-K'-OH or -J'-O-PO(OH)2, where J' and K' are independently a straight or branched alkyl group having 1 to 5 carbon atoms; R6 is a hydroxyl group, a halogen atom, a C1-C5 alkoxy group or a C1-C5 acyloxy group; A1 and A2 independently represent OH, a group of formula (o), or a group of formula (p), (q) or (r), wherein Z represents a straight or branched C1-10 alkyl group, and pharmaceutically acceptable salts thereof; 2. Compounds of general formula (Γ) according to claim 1 - in the formula R1 is a group of general formula (a), (b), (c), (d), (e), (f), (g) or (h), where J, K and Q are independently a straight or branched alkyl group having 1-15 carbon atoms, L is O, NH or CH2, M is O or NH and G is NH, O, S, SO or SO2; R2 is a straight or branched alkyl group having 5-15 carbon atoms; R3 is a straight or branched acyl group having 5-15 carbon atoms, or a group of general formula (i), (j), (k), (1) or (m), where E is NH, O, S, SO or SO2, A, B and D are independently a straight or branched alkyl group having 1-15 carbon atoms;R4 is a straight or branched alkyl group having 4 to 20 carbon atoms, or a group of the general formula (n), where U and V are independently a straight or branched alkyl group having 2 to 15 carbon atoms and W is a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms; R5 is a hydrogen atom or a group of the general formula -J', -J'-OH, -J'-O-K', -J'-O-K'-OH or -J'-O-PO(OH)2, where J' and K' are independently a straight or branched alkyl group having 1 to 5 carbon atoms; R6 is a hydroxyl group, a halogen atom, a C1-C5 alkoxy group or a C1-C5 acyloxy group; A1 and A2 are independently OH, a group of formula (o), or a group of formula (p), (q) or (r), wherein Z is a straight or branched alkyl group having 1 to 10 carbon atoms, and pharmaceutically acceptable salts thereof; 3. Compounds according to claim 2, wherein R2 is a straight or branched alkyl group having 8 to 15 carbon atoms.

4. Compounds according to claim 2, wherein R2 is a straight or branched alkyl group having 9-12 carbon atoms.

5. Compounds according to claim 2, wherein R2 is a straight or branched alkyl group having 10 carbon atoms.

6. Compounds according to claim 2, wherein A1 and A2 are independently OH or -O-PO(OH)2.

7. Compounds according to claim 2, wherein R6 is hydroxyl.

8. Compounds according to claim 2, wherein R5 is a straight or branched alkyl group having 1-5 carbon atoms.

9. Compounds according to claim 2, wherein R1 is a group of formula (a), (b), (e) or (h), wherein J, K and Q are independently a straight or branched alkyl group having 1-15 carbon atoms.

10. Compounds according to claim 2, wherein R3 is a group of formula (i) or (j), wherein A, B and D are independently a straight or branched alkyl group having 1-15 carbon atoms.

11. Compounds according to claim 10, wherein the double bonds in R3 are in the cis configuration.

12. Compounds according to claim 10, wherein the double bonds in R3 are in the trans configuration.

13. Compounds according to claim 2, wherein R4 is a straight or branched alkyl group having 4 to 20 carbon atoms, or a group of general formula (n) in which U is a straight or branched alkyl group having 2 to 5 carbon atoms, V is a straight or branched alkyl group having 5 to 12 carbon atoms and W is a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms.

14. Compounds according to claim 2, wherein A1 and A2 are independently OH or -O-PO(OH)2; HU 221 342 Bl R1 is a group of general formula (a), (b), (e) or (h), wherein J, K and Q are independently straight or branched alkyl groups having 1-15 carbon atoms; R2 is a straight or branched alkyl group having 8-15 carbon atoms; R3 is a group of general formula (i) or (j), wherein A, B and D are independently straight or branched alkyl groups having 1-15 carbon atoms; R4 is a group of the general formula (n) wherein U is a straight or branched alkyl group having 2 to 5 carbon atoms, V is a straight or branched alkyl group having 5 to 12 carbon atoms, and W is a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms; and R5 is a straight or branched alkyl group having 1 to 5 carbon atoms; and R6 is a hydroxyl group.

15. Compounds according to claim 2, wherein A1 and A2 are independently -O-PO(OH)2; R> is a group of formula (a), (b), (e) or (h), wherein J and Q are independently a straight or branched alkyl group having 1-5 carbon atoms and K is a straight or branched alkyl group having 8-15 carbon atoms; R2 is a straight or branched alkyl group having 8-15 carbon atoms; R3 is a group of formula (i), wherein A is a straight or branched alkyl group having 5-12 carbon atoms and B is a straight or branched alkyl group having 6-12 carbon atoms; R4 is a group of general formula (n) in which U is a straight or branched alkyl group having 2 to 5 carbon atoms, V is a straight or branched alkyl group having 5 to 12 carbon atoms and W is a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms;and R5 is a straight or branched alkyl group having 1 to 5 carbon atoms; and R6 is a hydroxyl group.; 16. Compounds according to claim 2, wherein A1 and A2 are -O-PO(OH)2; R1 is a group of formula (b), (e) or (h), wherein J and Q are independently a straight or branched alkyl group of 1-3 carbon atoms and K.is a straight or branched alkyl group having 10-12 carbon atoms; R2 is a straight or branched alkyl group having 9-12 carbon atoms; R3 is a group of the general formula (i) in which A is a straight or branched alkyl group having 8-12 carbon atoms and B is a straight or branched alkyl group having 6-10 carbon atoms; R4 is a group of the general formula (n) in which U is a straight or branched alkyl group having 2-4 carbon atoms, V is a straight or branched alkyl group having 5-10 carbon atoms and W is a hydrogen atom or a straight or branched alkyl group having 1-3 carbon atoms; and R5 is a straight or branched alkyl group having 1-3 carbon atoms; and R6 is a hydroxyl group.

17. The compound of claim 2, which is the compound of formula (1-2), or a pharmaceutically acceptable salt thereof.

18. The compound of claim 2, which is the compound of formula (1-1), or a pharmaceutically acceptable salt thereof.