KR100473325B1 - New compound with antiviral activity - Google Patents

Abstract

The present invention relates to novel compounds having antiviral activity, drugs and antiviral substances containing them as active ingredients, and to provide antiretroviral active compounds having low anticoagulant activity and cytotoxicity. Provided is a compound consisting of a glycoside or a salt thereof in which the hydroxy acid at the position is fully sulfated or the lipid is bonded at the 2 position of KDN at which the hydroxyl group at the 4, 5, 7, 8, and 9 positions are fully sulfated.

The novel compounds of the present invention have low anticoagulant action and low toxicity to a living body, and thus have an optimal effect as a pharmaceutical.

Description

New compound with antiviral activity

The present invention relates to novel compounds having antiviral activity, to drugs and antiviral substances containing them as active ingredients, and in particular to drugs and anti-HIV active compounds including sulfated nonneuronic acid.

Conventional azidothymidine (hereinafter referred to as 'AZT') and dideoxy inosine (hereinafter referred to as 'DDI') have been used as a medicine for AIDS. They inhibit the reverse transcriptase of HIV and have a life-long effect on patients, but AZT causes bone marrow disorders after long-term administration, and DDI causes side effects such as acute pancreatitis and peripheral neuropathy. And either one shows their resistant virus.

Recently, there is a sulfated polysaccharide that is expected as an AIDS treatment drug. For example, dextran sulfate (I) (JP-A 63-45233), polyvinyl alcohol sulfate (II) (Antimicrob Agents Chemother 34, 134-138 (1990)), oligosaccharide sulfate (JP 2) It is widely known that polysulfate compounds such as -304025) inhibit the growth of HIV. These compounds simply combine sulfuric acid groups with polysaccharides, oligosaccharides or organic polymers.

In addition, sulfate-modified cyclodextrin (III) is a lipid-soluble group such as aryl or alkyl introduced into the cyclodextrin, which also has a proliferation inhibitory activity against retroviruses, particularly HIV. -136001 publication)

Moreover, as an antiviral agent which has a sulfated polysaccharide as an active ingredient, what used the sulfated oligosaccharide glycoside acylate is known (Unexamined-Japanese-Patent No. 6-256373). The anti-HIV activity of sulfated polysaccharide was originally thought to be due to its reverse transcriptase inhibitory activity, but now it is thought that the sulfated polysaccharide and HIV are due to the interaction of the envelope protein gp120.

However, since sulfated polysaccharides generally have inhibitory activity (anticoagulant activity) of the blood coagulation system, they cannot be said to be suitable as drugs.

1 is a graph showing the dependence of activity on chain length in a compound in which two chains of alkyl glycerol are glycoside bonded.

Figure 2 shows the reaction route from Example 1 to 6.

Figure 3 shows the reaction route from Example 7 to 12.

Figure 4 shows the reaction route from Example 13 to 17.

Figure 5 shows the reaction route from Example 18 to 21.

Figure 6 shows the reaction route from Example 22 to 25.

7 shows the reaction pathways from Examples 26 to 29.

8 shows the reaction pathways from Examples 30 to 34.

9 shows the reaction pathways from Examples 35 to 36.

10 shows the reaction pathways from Examples 37 to 41.

Figure 11 shows the reaction route from Example 42 to 45.

12 shows the reaction pathways from Examples 46 to 51.

13 shows the reaction pathways from Examples 52 to 56.

14 shows the reaction pathways from Example 57 to 60B.

Figure 15 shows the reaction pathways from Example 60C to 63.

Figure 16 shows the reaction route from Example 64 to 68.

※ Explanation of main parts of drawing

Disclosure of the Invention

The present invention has been made to solve the above problems, and an object thereof is to provide an antiviral active compound, particularly an HIV active compound, having low anticoagulant activity and cytotoxicity.

MEANS TO SOLVE THE PROBLEM In order to solve the above subjects, the present inventors conducted research and found that the following compound achieves the said objective, and came to complete this invention.

(1) A compound or a salt thereof in which all hydroxyl groups of the sugar residue portion of the glycoside consisting of a monosaccharide-lipid having a fat bonded to the anomer carbon position of the sugar are all sulfated.

(2) The compound or salt thereof according to (1), wherein the linkage between the sugar residue moiety and the lipid moiety is an O-glycosidic bond or an S-glycosidic bond.

(3) The compound or salt thereof according to (2), wherein the fat is a chain fat, and the chain fat has a branched structure.

(4) A compound or a salt thereof in which all hydroxyl groups of the nonneuronic acid residue portion of a glycoside composed of a monosaccharide-lipid having a fatty portion bonded to an anomer carbon position of a nonulonic acid derivative are sulfated.

(5) The sialic acid residue portion of the glycoside consisting of a monosaccharide-lipid having a fatty portion bonded to the anomer carbon position of sialic acid or 2-keto-3-dioxy-D-glycero-2-nonneuronic acid (KDN). Or a compound or a salt thereof in which the hydroxyl groups of the residue portion of 2-keto-3-dioxy-D-glycero-2-nonneuronic acid (KDN) are all sulfated.

(6) The compound described in (5), wherein the linkage between the sialic acid residue or the 2-keto-3-dioxy-D-glycero-2-nonneuronic acid (KDN) residue portion and the lipid portion is the residue thereof. A compound or a salt thereof, wherein the compound is an O-glycosidic bond or an S-glycosidic bond or an amide bond in one position of the residue thereof.

(7) The compound or salt thereof according to (6), wherein the fat is a chain fat, and the chain fat has a branched structure.

(8) The compound or salt thereof according to (7), wherein the branch is branched at two positions of the main chain of the fatty portion.

(9) The compound or salt thereof according to (8), wherein the lipid moiety has two chains by the branching.

(10) The compound or salt thereof according to (9), wherein the fatty moiety has an alkyl group having 1 to 4 atoms forming the skeleton at the position of the branch.

(11) The compound or salt thereof according to (9) or (10), wherein the total number of atoms forming the skeleton of the lipid is 22 to 60.

(12) The compound or salt thereof according to (11), wherein the branched chain contains an unsaturated bond between carbons.

(13) The compound or salt thereof according to (11), wherein the branched chain is straight chain.

(14) The compound or salt thereof according to (11), wherein the branched chains each include an ester bond or an ether bond.

(15) The compound or a salt thereof, wherein the ester bond or ether bond of the compound described in (14) is present at 1 or 2 positions of the branched chain.

(16) A compound or a salt thereof, wherein the number of atoms forming a skeleton per branched chain of the compound described in (11) is 10 to 28.

(17) A compound or a salt thereof, wherein the number of atoms forming a skeleton per branched chain of the compound described in (16) is 18 to 26.

(18) A compound or a salt thereof, wherein the number of atoms forming a skeleton per branched chain of the compound described in (17) is 24.

(19) The compound or salt thereof according to (18), wherein the branched chains are the same length each.

(20) The compound or salt thereof according to (19), wherein the branched chains are the same.

(21) The compound according to (20), wherein the branched chain has an ester bond or an ether bond at one or two positions of the branched chain, or a salt thereof.

(22) The compound or salt thereof according to (21), wherein the branched chain is straight chain.

(23) A pharmaceutical comprising a pharmaceutically effective amount of the compound according to any one of (1) to (3).

(24) An antiviral agent comprising a pharmaceutically effective amount of the compound according to any one of (1) to (3).

(25) An anti-HIV agent comprising a pharmaceutically effective amount of the compound according to any one of (1) to (3).

(26) Human immunodeficiency virus (HIV), ferrin immunodeficiency virus (FIV), and perrin, which contain a pharmaceutically effective amount of the compound according to any one of (4) to (22). A pharmaceutical composition for treating viral diseases that mediates Leukemia virus (FeLV), Herpes simplex II virus (HSV II), Parainfluenza virus, or Respiratory Synthetic Virus (RSV).

(27) An antiviral agent comprising a pharmaceutically effective amount of the compound according to any one of (4) to (22).

(28) An anti-HIV agent comprising a pharmaceutically effective amount of the compound according to any one of (4) to (22).

In the scope of the present invention, a medicament (claims 23 and 26) containing an pharmaceutically effective amount of the compound of any one of (1) to (22), an antiviral agent (claims 24 and 27), in particular Anti-HIV agents (claims 25 and 28) are also included.

However, the pharmaceutical composition according to any one of (5) to (22) above the pharmaceutical, antiviral agent, and anti-HIV agent containing a pharmaceutically effective amount of the compound according to any one of (1) to (3) above Medicines, antiviral agents, and anti-HIV agents containing an effective amount are useful as pharmaceuticals because of their low anticoagulant action and low toxicity to living organisms.

Particularly, in the above compound, when the number of atoms forming the skeleton per branched chain is 21 (18), and each branched chain is the same, the branched chain is ether-bonded at 1 or 2 positions. It can be seen that the straight chain having a is useful as a constraint (12, 13, 29, 50 and 59).

Furthermore, the scope of the present invention includes the use of an antiviral agent and an anti-HIV agent containing a pharmaceutically effective amount of the compound according to any one of the above (1) to (22) as a medicine, an antiviral agent, and an anti-HIV agent, The method also includes a method of treating certain diseases (viral diseases or acquired immunodeficiency syndrome caused by HIV).

Best mode for carrying out the invention

Definition of Terms

The term " nonneuronic acid " used in the present specification is the same as that of non-neuronic acid generally used, and refers to an acidic sugar having a carboxyl group and 9 carbon atoms in one position.

Thus, the <nonneuronic acid derivatives> used herein naturally include neuramic acid (5-amino-3,5-dideoxy-D-glycero-D-galacto-nonneuronic acid) and neuramic acid. Derivatives are also included. In addition, since <sialic acid> mentioned later is also an acyl derivative of neuramic acid, it is contained in <nonneuronic acid derivative>.

<KDN> as used herein means 2-keto-3-deoxy-D-glycero-2-nonulonic acid. As used herein, <sialic acid> refers to a generic name for a series of derivatives that are substances having a neuramic acid (Neuraminic acid) as a basic structure (Inoue Yasuo <chemistry of biomolecules of sugars> p80 -81) include acyl derivatives, specifically, such as N-acetylneuraminic acid and N-glycorylneuraminic acid.

<Two chains> used in this specification (for example, (9), Claim 9) means what consists of two chains whose number of atoms which form a skeleton is seven or more. Therefore, the extent of <an alkyl group having a total number of atoms forming a skeleton> of claims 10 and (10) is not referred to as a <chain> constituting <two chains>.

<Atom forming a skeleton> refers to an atom constituting the skeleton portion of the chain, and includes a carbon atom, an oxygen atom, a nitrogen atom, a sulfur atom and the like. However, atoms having a monovalent atomic value, for example, hydrogen atoms and the like, are not included in <atoms forming a skeleton> because they cannot form a skeleton portion of the chain.

Salt is necessary for neutralizing carboxylic acid and sulfonic acid in the molecule such as sodium salt and potassium salt, and is bound to cations that do not degrade the activity. The cation to be bound may be any one as long as it does not degrade the activity of the compound of the present invention.

<Per>

The compound of the present invention is a compound or a salt thereof in which all hydroxyl groups, which are sugar residue portions of glycosides consisting of a monosaccharide-lipid, in which a lipid is bound to an anomer position of a sugar, are all sulfated, and this has excellent antiretroviral activity. (1 above, claim 1). Conventionally, sulfated polysaccharides having antiretroviral activity have been found, but since sulfate groups have been introduced into monosaccharide-fat glycosides, no compounds having antiretroviral activity have been found. The significance of the present invention lies in the fact that 100% introduced compounds or derivatives thereof have excellent antiviral activity.

Since the sugar of the glycoside is sialic acid or KDN, it is natural that the antiviral activity is strong, but at the same time, the cytotoxicity is low, and the object of the present invention as a medicine can be suitably achieved ((5) to (22). And (26) to (28) or claims 5 to 22 and claims 26 to 28).

In this case, the sugar moiety moiety of the compound of the present invention becomes non-uronic acid in which all of the hydroxyl groups are sulfated (4, 7, claim 4), and 4 and 7 when the non-neuronic acid is N-acetylneuraminic acid. , Hydroxyl groups at positions 8 and 9 are all sulfated, and in the case of N-glycolylneuraminic acid, hydroxyl groups at positions 4, 7, 8, and 9 are all sulfated, and sulfates at position 5 are also sulfated. will be. In the case of KDN, all hydroxyl groups at positions 4, 5, 7, 8, and 9 are sulfated.

Any combination of the monosaccharide and the lipid of the compound of the present invention may be any. Therefore, the linkage between the monosaccharide and the lipid may be an S-glycoside bond as well as an O-glycoside bond. Moreover, when the sugar residue of the compound of this invention was nonneuronic acid, the amide bond and ester bond which use the carboxyl group of 1-position as well as the glycosidic bond with a 2-position carbon atom become possible.

Such amide bond or ester bond may be sufficient as the bond of the monosaccharide and the lipid of the compound of the present invention. Thus, in general, <monosaccharide> means that glycosides are monosaccharide and fat-bonded. However, when <monosaccharide> of the present invention is used, not only monosaccharides and lipids are glycosidic, but also amide-bonded. It means what is and what is ester-bonded. Therefore, glycoside-bonded at 1 position of monosaccharide such as glucose and glycoside-bonded at 2-position of nonneuronic acid, as well as amide bond and ester bond at 1-position of nonneuronic acid are referred to in the present invention. It is included in the concept of>.

However, when comprehensively considering the ease of manufacture, the strength of the activity, etc., it is preferable that they are O-glycoside bonds, S-glycoside bonds, and amide bonds (the above (6) and claims 6).

<Fat>

In the compound of the present invention, <fat> is a fat in a broad sense including steroidoids, carotenoids, terpenoids, and the like, and conceptually includes the same as cholesterol.

However, in the compound of the present invention, it is preferable that the fat is a chain-type fat, and more preferably, the chain-type fat has a branched structure (above (7) and claims 7 above). The branch may be two or three, but these branches are branched at position 2, the main chain of the lipid moiety. As a result, the fat is preferably composed of two chains branched at the β-position (β-position to the sugar residue) of the fatty portion (above (8) and (9), claims 8 and 9). The branched portion may have an alkyl group having 1 to 4 atoms forming the skeleton (above (10) and claim 10). In addition, the alkyl group whose number of atoms which form a skeleton here is 1-4 contains a methyl group, an ethyl group, a propyl group, etc.

The two chains may be a hydrocarbon chain or may contain a hetero atom such as oxygen, nitrogen, or sulfur in the hydrocarbon chain. And it is preferable that the number of the atoms which form a lipid skeleton is 22-60 irrespective of the kind of member (the said (11) and Claim 11).

In addition, the two chains may each contain an unsaturated bond between carbons (above (12) and claim 12). In addition, although the said two chains may be branched again, it is preferable that they are a straight chain (said (13), Claim 13).

When a member of the two chains contains a hetero atom, each branched chain preferably includes an ester bond or an ether bond (above (14) and claims 14), and an ester bond or ether If it was a bond, it is preferred that it is at one or two positions of the branched chain (see (15) above, claim 15).

Here, when an ester bond or an ether bond exists at the 1 position of a branched chain, the compound belonging to the present invention becomes a sialoglycerolipid sulfate derivative having excellent antiretroviral activity (as well as an ether bond) Is an alkylglycerol having a long chain alcohol bound to a glycerin residue, and an acylglycerol in the case of an ester bond).

Moreover, when ester bond or ether bond exists in the 2 position which is a branched chain, in the glycerol area | region, the glycerol residue part turns into the similar glycerol suitably modified.

The length of the branched chain is preferably from 10 to 28 of the atoms forming the skeleton (above (16) and claim 16), more preferably from 18 to 26 (above (17) and claim 17). 24, particularly preferred (the above (18), claims 18). In addition, although the length of a branched chain may differ, respectively, it is preferable that they are the same length ((19), claim 19), and it is more preferable if the constituent atoms and structures are also the same (the above (20), claim 20). .

<Administration method>

When the compound of the present invention is used as a therapeutic agent, it is administered alone or in combination with a pharmaceutically acceptable organic or inorganic carrier (solid or liquid). This composition is determined by the solubility, chemical properties, route of administration, dosing schedule, etc. of the compound.

The compound of the present invention as a medicament can be administered by any suitable administration route. Specifically, the compound of the present invention is used in animals such as intraperitoneal administration, subcutaneous administration, transdermal administration, rectal administration, intravenous administration to vein or artery and topical administration by injection, etc. It can be administered by intramuscular administration, intraarterial administration, local administration by injection, intraperitoneal administration, intrathoracic administration, oral administration, subcutaneous administration, intramuscular administration, sublingual administration, transdermal administration, inhalation or rectal administration.

<Form of pharmaceutical>

In the case of administering a compound belonging to the present invention as a medicament, injection, suspension, tablet, granule, powder (powder state), capsule, ointment, cream, suppository (anal drug), tape, depending on the administration method and purpose of administration It may be administered in the shape of the back. When preparing these formulations, a solvent, a solubilizer, an isotonicity agent (expansion regulator), a preservative, an oxidation resistant agent, an excipient, a binder, a softening agent, a stabilizer, and the like can be added.

As a solvent, water, saline, etc. are used. As a solubilizer, ethanol, polysorbates, chromophore, etc. are used, and excipients, for example, lactose, sugar cane, starch, cellulose, crystals, are used. Cellulose, dextrin, mannitol, maltose, kaolin, calcium hydrogen phosphate, soft silicic acid, calcium carbonate and the like are used, and as binders, for example, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, ethyl cellulose, carboxymethyl Cellulose, gum arabic, etc. are used, and as a disintegrating agent, for example, starch, carboxymethylene cellulose calcium, etc. are used, and as a lubricant, magnesium stearate, tar, hardening oil, etc. are used, for example, as a stabilizer, For example, lactose, anitol, maltose, polysorbates, macrogols, polyoxyethylene hydroxide castor oil, etc. are mentioned.

If necessary, glycerin, dimethylacetamido, 70% sodium lactate, surfactants, and basic substances (e.g. sodium hydroxide, ethylenediamine, ethanolamine, sodium carbonate, arginine, megmine, trisamino Methane) is added. The compounds of the present invention can be prepared in the form of injections, tablets, granules, capsules and the like using these components.

When orally administering a compound belonging to the present invention, it may be administered in the form of granules, fine granules, powders (powders), tablets, light syrups, soft capsules, syrups, emulsions, suspensions, liposomes, or liquids. There is a number. Liquid preparations for oral administration, ie emulsions, syrups, suspensions, solutions, and the like include water or vegetable oils which are commonly used inert diluents. In addition to generally inert diluents, the formulations may also include auxiliary wetting agents, suspending aids, sweetening agents, fragrances, coloring or preservatives, and the like.

It may be included as a liquid formulation in the wexel of an absorbable substance such as gelatin. Intravenous administration, intramuscular administration, subcutaneous administration, etc., may be used as an injection powder and prepared as needed for injection. As a solvent or suspending agent for preparation of parenteral preparations, that is, injections and the like, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like can be given. What is necessary is just to prepare a preparation in a conventional method.

<Treatment>

It is desirable to increase or decrease the clinical dose appropriately according to age, disease state, symptoms, and the presence of simultaneous administration. The daily amount of the compound of the present invention may be administered once a day or divided into two or three times a day at appropriate intervals, or may be administered intermittently. The dose of the compound of the present invention is determined so that the total dose does not exceed a certain amount in single and repeated doses in consideration of the results of animal experiments and various situations. The specific dosage will vary depending on the method of administration, the situation of the patient or treated animal, such as age, weight, sex, sensitivity, diet (dietary), time of administration, medication used, the patient or the extent of the disease. Quantitative doses and frequency of administration should be determined by a specialist's quantitative determination test based on the above guidelines.

Synthesis of Compound

Example 1

Sodium [methyl5-acetamido-3,5-dideoxy-4,7,8,9 tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto-2-nonuro Filanoside] Onate:

Methyl 5-acetamido-3,5- dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosidic acid [Chem. Ber., 99, 611 (1966)] (200 mg, 0.58 mmol) and trimethyl iodide trimethylamine complex (1600 mg, 11.5 mmol) in dry dimethylformamide (5.8 mL) at 80-85 ° C. under argon. Stir for 2 hours.

The reaction mixture was directly purified by silica gel column chromatography (209 g, chloroform) / methanol / water, 5: 4: 1) and treated in the range of Dowex 50W-X-8 (Na type). Again, the residue was purified by gel chromatography (Sephadex G-25, 400 ml, water) to obtain the title compound (359 mg, 82%) as a white solid.

¹ H-NMR (D ₂ O) δ: 3.37 (s, 3H, OCH ₃ ), 2.88 (dd, 1H, J = 4.0, 11.7 Hz, H-3eq), 1.97 (s, 3H, NAc), 1.77 ( t, 1H, J = 12.1 Hz, H-3ax).

Example 2

Sodium [methyl 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-β-D-galacto-2-no Neurofilanoside] Onate:

Methyl5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosidonic acid [Chem. Ber., 99, 611 (1966)] (200 mg) Was reacted by the general method described in Example 1 to obtain the title compound (218 mg, 50 g) as a white solid.

¹ H-NMR (D ₂ O) δ: 3.33 (s, 3H, OCH ₃ ), 2.57 (dd, 1H, J = 5.1, 13.2 Hz, H-3eq), 1.96 (s, 3H, NAc), 1.90 ( t, 1H, J = 13.1 Hz, H-3ax).

Example 3

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-hexyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosyl) onate] -1,2di-O- Hexyl-Sn-glycerol [JP-A-125394] (19 mg) was reacted by the general method described in Example 1 to obtain the title compound (15 mg, 46%) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 3.02 (dd, 1H, J = 4.9, 12.6 Hz, H-3eq), 1.92 (s, 3H, NAc), 1.83 (t, 1H, J = 12.1 Hz, H -3ax), 1.39-1.26 (m, 12H, 6CH ₂ ), 0.90 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

Example 4

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-β-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-hexyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosyl) onate] -1,2di-O- Hexyl-Sn-glycerol [JP-A-125394] (26 mg) was reacted by the general method described in Example 1 to obtain the title compound (22 mg, 48%) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 2.83 (dd, 1H, J = 5.1, 12.8 Hz, H-3eq), 2.03 (s, 3H, NAc), 1.87 (t, 1H, J = 12.3 Hz, H -3ax), 1.37-1.34 (m, 12H, 6CH ₂ ), 0.90 (t, 3H, J = 6.8H _Z , CH ₂ CH ₃ ), 0.90 (t, 3H, J = 7.0 Hz CH ₃ ).

Example 5

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto- 2-nonurophyllanosyl onate] -1,2-di-O-decyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosyl) onate] -1,2di-O- Decyl-Sn-glycerol [JP-A-125394] (190 mg) was reacted by the general method described in Example 1 to obtain the title compound (268 mg, 88%) as a white solid.

¹ H-NMR (D ₂ O) δ: 2.94 (dd, 1H, J = 5.0, 13.0 Hz, H-3eq), 1.99 (s, 3H, NAc), 1.96 (t, 1H, J = 12.5 Hz, H -3ax), 1.44-1.21 (m, 28H, 14CH ₂ ), 0.89 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 6

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-β-D-galacto- 2-nonurophyllanosyl onate] -1,2-di-O-decyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosyl) onate] -1,2di-O- Decyl-Sn-glycerol [JP-A-125394] (197 mg) was reacted by the general method described in Example 1 to obtain the title compound (240 mg, 76%) as a white solid.

¹ H-NMR (D ₂ O) δ: 2.67 (dd, 1H, J = 5.0, 13.0 Hz, H-3eq), 2.01 (s, 3H, NAc), 1.93 (t, 1H, J = 12.2 Hz, H -3ax), 1.42-1.20 (m, 28H, 14CH ₂ ), 0.88 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 7

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-tetradecyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosyl) onate] -1,2di-O- Tetradecyl-Sn-glycerol [JP-A 59-164798] (406 mg) was reacted by the general method described in Example 1 to obtain the title compound (479 mg, 78%) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 3.01 (dd, 1H, J = 4.9, 11.9 Hz, H-3eq), 1.93 (s, 3H, NAc), 1.74 (t, 1H, J = 12.1 Hz, H -3ax), 1.38-1.25 (m, 44H, 22CH ₂ ), 0.90 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 8

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-β-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-tetradecyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-βα-D-galacto-2-nonurophyllanosyl) onate] -1,2di-O- Tetradecyl-Sn-glycerol [JP-A 59-164798] (87 mg) was reacted by the general method described in Example 1 to obtain the title compound (120 mg, 91%) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 2.83 (dd, 1H, J = 5.5, 12.8 Hz, H-3eq), 2.03 (s, 3H, NAc), 1.85 (t, 1H, J = 12.0 Hz, H -3ax), 1.45-1.20 (m, 44H, 22CH ₂ ), 0.90 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 9

3-O- [Sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-octadecyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosyl) onate] -1,2di-O- Octadecyl-Sn-glycerol [JP-A-125394] (45 mg) was reacted by the general method described in Example 1 to obtain the title compound (44 mg, 66%) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 3.02 (dd, 1H, J = 5.1, 13.2 Hz, H-3eq), 1.92 (s, 3H, NAc), 1.82 (t, 1H, J = 12.5 Hz, H -3ax), 1.38-1.22 (m, 60H, 30CH ₂ ), 0.90 (t, 6H, J = 6.9 Hz, 2CH ₂ CH ₃ ).

Example 10

3-O- [Sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto- 2-nonurophyllanosyl onnate] -2-O- (sodium oxalfonyl) -1-O-octadecyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosyl) onate] -1-O-octadecyl- Sn-glycerol [H1-125394] (132 mg) was reacted by the general method described in Example 1 to obtain the title compound (125 mg, 53%) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 3.07 (dd, 1H, J = 5.1, 12.1 Hz, H-3eq), 1.95 (s, 3H, NAc), 1.68 (t, 1H, J = 12.1 Hz, H -3ax), 1.36-1.22 (m, 30H, 15CH ₂ ), 0.90 (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ).

Example 11

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-β-D-galacto- 2-nonurophyllanosyl onnate] -2-O- (sodium oxalfonyl) -1-O-octadecyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosyl) onate] -1-O-octadecyl- Sn-glycerol [H1-125394] (66 mg) was reacted by the general method described in Example 1 to obtain the title compound (31 mg, 49%) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 2.81 (dd, 1H, J = 4.4, 12.1 Hz, H-3eq), 2.03 (s, 3H, NAc), 1.88 (t, 1H, J = 11.9 Hz, H -3ax), 1.38-1.17 (m, 30H, 15CH ₂ ), 0.90 (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ).

Example 12

3-O- [Sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-docosyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosyl) onate] -1,2-di-O Docosyl-Sn-glycerol [0011] (502 mg) was reacted by the general method described in Example 1 to give the title compound (447 mg, 54%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 50 ° C.) δ: 2.96 (br.dd, 1H, H-3eq), 1.97 (s, 3H, NAc), 1.83 (br.t, 1H, H-3ax), 1.40-1.21 (m, 76H, 38CH ₂ ), 0.89 (t, 6H, J = 6.4 Hz, 2CH ₂ CH ₃ ).

Example 13

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-β-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-docosyl-Sn-glycerol:

3-O- [sodium (5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosyl) onate] -1,2-di-O Docosyl-Sn-glycerol [0011] (44 mg) was reacted by the general method described in Example 1 to give the title compound (25 mg, 40%) as a white solid.

¹ H-NMR (CDCl ₃ CD ₃ OD-D ₂ O, 3: 4: 2) δ: 2.75 (br.dd, 1H, H-3eq), 2.02 (s, 3H, NAc), 1.89 (br.t , 1H, H-3ax), 1.40-1.18 (m, 76H, 38CH ₂ ), 0.89 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

Example 14

3-S- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-tetradecyl-Sn-thioglycerol:

3-S- [sodium (5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosyl) onate] -1,2-di-O Tetradecyl-Sn-thioglycerol [JP-A No. 64-52794] (41 mg) was reacted by the general method described in Example 1 to obtain the title compound (47 mg, 77%) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 3.17 (dd, 1H, J = 5.1, 12.1 Hz, H-3eq), 1.92 (s, 3H, NAc), 1.77 (t, 1H, J = 11.7 Hz, H -3ax), 1.41-1.23 (m, 44H, 22CH ₂ ), 0.90 (t, 6H, J = 7.1 Hz, 2CH ₂ CH ₃ ).

Example 15

3-O- [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonuro Filanosyl onate] -1,2-di-O-ecosyl-Sn-glycerol:

<A>: 3-O-benzyl-1,2-di-O-ecosyl-Sn-glycerol:

3-0 benzyl-Sn-glycerol [Agric. Bio. Chem., 46, 255 (1982)] (30 mg, 1.65 mmol) and 1-bromoeichoic acid (2.38 g, 6.58 mmol) and powdered sodium hydroxide (293 mg, 7.33 mmol) in benzene (10 ml), It was heated to reflux for two days while removing water. The reaction solution was diluted with ether, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The remaining sediment was purified by silica gel column chromatography (100 g, hexane: toluene = 3: 2) to give the title compound (929 mg, 76%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.26 (m, 5H, C ₆ H ₅ ), 4.55 (s, 2H, CH ₂ Ph), 1.25 (m, 68H, 34CH ₂ ), 0.08 (t, 6H , J = 6.6Hz, 2CH ₂ CH ₃ )

<B>: 1,2-di-O-ecosyl-Sn-glycerol:

3-O-benzyl-1,2-di-O-ecosyl-Sn-glycerol (1.47 g, 1.98 mmol) and 10% palladium carbon (200 mg) in ethyl acetate (30 ml) at room temperature under hydrogen stream Stirred for 18 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (934 mg, 72%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (m, 68H, 34CH ₂ ), 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

<C>: 3-O- [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-ecosyl-Sn-glycerol:

1,2-di-O-ecosyl-Sn-glycerol (497 mg, 0.76 mmol) and methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3 , 5-trideoxy-D-glycero-β-D-galacto-2-nonurophyllanosonate [Chem. Ber., 99, 611 (1966)] (422 mg, 0.83 mmol) and cyanide A dry chloroform (5.0 ml) mixture of mercury (336 mg, 1.33 mmol), mercury embrittlement (478 mg, 1.33 mmol), and dried Molecular Sieve 4A (1.0 g) was added at room temperature under nitrogen stream for 24 hours. Stirred. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and then purified by medium pressure silica gel column chromatography (125 g, toluene: ethyl acetate = 3: 2) to give the title compound (390 mg, 46%) as white. Obtained as a powder.

¹ H-NMR (CDCl ₃ ) δ: 3.79 (s, 3H, OCH ₃ ), 2.60 (dd, 1H, J = 4.8, 12.8 Hz, H-3eq), 2.14, 2.13, 2.06, 2.04, 1.88 (5s, 15H, 5Ac), 1.98 (t, 1H, J = 12.8 Hz, H-3ax), 1.25 (m, 68H, 34CH ₂ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 16

3-O-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid) -2-yl] -1,2-di-O Eicosyl-Sn-glycerol:

3-O- [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonuro Filanosyl onate] -1,2-di-O-ecosyl-Sn-glycerol (455 mg, 0.40 mmol) and sodium methoxide (780 μl, 4.0 mmol) were mixed with THF: methanol (1: 1) solvent ( 13 ml) was stirred for 24 hours, 3N-sodium hydroxide (360 µ1) was added to the reaction mixture, and the mixture was stirred for 1 hour at 60 ° C. After the reaction mixture was concentrated under reduced pressure, the remaining sediment was concentrated with ethanol and water. The precipitate was filtered, washed with water, methanol, and ether in turn, and dried in vacuo to yield the title compound (365 mg, 96%) as a white powder.

¹ H-NMR (CDCl ₃ -CD ₃ 0D, 1: 1) δ: 2.79 (dd, 1H, J = 3.9, 12.3 Hz, H-3eq), 2.03 (s, 3H, NAc), 1.69 (t, 1H , J = 11.5 Hz, H-3ax), 1.43-1.20 (m, 68H, 34CH ₂ ), 0.89 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 17

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-ecosyl-Sn-glycerol:

3-O-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid) -2-yl] -1,2-di-O Eicosyl-Sn-glycerol (241 mg) was reacted in the general manner described in Example 1 to give the title compound (236 mg, 67%) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 3.0 ₂ (dd, 1H, J = 4.4, 12.4 Hz, H-3eq), 1.92 (s, 3H, NAc), 1.80 (t, 1H, J = 11.0 Hz, H-3ax), 1.44-1.13 (m, 68H, 34CH ₂ ), 0.909 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 18

3-O- [methyl 5-acetamido-4,7,8,9-tetra-O- (acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonneuro Filanosyl onate] -1,2-di-O-tetracosyl-Sn-glycerol:

<A>: 3-O-benzyl-1,2-di-O-tetracosyl-Sn-glycerol:

3-O-benzyl-Sn-glycerol [Agric. Bio Chem., 46, 255 (1982)] and 1-bromotetracoic acid [J. Am. Chem. Soc., 115, 3840 (1993)] was reacted in the general manner described in Example 15-A to afford the title compound (1.47 g, 90%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.26 (m, 5H, C ₆ H ₅ ), 4.55 (s, 2H, CH ₂ Ph), 1.25 (m, 84H, 42CH ₂ ), 0.88 (t, 6H , J = 6.6 Hz, 2CH ₂ CH ₃ ).

<B>: 1,2-di-O-tetracosyl-Sn-glycerol:

General method described in Example 15-B using 3-O-benzyl-1,2-di-O-tetracosyl-Sn-glycerol (1.47 g) using a solvent of toluene-ethyl acetate 1: 1 (30 ml) Reaction to give the title compound (0.80 g, 66%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (m, 84H, 42CH ₂ ) 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

<C>: 3-O- [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-tetracosyl-Sn-glycerol:

1,2-di-O-tetracosyl-Sn-glycerol (497 mg, 0.76 mmol) and methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3 , 5-tridioxy-D-glycero-β-D-galacto-2-nonurophyllanosonate [Chem. Ber., 99, 611 (1966)] (422 mg, 0.83 mmol) is provided in Example 15. Reaction was carried out by the general method described in -C to give the title compound (224 mg, 14%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.79 (s, 3H, OCH ₃ ), 2.60 (dd, 1H, J = 4.8, 12.8 Hz, H-3eq), 2.14, 2.13, 2.04, 2.03, 1.88 (5s, 15H, 5Ac), 1.98 (t, 1H, J = 12.8 Hz, H-3ax), 1.25 (m, 84H, 42CH ₂ ), 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

Example 19

3-O-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid 2-yl] -1,2-di-O-tetra Kosyl-Sn-Glycerol:

3-O- [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonuro Filanosyl) onate] -1,2-di-O-tetracosyl-Sn-glycerol (240 mg) was reacted in the general manner described in Example 16 to give the title compound (160 mg, 79%) as a white solid. Got it.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1) δ: 2.81 (dd, 1H, J = 3.7, 12.1 Hz, H-3eq), 2.03 (s, 3H, NAc), 1.66 (t, 1H , J = 11.3 Hz, H-3ax), 1.38-1.16 (m, 84H, 42CH ₂ ), 0.89 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 20

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9 tetra-O- (sodiumoxy sulfonyl) -D-glycero-α-D-galacto-no Neurophyllanosyl onnate] -1,2-di-O-tetracosyl-Sn-glycerol:

3-O-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosonic acid) -2-yl] -1,2-D -O-tetracosyl-Sn-glycerol (80 mg) was reacted by the general method described in Example 1 to give the title compound (21 mg, 19%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 50 ° C.) δ: 2.96 (br.dd, 1H, H-3eq), 2.01 (s, 3H, NAc), 1.81 (br.t, 1H, H-3ax), 1.36-1.10 (m, 84H, 42CH ₂ ), 0.89 (t, 6H, J = 6.4 Hz, 2CH ₂ CH ₃ ).

Example 21

3-O- [methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonneupilar Nosyl onnate] -1,2-di-O-hexacosyl-Sn-glycerol:

<A>: 3-O-benzyl-1,2-di-O-hexacosyl-Sn-glycerol:

3-O-benzyl-Sn-glycerol [Agric. Bio Chem., 40, 391 (1976)] (242 mg) and 1-bromohexacoic acid [J. [Agric. Bio. Chem. 46, 255 (1982)] (1.30 g) to Example 15-A. The reaction was carried out by the general method described. The obtained compound was subjected to debenzylation without any purification immediately by the general method described in Example 15-B to give the title compound (615 mg, 57%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (m, 92H, 46CH ₂ ), 0.88 (t, 6H, 6Hz, 2CH ₂ CH ₃ ).

<B>: 3-O- [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto- 2-nonurophyllanosyl onnate] -1,2-di-O-hexacosyl-Sn-glycerol:

1,2-di-O-hexacosyl-Sn-glycerol (610 mg, 0.74 mmol) and methyl 5- acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3 , 5-tridioxy-D-glycero-β-D-galacto-2-nonurophyllanosonate [Chem. Ber., 99, 611 (1966)] (454 mg, 0.89 mmol) was prepared in Example 15 Reaction was carried out by the general method described in -C to give the title compound (76 mg, 8%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.79 (s, 3H, OCH ₃ ), 2.60 (dd, 1H, J = 4.8, 12.8 Hz, H-3eq), 2.14, 2.13, 2.04, 2.02, 1.88 (5s, 15H, 5Ac), 1.97 (t, 1H, J = 12.8 Hz, H-3ax), 1.25 (m, 92H, 46CH ₂ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 22

3-O- [5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid-2-yl] -1,2-di-O-hexa Kosyl-Sn-Glycerol:

3-O- [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurono Filanosyl) onate] -1,2-di-O-hexa-cosyl-Sn-glycerol (76 mg) was reacted in the general manner described in Example 16 to give the title compound (51 mg, 78%) as a white solid. Got it.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1, 60 ° C.) δ: 2.76 (dd, 1H, J = 4.4, 12.8 Hz, H-3eq), 2.02 (s, 3H, NAc), 1.75 ( t, 1H, J = 11.7 Hz, H-3ax), 1.42-1.14 (m, 92H, 46CH ₂ ), 0.89 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 23

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9 tetra-O- (sodiumoxy sulfonyl) -D-glycero-α-D-galacto-2 Nonurophyllanosyl onnate] -1,2-di-O-hexacosyl-Sn-glycerol:

3-O-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid) -2-yl] -1,2-di-O Hexacosyl-Sn-glycerol (47 mg) was reacted by the general method described in Example 1 to give the title compound (29 mg, 45%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 60 ° C.) δ: 2.96 (br.dd, 1H, H-3eq), 1.96 (s, 3H, NAc), 1.79 (br.t, 1H, H-3ax), 1.42-1.14 (m, 92H, 46CH ₂ ), 0.88 (br.t, 6H, J = 6.2 Hz, 2CH ₂ CH ₃ ).

Example 24

3β- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9 tetra-O- (sodiumoxy sulfonyl) -D-glycero-α-D-galacto-2-no Neurofilanosyl onnate] -5-cholester:

3β-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosonic acid) -2-yl] -5-cholester 61-243096] (387 mg) was reacted by the general method described in Example 1 to obtain the title compound (232 mg, 37%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1) δ: 2.92 (dd, 1H, J = 4.5, 11.5 Hz, H-3eq), 1.96 (s, 3H, NAc), 0.99 (s, _{3H, CH 3 -19chole), 0.68} (s, 3H, CH 3 -18chole).

Example 25

Sodium [oleyl 5-acetamido-3,5-dideoxy-4,7,8,9 tetra-O- (sodiumoxy sulfonyl) -D-glycero-α-D-galacto-2-ino Neurofilanoside] Onate:

<A>: Sodium (oleyl 5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanoside) onate:

Methyl (oleyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanoside ) Onate [JP-A 63-264493] (115 mg, 0.154 mmol) was dissolved in methanol (1.5 ml), 3N caustic soda (0.30 ml) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was dried under reduced pressure and the remaining sediment was purified by gel chromatography (Sephadex LH-20, 180 ml, methanol) to obtain the title compound (78 mg, 87%) as a white solid.

¹ H-NMR (CD ₃ OD) δ: 5.34 (m, 2H, CH = CH), 2.81 (dd, 1H, J = 4.0, 12.1 Hz, H-3aq), 2.00 (s, 3H, NAc), 1.59 (t, 1H, J = 11.7 Hz, H-3ax), 1.42-1.23 (m, 20H, 10CH ₂ , OPO (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ).

<B>: Sodium [oleyl 5-acetamido-3,5-dideoxy-4,7,8,9 tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto -2-Nonurophyllanoside] Onate:

Sodium (oleyl 5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanoside) onate (62 mg) was prepared in general as described in Example 1 Reaction was carried out to give the title compound (86 mg, 82%) as a white solid.

¹ H-NMR (CD ₃ OD,) δ: 3.03 (dd, 1H, J = 3.7, 12.3 Hz, H-3eq), 2.19 (m, 4H, CH ₂ CH = CHCH ₂ ), 1.92 (s, 3H, NAc), 1.73 (t, 1H, J = 12.1 Hz, H-3ax), 1.42-1.22 (m, 20H, 10CH ₂ ), 0.90 (t, 3H, J = 6.8 Hz, CH ₂ CH ₃ ).

Example 26

Sodium [octadecyl 5-acetamido-3,5-dideoxy-4,7,8,9 tetra-O- (sodiumoxy sulfonyl) -D-glycero-α-D-galacto-2-no Neurofilanoside] Onate:

<A>: Methyl (octadecyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-no Neurofilanoside) Onate:

Methyl (oleyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanoside ) Onate [JP-A 63-264493] (111 mg, 0.149 mmol) was dissolved in ethanol (1.5 ml), 10% palladium-carbon (16 mg) was added, and the mixture was stirred at room temperature in a hydrogen gas state for 18 hours. . The reaction solution was filtered through Celite to give the title compound (107 mg, 96%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.79 (s, 3H, COOCH ₃ ), 2.58 (dd, 1H, J = 4.8, 12.8 Hz, H-3eq), 2.15, 2.14, 2.04, 2.03, 1.88 (5s, 15H, 5Ac), 1.95 (t, 1H, J = 12.6 Hz, H-3ax), 1.38-1.19 (m, 30H, 15CH ₂ ), 0.88 (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ).

<B>: Sodium [octadecyl 5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanoside] Onate:

Methyl (octadiyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanoside ) Onate (107 mg) was reacted by the general method described in Example 25-A to give the title compound (70 mg, 83%) as a white solid.

¹ H-NMR (CD ₃ OD,) δ: 2.81 (dd, 1H, J = 3.8, 12.3 Hz, H-3eq), 2.00 (s, 3H, NAc), 1.59 (t, 1H, J = 11.9 Hz, H-3ax), 1.38-1.22 (m, 30H, 15CH ₂ ), 0.90 (t, 3H, J = 6.8 Hz, CH ₂ CH ₃ ).

<C>: Sodium [octadecyl 5-acetamido-3,5-dideoxy-4,7,8,9 tetra-O- (sodiumoxy sulfonyl) -D-glycero-α-D-galacto -2-Nonurophyllanoside] Onate:

Sodium (octadisil 5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanoside) onate (72 mg) was prepared in general as described in Example 1. Reaction was carried out to give the title compound (109 mg, 92%) as a white solid.

¹ H-NMR (CD ₃ OD,) δ: 3.02 (dd, 1H, J = 3.7, 11.4 Hz, H-3eq), 1.92 (s, 3H, NAc), 1.73 (t, 1H, J = 11.7 Hz, H-3ax), 140-1.31 (m, 30H, 15CH ₂ ), 0.90 (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ).

Example 27

Methyl [2,2-bis (docosyloxymethyl) propyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D- Galacto-Nurophyllanoside] Onate:

<A>: 2,2-bis (docosyloxymethyl) propanol:

1,1,1-tris (hydroxymethyl) ethane (1.0 g, 8.32 mmol) and sodium hydroxide (732 mg, 18.3 mmol) were stirred in dry dimethylformamide (30 ml) at room temperature for 15 minutes. Subsequently, the mixture was frozen in ice, and added dobromic acid bromide (7.1 g, 18.3 mmol) and benzene (10 ml), followed by stirring at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, suspended in chloroform and washed with 2N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the remaining sediment was purified by silica gel column chromatography (130 g, toluene / ethyl acetate, 19: 1) to obtain the title compound (2.32 mg, 38%) as a white powder. Got it.

¹ H-NMR (CDCl ₃ ) δ: 3.56 (d, 2H, J = 5.9 Hz, CH ₂ OH), 1.26 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ), 0.85 (s, 3H, CCH ₃ ).

<B> Methyl [2,2-bis (docosyloxymethyl) propyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α -D-galacto-2-nonurophyllanoside] Onate:

2,2-bis (docosyloxymethyl) propanol (1.20 g, 1.63 mmol) and methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3, 5-tridioxy-D-glycero-β-D-galacto-2-nonurophyllanosonate [Chem. Ber., 99, 611 (1966)] (913 mg, 1.79 mmol) was prepared in Example 15-. The reaction was carried out by the general method described in C, to obtain the title compound (786 mg, 40%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.78 (s, 3H, COOCH ₃ ), 2.57 (dd, 1H, J = 4.4, 12.8 Hz, H-3eq), 2.13, 2.12, 2.04, 2.02, 1.88 (5s, 15H, 5Ac), 1.95 (t, 1H, J = 12.5 Hz, H-3ax), 1.25 (m, 76H, 38CH ₂ ), 0.90 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 28

2,2-bis (docosyloxymethyl) propyl 5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosidonic acid:

Methyl [2,2-bis (docosyloxymethyl) propyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D- Galacto-2-nonurophyllanoside] onate (786 mg) was reacted by the general method described in Example 16 to give the title compound (599 mg, 90%) as a white solid.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1, 60 ° C.) δ: 2.79 (dd, 1H, J = 4.8, 12.8 Hz, H-3eq), 2.02 (s, 3H, NAc), 1.75 ( t, 1H, J = 11.9 Hz, H-3ax), 1.36-1.22 (m, 76H, 38CH ₂ ), 0.92 (s, 3H, CCH ₃ ), 0.89 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 29

Sodium [2,2-bis (docosyloxymethyl) propyl 5-acetamido-3,5- didideoxy-4,7,8,9 tetra-O- (sodium oxalfonyl) -D-glycero- α-D-galacto-2-nonurophyllanoside] onate:

Example of 2,2-bis (docosyloxymethyl) propyl 5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosidonic acid (94 mg) Reaction was carried out by the general method described in 1, to obtain the title compound (63 mg, 47%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 60 ° C.) δ: 2.93 (br.dd, 1H, H-3eq), 1.96 (s, 3H, NAc), 1.80 (br.t, 1H, H-3ax), 1.43-1.16 (m, 76H, 38CH ₂ ), 0.92 (s, 3H, CCH ₃ ), 0.89 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

Example 30

Methyl [2,2-bis (eicosyloxymethyl) propyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D- Galacto-2-nonurophyllanoside] Onate:

<A>: 2,2-bis (eicosyloxymethyl) propanol:

1,1,1-tris (hydroxymethyl) ethane (0.50 g, 4.16 mmol) and bromic acid (3.30 g, 9.15 mmol) were reacted in the usual manner as described in Example 27-A to give the title compound (1.43 g, 51%) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.57 (d, 2H, J = 5.9 Hz, CH ₂ OH), 1.26 (m, 68H, 34CH ₂ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ), 0.85 (s, 3H, CCH ₃ ).

<B>: Methyl [2,2-bis (eicosyloxymethyl) propyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero- α-D-galacto-2-nonurophyllanoside] Onate:

2,2-bis (eicosyloxymethyl) propanol (267 mg, 0..392 mmol) with methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2 , 3,5-tridioxy-D-glycero-β-D-galacto-2-nonurophyllanosonate [Chem. Ber., 99, 611 (1966)] (200 mg, 0.392 mmol) Reaction was carried out by the general method described in Example 15-C to give the title compound (175 mg, 39%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.78 (s, 3H, COOCH ₃ ), 2.58 (dd, 1H, J = 4.8, 12.8 Hz, H-3eq), 2.13, 2.13, 2.04, 2.02, 1.89 (5s, 15H, 5Ac), 1.95 (dd, 1H, J = 12.5, 12.8 Hz, H-3ax), 1.25 (m, 68H, 34CH ₂ ), 0.90 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 31

2,2-bis (eicosyloxymethyl) propyl 5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosidonic acid:

Methyl [2,2-bis (eicosyloxymethyl) propyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D- Galacto-2-nonurophyllanoside] onate (174 mg) was reacted by the general method described in Example 16 to give the title compound (127 mg, 87%) as a white solid.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1) δ: 2.75 (dd, 1H, J = 4.6, 12.6 Hz, H-3eq), 2.03 (s, 3H, NAc), 1.75 (t, 1H , J = 11.7 Hz, H-3ax), 1.43-1.19 (m, 68H, 34CH ₂ ), 0.92 (s, 3H, CCH ₃ ), 0.89 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 32

Sodium [2,2-bis (eicosyloxymethyl) propyl 5-acetamido-3,5-dideoxy-4,7,8,9 tetra-O- (sodium oxalfonyl) -D-glycero- α-D-galacto-2-nonurophyllanoside] onate:

2,2-bis (eicosyloxymethyl) propyl 5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosidone (103 mg) Reaction was carried out by the general method described in Example 1, to obtain the title compound (96 mg, 64%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 60 ° C.) δ: 2.96 (br.dd, 1H, H-3eq), 1.98 (s, 3H, NAc), 1.78 (t, 1H, J = 12.6 Hz, H-3ax), 1.37-1.17 (m, 68H, 34CH ₂ ), 0.94 (s, 3H, CCH ₃ ), 0.90 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 33

Methyl (3,5-didocosyloxysulfonyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto- Nonneufilanoside) onate:

<A>: 3,5-didocosyloxypropanol:

Florogelcinol (2.0 g, 15.9 mmol) and sodium hydroxide (1.59 g, 39.7 mmol) were stirred in dry dimethylformamide (30 ml) for 15 minutes at room temperature, followed by dodecyl bromide (13.0 mg, 33.3 mmol). ) And benzene (30 ml) were added, and the mixture was stirred at 40 ° C for 2 days. The reaction solution was diluted with chloroform and washed with 2N hydrochloric acid, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the remaining sediment was purified by silica gel column chromatography (90 g, hexane / ethyl acetate, 6: 1) to obtain the title compound (2.40 mg, 20%) as a pale yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 6.06 (d, 1H, J = 2.2 Hz, H-4phenyl), 5.99 (2d, 2H, J = 2.2 Hz, H-2.6phenyl), 3.89 (t, 4H, J = 6.8 Hz, 20CH ₂ ), 1.39-1.17 (m, 72H, 36CH ₂ ), 0.88 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

<B>: Methyl (3,5-didocosyloxyphenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D- Galacto-2-nonurophyllanoside) onate:

3,5-Didocosyloxypropenol (1.20 g, 1.61 mmol) and sodium hydroxide (77.5 g, 1.94 mmol) were stirred in dimethylformamide: benzene (1: 40 ml) at room temperature for 20 minutes. Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5 tridioxy-D-glycero-β-D-galacto-2- Nonneufilanosonate [Chem. Ber., 99, 611 (1966)]) (823 mg, 1.61 mmol) was added and stirred at room temperature for 3 hours. The reaction solution was diluted with chloroform and washed with 2N hydrochloric acid, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the remaining sediment was purified by silica gel column chromatography (90 g, toluene / ethyl acetate, 2: 3) to obtain the title compound (386 mg, 20%) as a pale yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 6.28 (2d, 2H, J = 1.8 Hz, H-2, 6phenyl), 6.22 (d, 1H, J = 1.8 Hz, H-4phenyl), 6.22 (d, 1H, J = 1.8 Hz, H = 4 phenyl), 3.78 (s, 3H, COOCH ₃ ), 2.58 (dd, 1H, J = 4.8, 12.8 Hz, H-3eq.), 2.14, 2.10, 2.03, 2.01, 1.90 (5s, 15H, 5Ac), 1.26 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

Example 34

3,5-Didocosyloxyphenyl 5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosidonic acid:

Methyl (3,5-didocosyloxyphenyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2 Nonurophyllanoside) onate (385 mg) was reacted by the general method described in Example 16 to give the title compound (163 mg, 50%) as a pale yellow powder.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1, 60 ° C.) δ: 6.42 (2d, 2H, J = 2.2 Hz, H-2, 6phenyl), 6.20 (d, 1H, J = 2.2 Hz , H-4phenyl), 2.86 (dd, 1H, J = 4.2, 12.6 Hz, H-3eq.), 2.02 (s, 3H, NAc), 1.95 (t, 1H, J = 11.9 Hz, H = 3ax) , 1.40-1.23 (m, 72H, 36CH ₂ ), 0.89 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 35

Sodium [3,5-Didocosyloxyphenyl 5-acetamido-3,5- didideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-β-D Galacto-nonurophyllanoside) onates:

3,5-Didocosyloxyphenyl 5-acetamido-3,5- didideoxy-D-glycero-α-D-galacto-2-nonurophyllanosidonic acid (16 mg) was described in Example 1 Reaction was carried out in the usual manner to give the title compound (11 mg, 47%) as a white solid.

¹ H-NMR (CDCl ₃ -D ₂ O, 1: 1, 50 ° C.) δ: 6.42 (br.s, 2H, H-2, 6phenyl), 6.17 (br.s, 1H, H-4phenyl) , 2.93 (br.dd, 1H, H-3eq.), 2.00 (s, 3H, NAc), 1.38-1.18 (m, 72H, 36CH ₂ ), 0.90 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 36

3-O- [methyl 5-acetamido-4,7,8,9-tetra-O- (acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonneuro Filanosyl onate] -1,2-di-O-docosanoyl-Sn-glycerol:

<A>: 3-O-benzyl-1,2-di-O-docosanoyl-Sn-glycerol:

3-O-benzyl-Sn-glycerol [Agric. Bio Chem., 40, 391 (1976)] (0.67 g, 3.68 mmol), Behenic acid (3.76 g, 11.04 mmol), dicyclohexylcarbodiimide (2.28 g, 11.04 mmol) and 4dimethylamino Pyridine (0.13 g, 1.06 mmol) was stirred in pyridine (37 mL) at room temperature for 22 hours. The reaction solution was filtered and the filtrate was dried under reduced pressure. The remaining sediment was purified by silica gel column chromatography (90 g, hexane / ethyl acetate, 9: 1) to give the title compound (1.55 g, 51%) as a pale yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 7.30 (m, 5H, C ₆ H ₅ ), 5.24 (m, 1H, H-2), 4.56 (d, 1H, J = 12.1 Hz, C ₆ H ₅ ), 4.52 (d, 1H, J = 12.1 Hz, C ₆ H ₅ CH), 1.25 (m, 72H, 36CH ₂ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

<B>: 1,2-di-O-docosanoyl-Sn-glycerol:

3-O-benzyl-1,2-di-O-docosanoyl-Sn-glycerol (1.25 g) was reacted in the general manner described in Example 15-B to give the title compound (0.98 g, 88%) as white Obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 5.08 (m, 1H, H-2), 4.32 (dd, 1H, J = 4.6, 11.9 Hz, H-3), 4.24 (dd.1H, J = 5.7, 11.9 Hz, H-3 '), 3.73 (m, 2H, CH ₂ -1), 1.25 (m, 72H, 36CH ₂ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

<C>: 3-O- [methyl 5-acetamido-4,7,8,9-tetra-O-levinoyl-3,5-dideoxy-D-glycero-α-D-galacto -2-nonurophyllanosyl) onate] -1,2-di-O-docosanoyl-Sn-glycerol:

Methyl 5-acetamido-3,5- dideoxy-D-glycero-D-galacto-2-nonurophyllanosonate [Chem. Ber., 99, 611 (1966)] (3.23 g, 10.0 mmol), 4-dimethylaminopyridine (0.61 g, 0.50 mmol), levrinic acid (12.3 ml, 120 mmol) and dicyclohexyl carbodiimide (24.76 g , 120 mmol) was stirred in pyridine (30 ml) at room temperature for 2 days. The reaction solution was filtered through Celite, and the filtrate was dried under reduced pressure. The remaining sediment was purified by silica gel column chromatography (170 g, chloroform / methanol, 24: 1) to give the title pentarebrinoyl product (4.62 g, 65%). Next, pentarebrinoyl (2.50 g, 3.07 mmol) was dissolved in acetyl chloride (30 ml), saturated with hydrochloric acid gas at 0 ° C, and left at 2 ° C for 5 days. The reaction solution was evaporated to dryness under reduced pressure to obtain the title chlorce (2.15 g, 95%). The chlorce (1.22 g, 1.66 mmol) and 1,2-di-O-docosanoyl-Sn-glycerol (0.89 g, 1.21 mmol) are then reacted in the usual manner as described in Example 15-C to give the title compound. (64 g, 4%) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 5.06 (dt, 1H, J = 4.6, 11.7 Hz, H-4), 3.81 (s, 3H, COOCH ₃ ), 2.19 (6H), 2.18, 2.17 (3s, 12H , 3CH ₃ CO), 1.89 (s, 3H, NAc), 1.85 (t, 1H, J = 12.5Hz, H-3ax), 1.25 (m, 72H, 36CH ₂ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 37

3-O-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosonic acid] -2-yl] -1,2-di -O-docosanoyl -Sn-glycerol:

3-O- [methyl (5-acetamido-4,7,8,9-tetra-O-levinoyl-3,5-dideoxy-D-glycero-α-D-galacto-2- Nonurophyllanosyl) onnate] -1,2-di-O-docosanoyl-Sn-glycerol (52 mg, 0.036 mmol) and lithium anhydride (49 mg, 0366 mmol) in anhydrous pyridine (1.8 ml) Stir at 80 ° C. for 6 hours. The reaction solution was directly purified by gel chromatography (Sepadics LH-20, 100 ml, chloroform / methanol, 1: 1) to obtain the title lithium salt (34.6 mg, 67%) as a white solid.

Then, lithium salt (34.6 mg) and 0.0242 mmol were dissolved in methanol (0.5 ml) and chloroform (0.5 ml), hydrazine acetate (48 mg, 0.524 mmol) was added, and it stirred at room temperature for 10 minutes. The reaction solution was brought to pH 4 in 0.1N hydrochloric acid, and then purified by gel column chromatography (Sepadic LH-20, 75 ml, chloroform / methanol 1: 1) to obtain the title compound (23 mg, 92%). Obtained as a white solid.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1, 40 ° C.) δ: 2.76 (dd, 1H, J = 4.2, 12.6 Hz, H-3eq), 2.03 (s, 3H, NAc), 1.74 ( t, 1H, J = 11.9 Hz, H-3ax), 1.28 (m, 72H, 36CH ₂ ), 0.89 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 38

3-O- [sodium 5-acetamido-3,5-dideoxy-4,7,8,9 tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto-2 Nonurophyllanosyl onnate] -1,2-di-O-docosanoyl-Sn-glycerol:

3-O-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid) -2-yl] -1,2-di-O Docosanoyl-Sn-glycerol (12 mg) was reacted in the general manner described in Example 1 to give the title compound (9 mg, 53%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 50 ° C.) δ: 2.94 (br.dd, 1H, H-3eq), 1.95 (s, 3H, NAc), 1.71 (t, 1H, J = 11.0 Hz, H-3ax), 1.26 (m, 72H, 36CH ₂ ), 0.87 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 39

3-O- [methyl (-4,5,7,8,9-penta-O-acetyl-3-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosyl onnate] -1,2-di-O-docosyl-Sn-glycerol:

1,2-di-O-docosyl-Sn-glycerol [JP-A1-125394] (467 mg) and methyl 4,5,7,8,9-penta-O-acetyl-2-chloro-2,3 -Dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosonate [Chem. Pharm. Bull., 39, 3140 (1991)] (281 mg) described in Example 15-C Reaction was carried out in the usual manner to give the title compound (313 mg, 48%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.80 (s, 3H, OCH ₃ ), 2.68 (dd, 1H, J = 4.0, 12.8 Hz, H-3eq), 2.15, 2.09, 2.04, 2.00, 2.00 (5s, 15H, 5Ac), 1.25 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

Example 40

3-O-[(3-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosonic acid) -2-yl] -1,2-di-O-docosyl-Sn- Glycerol:

3-O- [methyl (4,5,7,8,9-penta-O-acetyl-3- didideoxy-D-glycero-α-D-galacto-2-nonurophyllanosyl) onate] -1,2-di-O-docosyl-Sn-glycerol (313 mg) was reacted by the general method described in Example 16 to obtain the title compound (186 mg, 75%) as a white solid.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1, 60 ° C.) δ: 2.68 (dd, 1H, J = 4.6, 12.6 Hz, H-3eq), 1.73 (t, 1H, J = 12.1 Hz, H-3ax), 1.29 (m, 76H, 38CH ₂ ), 0.89 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 41

3-O- [sodium 3-dideoxy-4,5,7,8,9-penta-O- (sodium oxofonyl) -D-glycero-α-D-galacto-2-nonurophyllanosyl Onate] -1,2-di-O-docosyl-Sn-glycerol:

3-O-[(3-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosonic acid) -2-yl] -1,2-di-O-docosyl-Sn- Glycerol (97 mg) was reacted by the general method described in Example 1 to give the title compound (15 mg, 10%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 50 ° C.) δ: 2.89 (br.dd, 1H, H-3eq), 1.81 (br.t, 1H, H-3ax), 1.26 ( m, 76H, 38CH ₂ ), 0.86 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 42

1-O- [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonuro Filanosyl) onate] -L-2,3-di-O-docosyl-Sn-glycerol:

<A>: L-1-O-Benzyl-2,3-di-O-isopropylidene-Sn-glycerol:

L-2,3-di-O-isopropylidene-Sn-glycerol (5.00 mg, 37.8 mmol) and 60% sodium hydroxide (3.03 g, 75.8 mmol) in dry dimethylformamide (110 ml) at room temperature After stirring for 10 minutes, benzyl bromide (6.7 ml, 56.7 mmol) was added, followed by stirring at room temperature for 3 hours. The reaction solution was diluted with ether, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was distilled under reduced pressure (110 ° C./3 torr) to obtain a benzylated product (6.65 g, 80%). Subsequently, this (6.65 g, 29.9 mmol) was dissolved in methylene chloride (30 ml), methanol (9 ml) and water (3 ml), trifluoroacetic acid (3 ml) was added, and 3 hours at room temperature. Was stirred. The reaction solution was neutralized with caustic soda, concentrated under reduced pressure, and the residue was purified by distillation under reduced pressure to obtain the title compound (4.71 mg, 86%).

¹ H-NMR (CDCl ₃ ) δ: 7.32 (m, 5H, C ₆ H ₅ ), 4.56 (s, 2H, CHO ₂ Ph).

<B>: L-1-O-Benzyl-2,3-di-O-docosyl-Sn-glycerol:

L-1-O-benzyl-Snglycerol (1.90 g) and 1-bromodocoic acid (9.70 g) were reacted in the general manner described in Example 15-A to give the title compound (7.0 g, 85%) as white. Obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 7.30 (m, 5H, C ₆ H ₅ ), 4.55 (s, 2H, CH ₂ Ph), 1.25 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

<C>: L-2,3-di-O-docosyl-Sn-glycerol:

L-1-O-benzyl-2,3-di-O-docosyl-Sn-glycerol (1.40 g) was reacted in the general manner described in Example 15-B to give the title compound (0.99 g, 79%) Was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

<D>: 3-O- [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto- Nonurophyllanosyl) onate] -L-2,3-di-O-docosyl-Sn-glycerol:

L-2,3-di-O-docosyl-Sn-glycerol (990 mg) and methyl-5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3 , 5-tridioxy-D-glycero-β-D-galacto-2-nonurophyllanosonate [Chem. Ber., 99 611 (1966)] (850 mg) was described in Example 15-C. Reaction was carried out in the usual manner to give the title compound (662 mg, 40%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.79 (s, 3H, OCH ₃ ), 2.60 (dd, 1H, J = 4.8, 12.8 Hz, H-3eq), 2.15, 2.09, 2.04, 2.00, 2.00 (5s, 15H, 5Ac), 1.96 (t, 1H, J = 12.8 Hz, H-3ax.), 1.25 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

Example 43

1-O-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid) -2-yl] -L-2,3-di -O-docosyl-Sn-glycerol:

1-O- [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurono Filanosyl] -L-2,3-di-O-docosyl-Sn-glycerol (632 mg) was reacted by the general method described in Example 16 to give the title compound (500 mg, 92%) as a white solid. Got it.

¹ H-NMR (CDCl ₃ -CD ₃ , 1: 1, 40 ° C.) δ: 2.77 (dd, 1H, J = 4.6, 13.4 Hz, H-3eq), 2.02 (s, 3H, NAc), 1.74 (t , 1H, J = 11.9 Hz, H-3ax), 1.28 (m, 76H, 38CH ₂ ), 0.89 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 44

1-O- [Sodium 5-acetamido-3,5- didideoxy-4,7,8,9-tetra-O- (sodium oxofonyl) -D-glycero-α-D-galacto- Nonurophyllanosyl) onate] -L-2,3-di-O-docosyl-Sn-glycerol:

1-O-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid) -2-yl] -L-2,3-di -O-Docosyl-Sn-glycerol (200 mg) was reacted by the general method described in Example 1 to give the title compound (237 mg, 83%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 40 ° C.) δ: 2.93 (br.dd, 1H, H-3eq), 1.96 (s, 3H, NAc), 1.77 (br.t, 1H, H-3ax), 1.28 (m, 76H, 38CH ₂ ), 0.87 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

Example 45

Methyl [2,2-bis (oleyloxymethyl) propyl5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D- Galacto-nonurophyllanoside] onate:

<A>: 2,2-bis (oleyloxymethyl) propanol:

1,1,1-tris (hydroxymethyl) ethane (1.0 g) and oleyl chloride (5.25 g) were reacted in the general manner described in Example 15-A to give the title compound (2.91 g, 5%). Was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 5.36 (m, 4H, 2CH = CH), 3.56 (d, 2H, J = 5.9 Hz, CH ₂ OH), 1.27 (m, 40H, 20CH ₂ ), 0.88 (t , 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ), 0.85 (s, 3H, CCH ₃ ).

<B>: Methyl [2,2-bis (oleyloxymethyl) propyl5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero- α-D-galacto-2-nonurophyllanoside] onate:

2,2-bis (oleyloxymethyl) propanol (400 mg) and methyl-5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-tri Deoxy-D-glycero-β-D-galacto-2-nonurophyllanosonate [Chem. Ber., 99 611 (1966)] (328 mg) was reacted by the general method described in Example 15-C. The title compound (564 mg, 80%) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 5.35 (m, 4H, 2CH = CH), 3.78 (s, 3H, COOCH ₃ ), 2.58 (dd, 1H, J = 5.0, 12.8Hz, H-3eq), 2.13 , 2.12, 2.04, 2.02, 1.88 (5s, 15H, 5Ac), 1.27 (m, 40H, 20CH ₂ ), 0.90 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 6.9 Hz, 2CH ₂ CH ₃ ).

Example 46

2,2-bis (Oleyloxymethyl) propyl5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosidonic acid:

Methyl [2,2-bis (oleyloxymethyl) propyl5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D- Galacto-2-nonurophyllanoside] onate (250 mg) was reacted by the general method described in Example 16 to give the title compound (190 mg, 89%) as a white solid.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1) δ: 5.35 (m, 4H, 2CH = CH), 2.76 (dd, 1H, J = 4.2, 13.4 Hz, H-3aq), 2.05 (s , 3H, NAc), 1.70 (t, 1H, J = 11.9 Hz, H-3ax), 1.30 (m, 40H, 20CH ₂ ), 0.92 (s, 3H, CCH ₃ ), 0.89 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 47

Sodium [2,2-bis (Oleyloxymethyl) propyl5-acetamido-3,5-dideoxy-4,7,8,9 -tetra-O- (sodium oxalfonyl) -D-glycero -α-D-galacto-2-nonurophyllanoside) onate:

2,2-bis (oyloxymethyl) propyl5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosidonic acid (913 mg) was carried out. The reaction was carried out by the general method described in Example 1, to obtain the title compound (63 mg, 47%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 50 ° C.) δ: 5.37 (m, 4H, 2CH = CH), 2.95 (dd, 1H, J = 5.3, 12.6 Hz, H-3eq) , 1.97 (s, 3H, NAc), 1.74 (t, 1H, J = 12.8 Hz, H-3ax), 1.28 (m, 40H, 20CH ₂ ), 0.94 (s, 3H, CCH ₃ ), 0.89 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ).

Example 48

Methyl [2,2-bis (docosyloxymethyl) propyl5-acetamido-4,7,8,9 tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-gal Lacto-2-nonurophyllanoside) onate:

<A> 2,2-bis (docosyloxymethyl) butanol:

1,1,1-tris (hydroxymethyl) propane (1.0 g) and 1-bromodocoic acid (7.3 g) were reacted in the general manner described in Example 15-A to give the title compound (3.12 g, 56 %) Was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.59 (d, 2H, J = 5.9 Hz, CH ₂ OH), 1.25 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 6.7 Hz, 2CH ₂ CH ₃ ), 0.84 (t, 3H, J = 7.5 Hz, CCH ₂ CH ₃ ).

<B> Methyl [2,2-bis (docosyloxymethyl) butyl5-acetamido-4,7,8,9 tetra-O-acetyl-3,5-dideoxy-D-glycero-α- D-galacto-2-nonurophyllanoside) onate:

2,2-bis (docosyloxymethyl) butanol (2.26g) and methyl5-acetamido-4,7,8,9-tetra-O-acetyl-2-chloro-2,3,5-tridi Oxy-D-glycero-β-D-galacto-2-nonurophyllanosonate [Chem. Ber., 99, 611 (1966)] (1.02 mg) was reacted by the general method described in Example 15-C The title compound (539 mg, 22%) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.78 (s, 3H, COOCH ₃ ), 2.58 (dd, 1H, J = 4.8, 12.8 Hz, H-3eq), 2.13, 2.12, 2.04, 2.02, 1.88 (5s, 15H, 5Ac), 1.95 (t, 1H, J = 12.5 Hz, H-3ax), 1.25 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ), 0.84 ( t, 3H, J = 7.5 Hz, CCH ₂ CH ₃ ).

Example 49

2,2-bis (docosyloxymethyl) butyl5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosidonic acid:

Methyl [2,2-bis (docosyloxymethyl) butyl5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D- Galacto-2-nonurophyllanoside] onate (520 mg) was reacted by the general method described in Example 16 to give the title compound (393 mg, 90%) as a white solid.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1, 60 ° C) δ: 2.72 (dd, 1H, J = 5.1, 12.1 Hz, H-3eq), 2.02 (s, 3H, NAc), 1.80 ( t, 1H, J = 11.9 Hz, H-3ax), 1.28 (m, 76H, 38CH ₂ ), 0.89 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ), 0.86 (t, 3H, J = 7.7 Hz, CCH ₂ CH ₃ ).

Example 50

Sodium [2,2-bis (docosyloxymethyl) butyl5-acetamido-3,5-dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero -α-D-galacto-2-nonurophyllanoside) onate:

2,2-bis (docosyloxymethyl) butyl5-acetamido-3,5- didideoxy-D-glycero-α-D-galacto-2-nonurophyllanosidonic acid (388 mg) was carried out. Reaction was carried out by the general method described in Example 1 to obtain the title compound (332 mg, 61%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 60 ° C.) δ: 2.95 (br.dd, 1H, H-3eq), 1.96 (s, 3H, NAc), 1.78 (br.t, 1H, H-3ax), 1.27 (m, 76H, 38CH ₂ ), 0.87 (t, 9H, J = 7.0 Hz, 3CH ₂ CH ₃ ).

Example 51

3-O- [methyl (5-N- (O-acetylglycolyl) -4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-gal Lacto-2-nonurophyllanosyl) onate] -1,2-di-O-docosyl-Sn-glycerol:

[1,2-di-O-docosyl-Sn-glycerol (400 mg) and methyl-5-N- (O-acetylglycolyl) -4,7,8,9-tetra-O-acetyl-2- Chloro-2,3,5-tridioxy-D-glycero-β-D-galacto-2-nonurophyllanosonate [Carbohydr. Res., 174, 73 (1988)] (300 mg) Reaction was carried out by the general method described in Example 15-C to give the title compound (66 mg, 10%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.60, 4.29 (2d, 2H, J = 5.0 Hz, NHCOOH ₂ ), 3.81 (s, 3H, 0CH ₃ ), 2.62 (dd, 1H, J = 4.8, 12.8 Hz, H-3eq), 2.20, 2.15, 2.13, 2.04, 2.01 (5s, 15H, 50Ac), 1.25 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 52

3-O-[(5-N-glycolyl-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid) -2 yl] -1,2-di-O Docosyl-Sn-glycerol:

3-O- [methyl 5-N- (O-acetylglycolyl) -4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto -2-Nonurophyllanosionate] -1,2-di-O-docosyl-Sn-glycerol (60 mg) was reacted by the general method described in Example 16 to give the title compound (43 mg, 88% ) Was obtained as a white solid.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1, 60 ° C.) δ: 2.78 (dd, 1H, J = 4.0, 12.0 Hz, H-3eq), 1.79 (t, 1H, J = 12.0 Hz, H-3ax), 1.28 (m, 76H, 38CH ₂ ), 0.89 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 53

3-O- [sodium (5-N- (O-sodium oxulfonyl) -3,5-dideoxy-4,7,8,9-tetra-O- sodium oxulfonyl) -D-glycero- α-D-galacto-2-nonurophyllanosyl onate] -1,2-di-O-docosyl-Sn-glycerol:

3-O- [5-N-glycolyl-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid-2-yl] -1,2-di-O- Docosyl-Sn-glycerol (41 mg) was reacted by the general method described in Example 1 to give the title compound (16 mg, 26%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 60 ° C.) δ: 2.99 (br.dd, 1H, H-3eq), 1.92 (br.t, 1H, H-3ax), 1.30 ( m, 76H, 38CH ₂ ), 0.90 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 54

3-S- [methyl (5-acetamido-4,7,8,9-tetra-O- (acetyl-3,5-dioxy-D-glycero-α-D-galacto-2-no Neurophyllanosyl onnate] -1,2-di-O-docosyl-Sn-thioglycerol:

<A>: 3-bromo-3-dioxy-1,2-di-O-docosyl-Sn-glycerol:

1,2-di-O-docosyl-Sn-glycerol (200 mg, 0.28 mmol), N-bromosuccinimiole (90 mg, 0.51 mmol) and triphenylphosphine (170 mg, 0.65 mmol) was stirred in toluene (12 ml) at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and the remaining sediment was purified by silica gel column chromatography (20 g, hexane / toluene, 3: 2) to obtain the title compound (168 mg, 77%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

<B>: 3-S- [methyl (5-acetamido-4,7,8,9-tetra-O- (acetyl-3,5-dideoxy-D-glycero-α-D-galacto -2- nonneuphylanosyl) onnate] -1,2-di-O-docosyl-Sn-thioglycerol:

Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-S-acetyl-3,5-dideoxy-2-thio-D-glycero-α-D-galacto- 2- nonneuphylanosonate [J. Carbohydr. Chem., 5,11 (1986)] (114 mg, 0.21 mmol) and sodium methoxide (11 mg, 0.20 mmol) in dry methanol (0.5 ml)- After stirring for 1 hour at 10 ℃, the reaction solution was dried under reduced pressure at 0 ℃. In the remaining sediment dry dimethylformamide (1.0 ml) and toluene (1.0) of 3-bromo-3-dioxy-1,2-di-O-docosyl-Sn-glycerol (160 mg, 0.21 mmol). ml) solution was added and stirred for 2 days at room temperature. The reaction solution was diluted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, the remaining sediment was purified by silica gel column chromatography (27 g, toluene-acetone, 5: 1) to obtain the title compound (85 mg, 34%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 3.79 (s, 3H, COOCH ₃ ), 2.91 (dd, 1H, J = 4.8, 13.0 Hz, H-3eq), 2.72 (m, 2H, SCH ₂ ), 2.15, 2.13, 2.04, 2.03, 1.88 (5s, 15H, 5Ac), 2.00 (t, 1H, J = 12.8 Hz, H-3ax.), 1.25 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 7.1 Hz, 2CH ₂ CH ₃ ).

Example 55

3-S-[(5-acetamido-3,5-dideoxy-D-glycero-α-D-galacto-nonurophyllanosonic acid) -2-yl] -1,2-di-O Docosyl-Sn-thioglycerol:

3-S [methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5- dideoxy-D-glycero-α-D-galacto-2-nonneupilar Nosyl) onate] -1,2-di-O-docosyl-Sn-thioglycerol (154 mg) was reacted by the general method described in Example 16 to give the title compound (115 mg, 86%) as a white solid. Got it.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1, 60 ° C.) δ: 2.94 (dd, 1H, J = 4.6, 12.8 Hz, H-3eq), 2.84 (m, 2H, SCH ₂ ), 2.02 (s, 3H, NAc), 1.84 (t, 1H, J = 11.6 Hz, H-3ax), 1.29 (m, 76H, 38CH ₂ ), 0.89 (t, 6H, J = 6.9 Hz, 2CH ₂ CH ₃ ) .

Example 56

3-S- [sodium 5-acetamido-3,5- dideoxy-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-α-D-galacto- 2- nonneuphylanosyl onnate] -1,2-di-O-docosyl-Sn-thioglycerol:

3-S [(5-acetamido-3,5- dideoxy-D-glycero-α-D-galacto-2-nonurophyllanosonic acid) -2-yl] -1,2-di- O-docosyl-Sn-thioglycerol (422 mg) was reacted in the general manner described in Example 1 to give the title compound (29 mg, 45%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ 1: 1, 50 ° C.) δ: 3.06 (br.dd, 1H, H-3eq), 2.90 (m, 2H, SCH ₂ ), 1.90 (s, 3H, NAc ), 1.30 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 57

1- [N- (5-acetamido-4,7,8,9-tetra-O- (acetyl-3,5-dideoxy-2-O-methyl-D-glycero-β-D-gal Lacto-2-nonurophyllanosonyl) amino] -2,2-bis (docosyloxymethyl) propane:

<A>: 2,2-bis (docosyloxymethyl) propyl methanesulfonate:

A mixture of 2,2-bis (docosyloxymethyl) propanol (7.37 g, 10 mmol) methanesulfonyl chloride (1.3 ml; 16.8 mmol) and pyridine (150 ml) was stirred at 70 ° C. for 1 hour and then reaction The solution was added to water. The precipitate was filtered, washed with water and acetone, and dried to afford the title compound (6.66 g; 82%).

¹ H-NMR (CDCl ₃ ) δ: 4.13 (s, 2H, CH ₂ OMs), 2.98 (s, 3H, CH ₃ SO ₂ ), 1.26 (m, 76H, 38CH ₂ ), 1.00 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

<B>: 1-azide-2,2-bis (docosyloxymethyl) propane:

A mixture of 2,2-bis (docosyloxymethyl) propyl methanesulfonate (22.7 g; 27.8 mmol) sodium azide (0.27 g; 83.5 mmol) and dimethylformamide (150 ml) was heated at 110 ° C. for 20 hours. After stirring, the reaction solution was added to water. The precipitate was filtered, washed with water and acetone, and dried to afford the title compound (20.8 g; 98%).

¹ H-NMR (CDCl ₃ ) δ: 1.25 (m, 76H, 38CH ₂ ), 0.89 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

<C>: 1-amino-2,2-bis (docosyloxymethyl) propane:

A mixture of 1-azide-2,2-bis (docosyloxymethyl) propane (12.8 g; 16.8 mmol) palladium hydroxide-carbon (6.0) and tetrahydrofuran (100 ml) was heated to 50 ° C. under a hydrogen gas atmosphere. Stirred for 3 h. The reaction solution was filtered through Celite, and the filtrate was dried under reduced pressure. The remaining sediment was purified by silica gel column chromatography (60 g, chloroform / methanol, 10: 1) to give the title compound (8 g, 65%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 2.65 (s, 2H, CH ₂ ), 1.25 (m, 76H, 38CH ₂ ), 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ), 0.87 (s , 3H, CCH ₃ ).

<D>: Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosi Donsan:

Methyl5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosidonic acid [Chem. Ber., 99, 611 (1966)] (150 g; 0.464 mmol), a mixture of acetic anhydride (2.3 ml), pyridine (2.3 ml) was stirred at room temperature for 7 hours, and then the reaction solution was dried under reduced pressure. It was dissolved in the remaining chloroform and treated with Anber-List-15 (H) to obtain the title compound (218 g, 96%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 3.33 (s, 3H, 0CH ₃ ), 2.56 (dd, 1H, J = 4.8, 13.2 Hz, H-3eq), 2.16, 2.11, 2.06, 2.04, 1.91 (5s, 15H, 5Ac).

<E>: 1- [N- (5-acetamido-4,7,8,9-tetra-O- (acetyl-3,5-dideoxy-2-O-methyl-D-glycero-β -D-galacto-2-nonurophyllanosonyl) amino] -2,2-bis (docosyloxymethyl) propane:

Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosidonic acid (260 mg 0.53 mmol), 1-amino-2,2-bis (docosyloxymethyl) propane (390 mg; 0.53 mg), dicyclohexylcarbodiimide (165 mg; 0.80 mmol), 1-hydroxybenzotriazole After stirring a mixture of (95 mg; 0.70 mmol) and chloroform (11 ml) for 17 hours at room temperature, the reaction solution was filtered through Celite and the solvent was distilled off under reduced pressure. Purification by the remaining silica gel column chromatography (60 g, chloroform-acetone, 17: 3) gave the title compound (620 mg, 97%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 3.18 (s, 3H, 0CH ₃ ), 2.51 (dd, 1H, J = 4.8, 13.2 Hz, H-3eq), 2.14, 2.08, 2.03, 2.01, 1.90 (5s, 15H, 5Ac), 1.77 (t, 1H, J = 11.7 Hz, H-3ax), 1.25 (m, 76H, 38CH ₂ ), 0.91 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 6.6 Hz, 2CH ₂ CH ₃ ).

Example 58

1- [N- (5-acetamido-3,5-dideoxy-2-O-methyl-D-glycero-β-D-galacto-2-nonurophyllanosonyl) amino] -2, 2-bis (docosyloxymethyl) propane:

1- [N- (5-acetamido-4,7,8,9-tetra-O- (acetyl-3,5-dideoxy-2-O-methyl-D-glycero-β-D-gal Lacto-2-nonurophyllanosonyl) amino] -2,2-bis (docosyloxymethyl) propane (620 mg; 0.51 mmol) sodium methoxide (28 mg; 0.52 mmol), methanol (5 ml), tetra The mixture of hydrofuran (5 ml) was stirred at room temperature for 7 hours, and then the reaction solution was neutralized by dryness under reduced pressure with Unburst-15 (H type) The remaining sediment was silica gel chromatography (50 g, chloroform / methanol, 10: 1) to give the title compound (480 g; 90%) as a white powder.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 1: 1) δ: 3.24 (s, 3H, OCH ₃ ), 2.40 (dd, 1H, J = 4.9, 13.9 Hz, H-3eq), 2.05 (s, 3H, NAc), 1.27 (m, 76H, 38CH ₂ ), 0.91 (s, 3H, CCH ₃ ), 0.89 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 59

1- [N- (5-acetamido-3,5-dideoxy-2-O-methyl-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-β -D-galacto-2-nonurophyllanosonyl) amino] -2,2-bis (docosyloxymethyl) propane:

1- [N- (5-acetamido-3,5-dideoxy-2-O-methyl-D-glycero-β-D-galacto-2-nonurophyllanosonyl) amino] -2, 2- Bis (docosyloxymethyl) propane (831 mg) The reaction was carried out in the general manner as described in Example 1, to obtain the title compound (810 g; 70%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 40 ° C.) δ: 2.66 (br.dd, 1H, J = 4.4, 12.5 Hz, H-3eq), 2.03 (s, 3H, NAc) , 1.79 (br.t, 1H, H-3ax), 1.31 (m, 76H, 38CH ₂ ), 0.91 (s, 3H, CCH ₃ ), 0.91 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ) .

Example 60

1- [N- (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-0-methyl-D-glycero-β-D-galacto -2- nonurophyllanosonyl) amino] -2,2-bis (eicosyloxymethyl) propane:

<A>: 2,2-bis (eicosyloxymethyl) propyl methanesulfonate:

2,2-bis (eicosyloxymethyl) propanol (1.19 g) was reacted by the general method described in Example 57-A to give the title compound (1.08 mg, 82%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 4.13 (s, CH ₂ 0Ms), 2.98 (s, 3H, CH ₃ SO ₂ ), 1.25 (m, 68H, 34CH ₂ ), 1.00 (s, 3H, CCH ₃ ) , 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

<B>: 1-azide-2,2-bis (eicosyloxymethyl) propane:

2,2-bis (eicosyloxymethyl) propyl methanesulfonate (1.05 g) was reacted by the general method described in Example 57-B to give the title compound (0.94 g, 96%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (m, 68H, 34CH ₂ ), 0.94 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

<C>: 1-amino-2,2-bis (eicosyloxymethyl) propane:

1-azide-2,2-bis (eicosyloxymethyl) propane (360 mg) was reacted by the general method described in Example 57-C to give the title compound (206 mg, 59%) as a white solid. .

¹ H-NMR (CDCl ₃ ) δ: 2.74 (s, 2H, CH ₂ ), 1.25 (m, 68H, 34CH ₂ ), 0.90 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.0Hz , 2CH ₂ CH ₃ ).

<D> 1- [N- (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-0-methyl-D-glycero-β-D Galacto-2-nonurophyllanosonyl) amino] -2,2-bis (eicosyloxymethyl) propane:

Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosidonic acid (179 mg ) And 1-amino-2,2-bis (eicosyloxymethyl) propane (206 mg) were reacted according to the general method described in Examples 57-E to give the title compound (327 mg, 94%) as a white solid. Got it.

¹ H-NMR (CDCl ₃ ) δ: 3.18 (s, 3H, 0CH ₃ ), 2.51 (dd, 1H, J = 5.0, 13.0 Hz, H-3eq), 2.14, 2.09, 2.04, 2.01, 1.91 (5s, 15H, 5Ac), 1.77 (t, 1H, J = 11.7, 0.91 Hz, H-3ax), 1.25 (m, 68H, 34CH ₂ ), 0.91 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 61

1- [N- (5-acetamido-3,5-dideoxy-2-0-methyl-D-glycero-β-D-galacto-2-nonurophyllanosonyl) amino] -2, 2-bis (eicosyloxymethyl) propane:

1- [N (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-O-methyl D-glycero-β-D-galacto-2 Nonurophyllanosonyl) amino] -2,2-bis (eicosyloxymethyl) propane (216 mg) was reacted by the general method described in Example 58 to give the title compound (202 mg, 74%) as white Obtained as a solid.

¹ H-NMR (CDCl ₃ -CD ₂ OD, 10: 1) δ: 3.22 (s, 3H, OCH ₃ ), 2.36 (dd, 1H, J = 4.8, 13.2 Hz, H-3eq), 2.04 (s, 3H, NAc), 1.26 (m, 68H, 34CH ₂ ), 0.90 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.1 Hz, 2CH ₂ CH ₃ ).

Example 62

1- [N-5-acetamido-3,5-dideoxy-2-0-methyl-4,7,8,9-tetra-O- (sodium sulfofonyl) -D-glycero-β- D-galacto-2-nonurophyllanosonyl amino] -2,2-bis (eicosyloxymethyl) propane:

1- [N (5-acetamido-3,5-dideoxy-2-O-methyl-D-glycero-β-D-galacto-2-nonurophyllanosonyl) amino] -2,2 Bis (eicosyloxymethyl) propane (422 mg) was reacted in the general manner described in Example 1 to give the title compound (49 mg, 36%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 40 ° C.) δ: 2.66 (br.dd, 1H, H-3eq), 2.02 (s, 3H, NAc), 1.78 (br.t, 1H, J = 12.3 Hz, H-3ax), 1.30 (m, 68H, 34CH ₂ ), 0.90 (s, 3H, CCH ₃ ), 0.90 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 63

1- [N- (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-0-ethyl-D-glycero-β-D-galacto -2- nonurophyllanosonyl) amino] -2,2-bis (docosyloxymethyl) propane:

<A>: Methyl (ethyl5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanoside) onate:

A mixture of N-acetylneuraminic acid (1.00 g; 3.23 mmol), Dax 50 (type H) (15 g), and dry ethanol (100 ml) was refluxed for 18 hours.

The reaction mixture was charged into a column, eluted with 2N hydrochloric acid-methanol (100 ml), and the solvent was removed under reduced pressure. The resulting residue, a mixture of acetic anhydride (20 ml) and pyridine (20 ml) was stirred at room temperature for 17 hours, and then the reaction solution was dried under reduced pressure. The remaining sediment was dissolved in chloroform, washed sequentially with 0.1-hydrochloric acid, water and saturated brine, and then dried over anhydrous magnesium sulfate to remove the solvent. The resulting residue, a mixture of sodium methoxide (31 mg; 0.575 mmol) and methanol (23 ml) was stirred at room temperature for 17 hours, and then neutralized with Dax 50 (H type) to remove the solvent. The residue was purified by silica gel column chromatography (40 g, chloroform / methanol, 4: 1) to give the title compound (142 mg, 12%) as a white powder.

¹ H-NMR (CD ₃ OD) δ: 3.78 (s, 3H, OCH ₃ ), 2.36 (dd, 1H, J = 4.9, 13.0 Hz, H-3eq), 2.00 (s, 3H, NAc), 1.62 ( dd, 1H, J = 11.4, 12.8 Hz, H-3ax), 1.16 (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ).

<B> Methyl (ethyl5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-β-D-galacto-2-nonneupilar Norseed) Onate:

Methyl (ethyl5-acetamido-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanoside) onate (142 mg) general described in Example 57-D Reaction was carried out to give the title compound (209 mg, 99%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.80 (s, 3H, COOCH ₃ ), 2.45 (dd, 1H, J = 5.1, 12.8 Hz, H-3eq), 2.15, 2.08, 2.03, 2.02, 1.89 (s, 15H, 5Ac), 1.87 (dd, 1H, J = 11.4, 12.8 Hz, H-3ax), 1.22 (t, 3H, J = 7.1 Hz, CH ₂ CH ₃ ).

<C>: ethyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosi Donsan:

Ethyl (Ethyl5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanoside) A mixture of onate (203 mg, 0.39 mmol), anhydrous lithium iodide (523 mg, 3.9 mmol) and pyridine (8.0 ml) was stirred at 90 ° C. for 14 h. The reaction solution was gel filtered (LH-20, 150 ml, methanol), and then purified by silica gel column chromatography (20 g, chloroform / methanol, 7: 3) to give the title compound (92 mg, 47%). Obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 3.52 (m, 2H, CH ₂ CH ₃ ), 2.56 (dd, 1H, J = 4.5, 12.2 Hz, H-3eq), 2.15, 2.11, 2.06, 2.04, 1.91 ( 5s, 15H, 5Ac), 1.92 (t, 1H, J = 11.8 Hz, H-3ax.), 1.24 (t, 3H, J = 7.0 Hz, CH ₂ CH ₃ ).

<D>: 1- [N- (ethyl5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2, O-ethyl-D-glycero-β -D-galacto-2-nonurophyllanosonyl) amino] -2,2 bis (docosyloxymethyl) propane:

Ethyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-β-D-galacto-2-nonurophyllanosidonic acid (92 mg ) And 1-amino-2,2-bis (docosyloxymethyl) propane (268 mg) were reacted according to the general method described in Examples 57-E to give the title compound (191 mg, 86%) as a white solid. Got it.

¹ H-NMR (CDCl ₃ ) δ: 2.52 (dd, 1H, J = 4.8, 13.2 Hz, H-3eq), 2.14, 2.08, 2.03, 2.01, 1.91 (5s, 15H, 5Ac), 1.76 (t, 1H , J = 12.4 Hz, H-3ax.), 1.25 (m, 76H, 38CH ₂ ), 1.19 (t, 3H, J = 7.0 Hz, 0CH ₂ CH ₃ ), 0.90 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 64

1- [N- (5-acetamido-3,5-dideoxy-2, O-ethyl-D-glycero-β-D-galacto-2-nonurophyllanosonyl) amino] -2, 2-bis (docosyloxymethyl) propane:

1- [N- (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-O-ethyl-D-glycero-β-D-galacto 2-nonurophyllanosonyl) amino] -2,2-bis (docosyloxymethyl) propane (185 mg) was reacted by the general method described in Example 58 to give the title compound (114 mg, 71%) Was obtained as a white solid.

¹ H-NMR (CDCl ₃ -CD ₂ OD, 10: 1) δ: 2.38 (dd, 1H, J = 4.8, 13.2 Hz, H-3eq), 2.04 (s, 3H, NAc), 1.26 (m, 76H , 38CH ₂ ), 1.17 (t, 3H, J = 7.0 Hz, 0CH ₂ CH ₃ ), 0.89 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.3 Hz, 2CH ₂ CH ₃ ).

Example 65

1- [N-5-acetamido-3,5-dideoxy-2, O-ethyl-4,7,8,9-tetra-O- (sodium oxalfonyl) -D-glycero-β- D-galacto-2-nonurophyllanosonyl amino] -2,2 bis (docosyloxymethyl) propane:

1- [N- (5-acetamido-3,5-dideoxy-2-O-ethyl-D-glycero-β-D-galacto-2-nonurophyllanosonyl) amino] -2, 2-Bis (docosyloxymethyl) propane (422 mg) was reacted in the general manner described in Example 1 to give the title compound (140 mg, 93%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 40 ° C.) δ: 2.67 (br.dd, 1H, H-3eq), 2.02 (s, 3H, NAc), 1.77 (br.t, 1H, H-3ax), 1.30 (m, 76H, 38CH ₂ ), 1.25 (s, 3H, J = 7.0 Hz, 0CH ₂ CH ₃ ), 0.91 (t, 6H, J = 6.8 Hz, 2CH ₂ CH ₃ ) , 0.90 (s, 3H, CCH ₃ ).

Example 66

1- [N-5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-0-methyl-D-glycero-α-D-galacto- 2- nonneuphylanosonyl amino] -2,2-bis (docosyloxymethyl) propane:

<A>: Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanoso Sidonic acid:

Methyl 5-acetamido-3,5- dideoxy-D-glycero-α-D-galacto-2-nonurophyllanososidonic acid [Chem. Ber., 99, 611 (1966)] (150 mg) was reacted by the general method described in Example 57-D to give the title compound (220 mg, 96%) as a white solid.

¹ H-NMR (CDCl ₃ -CD ₂ OD, 1: 1) δ: 3.20 (s, 3H, 0CH ₃ ), 2.42 (dd, 1H, J = 4.4, 12.5 Hz, H-3eq), 1.96, 1.95, 1.87, 1.83, 1.70 (5s, 15H, 5Ac), 1.56 (t, 1H, J = 12.5 Hz, H3ax).

<B>: 1- [N- (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-0-methyl-D-glycero-α- D-galacto-2-nonurophyllanosonyl) amino] -2,2-bis (docosyloxymethyl) propane:

Methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-α-D-galacto-2-nonurophyllanososidonic acid (191 mg) and 1-amino-2,2-bis (docosyloxymethyl) propane (396 mg) were reacted in the general manner described in Examples 57-E to give the title compound (345 mg, 73%) as white. Obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 3.36 (s, 3H, 0CH ₃ ), 2.13, 2.08, 2.03, 2.01, 1.89 (5s, 15H, 5Ac), 1.98 (t, 1H, J = 11.7Hz, H- 3ax), 1.25 (m, 76H, 38CH ₂ ), 0.90 (s, 3H, CCH ₃ ), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 67

1- [N- (5-acetamido-3,5-dideoxy-2-0-methyl-D-glycero-α-D-galacto-2-nonurophyllanosonyl amino] -2,2 Bis (docosyloxymethyl) propane:

1- [N- (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-0-methyl-D-glycero-α-D-galacto 2-nonurophyllanosonyl) amino] -2,2-bis (docosyloxymethyl) propane (340 mg) was reacted by the general method described in Example 58 to give the title compound (216 mg, 74%). Obtained as a white solid.

¹ H-NMR (CDCl ₃ -CD ₃ OD, 10: 1) δ: 3.36 (s, 3H, OCH ₃ ), 2.55 (dd, 1H, J = 4.8, 13.2 Hz, H-3eq), 2.03 (s, 3H, NAc), 1.82 (dd, 1H, J = 11.2, 13.0 Hz, H3ax), 0.88 (t, 6H, J = 7.0 Hz, 2CH ₂ CH ₃ ).

Example 68

1- [N-5-acetamido-3,5-dideoxy-2, O-ethyl-D-4,7,8,9-tetra-O- (sodium oxofonyl) -D-glycero- α-D-galacto-2-nonurophyllanosonyl amino] -2,2 bis (docosyloxymethyl) propane:

1- [N- (5-acetamido-3,5-dideoxy-2-O-ethyl-D-glycero-α-D-galacto-2-nonurophyllanosonyl) amino] -2, 2-Bis (docosyloxymethyl) propane (117 mg) was reacted in the general manner described in Example 1 to give the title compound (98 mg, 60%) as a white solid.

¹ H-NMR (CD ₃ OD-D ₂ O, 1: 1, 40 ° C.) δ: 2.55 (br.dd, 1H, J = 5.1, 13.6 Hz, H-3eq), 1.99 (s, 3H, NAc) , 1.30 (m, 76H, 38CH ₂ ), 0.90 (br.t, 9H, J = 6.6 Hz, CCH ₃ and 2CH ₂ CH ₃ ).

[Evaluation of Growth Inhibition and Cytotoxicity of HIV-1]

25 μl of various concentrations of the test specimens are placed in a 24-well microplate, and immediately 1 ml of heat T cells (H9 cells, 1.2 × 10 5 / ml) are added. Cover and incubate for 1 hour at 37 ° C. Then 25 μl of AIDS virus (HIV-1, IIIb, 100TCID50) is added and mixed well. Once again, the lid is covered and incubated under carbon dioxide at 37 ° C. for 3 days. On day 4, 200 μl of the culture solution of each well is transferred to a new microplate, 500 μl of medium is added thereto, followed by incubation for 2 days.

90 µl of the supernatant that emerged on the 6th day of culture was taken and the amount of p24, a component of HIV-1 contained therein, was measured by ERIS method using an anti-p24 antibody. Meanwhile, using 100 μl of the remaining culture cell suspension as a sample, the number of viable cells was measured by MTT method. The obtained values were expressed as a percentage (%) relative to each negative control value (solvent used for dissolving the test sample) as the anti-HIV activity and cytotoxicity. Subsequently, in order to express anti-HIV activity and cytotoxicity in one meaning, the concentrations of the test specimens for each 50% value were obtained from the graphs, respectively, as IC 50 and CC 50D.

Results for anti-HIV activity

In Table 1, compounds having an IC50 (μM) of 100 μM or less are shown together with their structural properties. [0037] In addition, the carbon number as a functional group is the alkyl group carbon number before the ether linkage of the fatty side chain, especially when the fatty acid was alkylglycerol. The alkyl group carbon number is shown.

TABLE 1

As a result, it can be seen that the lipid that is glycoside-bonded to the nonneuronic acid (sialic acid and KDN) is preferably an alkyl group, a carbonyloxy group or an oxycarbonyl group. In addition, when comparing Example 7 (O-glycoside) and Example 14 (S-glycoside), no significant difference in activity can be found. Therefore, the O-glycoside bond is good for the sugar-lipid bond, Glycoside binding is also good.

In addition, when comparing Example 29 and Example 59, which differ only in whether an O-glycoside bond or an amide bond, there is no difference in activity, it can be concluded that the linkage between sugar and lipid is not related to any form of linkage. have.

Speaking only of the cyroglycerol lipid sulfate derivatives, as can be seen by comparing Example 9 (18 alkyl double-chain carbon atoms, IC50; 3.8) and Example 11 (18 alkyl single-chain carbon atoms, IC50; 13.0), In the case of one chain or two chains, the two chains have activity, but in general, the two chains have high activity. Therefore, although an alkyl chain may be one chain, it can be said that it is preferable that it is two chains.

Further, as can be seen when comparing Example 38 (22 alkyl double-chain carbon atoms, glyceroester IC50; 2.5) and Example 12 (22 alkyl double-chain carbon atoms, IC50; 0.8), the glycerol lipid moiety is alkylglycerol. Or acylglycerol has high activity. Therefore, the activity is not influenced by the binding form of the glycerin skeleton and the long chain alkyl group, and is considered to depend mainly on the length of the long chain alkyl group bonded to the glycerin skeleton.

Here, as for the two-chain alkylglycerol bonded to glycosidic, when the carbon number of the alkyl group which is an alkyl glycerol is noticed, as shown in FIG. 1, it is C18 (Example 9), C20 (Example 17), and carbon number It can be seen that there is a minimum value of IC50 in the vicinity of 22 (Example 12) and C24 (Example 20).

Therefore, when the cyaliglyceride sulfate derivative of the present invention is alkyl glycerol or acyl glycerol, the carbon number of the alkyl chain bonded to the glycerin residue is preferably 18 to 24.

Since the activity mainly depends on the length of the long-chain alkyl group bonded to the glycerin skeleton, the long-chain alkyl chain may be saturated or unsaturated and may have a branched chain. Here, when carbon number 24 is the same alkylglycerol as Example 20, it corresponds to 25 as <the number of atoms which form a skeleton> per side chain.

This is because <atoms forming a skeleton> include oxygen atoms involved in ether bonding in addition to carbon, which is an alkyl group. Also, in the case of analogous glycerol as in Example 29 or Example 32, the carbon atom of the methylene group between the carbon atom at the β-position of the main chain of the glycerin residue and the oxygen atom of the ether bond is also the number of <atoms forming a skeleton>. In the case of Example 29, the number of <atoms for forming a skeleton> is included in the formula, and thus, in the case of Example 32, the number is 22.

The glycerin residue may have a methyl branch or may have a methylene group between the main chain and the ether bond or ester bond of the glycerin residue (Examples 29 and 32). Therefore, the glycerin residue may have a short alkyl group such as a methyl group, an ethyl group, a propyl group or a butyl group in the carbon atom at the β-position of the main chain (in this case, since the alkyl group does not have a sufficient length) One to three carbons may be interposed between the main chain of the glycerin residue and the ether bond or ester bond).

Here, in comparing Example 29 with Example 12, Example 29 differs in Example 12, although the length of the two chains extending at the carbon atom at the main chain β-position of the glycerin residue is the same. That is, in Example 29, the number of <skeleton forming atoms> per two chains extending from the carbon atom at the?

Therefore, in the case of two chains, the number of <atoms forming a skeleton> per side chain and the number of carbons constituting the alkyl chain may be different. In addition, Example 29 has the advantage of being easy to manufacture because the two chains are all identical chains of members and atoms of each other.

Next, CC50 is shown in [Table 2].

TABLE 2

These results show that the compounds of the present invention generally have low cytotoxicity.

Measurement of antiviral activity of non-HIV viruses

Human parainfluenza virus, Respiratory syncytial virus (RSV) and Herpes simplex II virus (HSVII) are plaque reduction assays. ), Ferline immunodeficiency virus (FIV) and Felineleukemia virus (FeLV) were measured by Reverse transscriptase assays and ELISA, respectively.

1) Plaque reduction assay

a) Preparation of Virus, Host Cell and Virus Stork Each virus was obtained from ATCC. Host cells used VERO cells for Paraflufluza virus and HEP2 cells for other viruses.

Virus-infected cells were added to fibroblasts growing in T150 flasks, cultured until 60-80% infection, treated with trypsin, and the cells were recovered and treated as virus stocks. E-MEM with 2-5% FBS, 100 U / ml penicillin, 2.5 ug / ml amphotericin, 10 ug / ml gentamicin was used.

b) preparation of the sample;

Suitably, the compound of Example 29 was diluted to 500, 100, 50, 10, 5, 1 ug / ml in medium or methyl cellulose, and then acyclovir was used as an alternative to HSV II.

Antiviral Activity

After supernatant was discarded by culturing cells in a monolayer (monolayer) in a 24-well microplate, 0.5 ml of diluted sample was added and incubated for 1 hour at 36-38 ° C. and 5-7% carbon dioxide. On the other hand, the same amount of medium was added to the cell control and the virus control as a control. The supernatant was removed and 0.5 ml of medium and 0.2 ml of virus stock were added to the sample and virus controls. After 1 hour of incubation again, 1 ml of the sample diluted with methylcellulose solution containing FBS was muti layler. On the other hand, only the same solution was added to the control.

Incubated under 5-7% CO ₂ at 36-38 ° C., the appearance of plaques was checked under a microscope, the monolayer was fixed with 10% formalin, washed with water, and then stained with 0.8% crystal biolet and dried. . The plaques were counted and the number of plaques in the sample plot was compared with the plaque counts in the virus control plot to make the decrease antiviral activity.

Cytotoxicity

Among the antiviral activity assays described above, the cells were cultured in the presence of various concentrations of samples without any virus infection step in the test zone, and the number of viable cells was compared with the cell control. The measurement of the viable cell number was made by the tetrazolium method for a microplate.

2) Reverse transcriptase assay

a) Preparation of virus, host cell and virus stock

Each virus was obtained from ATCC. The virus stock of FIV was incubated in the Eagle's balanced salt solution containing 10% FBS with the same virus using CRFT cells, and the supernatant was transferred to virus stock. did. For FelV, ATCC VR-717 was used.

b) preparation of the sample;

The compound of Example 29 was diluted in the medium to the same concentration as above.

c) measuring method

One kind of virus was configured as follows.

Control badge

Cell Control Medium + Cells

Cytotoxic Media + Cells + Samples

Virus Control Medium + Cell + Virus

Test medium medium + cell + virus + sample

Color Control Badges + Samples

Incubate CRFL cells in a monolayer on a 96-hole microplate, discard the supernatant, add 0.2 ml of medium to the media control, cell control, and virus controls, and dilute the samples with cytotoxic, test, and color controls, respectively. 0.2, 0.1, and 0.2 ml were added and incubated under 5-7% CO 2 at 36-38 ° C. for 1 hour. Subsequently, the supernatant of the virus control group and the test group was discarded, 0.1 ml of virus stock was added and incubated for 1 hour, the supernatant was removed, 0.2 ml of medium was added to the virus control group, and the sample diluted in the same amount was added to the test group. Culture was continued.

Reverse transcriptase assay, ELISA

The supernatant of the cell control, virus control and test specimens was quantified by the measurement kits of Amersham LIFESCIEN and Synbiotics, respectively. It was. Antiviral activity was expressed as% of test versus virus control by subtracting cell control values from test and virus control values, respectively.

Cytotoxicity

Survival numbers of cells of cytotoxic and cell control cells were quantified by the Tetrazolium method for microplates as described above and expressed as the percentage of the former cell number relative to the latter cell number.

Results of antiviral activity and toxicity of non-HIV viruses

The test results of antiviral activity are shown in [Table 3].

Table 3 Antiviral Activity of the Compound

From these results, it can be seen that the compound of the present invention has not only anti-HIV activity but also antiviral activity against other viruses.

In addition, CC50 for cytotoxicity was calculated for each virus by the same method as the HIV described above, and all showed a value of 500 μM or more.

As described above, since the compound of the present invention is low in toxicity and has antiviral activity against other viruses, it can be concluded that the compound of the present invention is effective as a medicament due to its high efficacy against diseases and high safety for the living body.

Anticoagulant

500 μl of a compound diluted with physiological saline was added to 400 μl of heat plasma, 100 μl of a 2% calcium chloride solution was added thereto, mixed, and then incubated at 37 ° C. for 30 minutes to measure the minimum concentration (μM) showing anticoagulation. Plasma coagulation was measured visually.

Toxicity Test

Compounds were administered intravenously to mice to determine their LD50 (mg / kg).

<Results of Anticoagulant and Toxicity Tests>

The results of anticoagulant and toxicity tests are shown in [Table 4].

TABLE 4

These results show that the compounds of the present invention generally have low cytotoxicity, in particular, have low anticoagulant action and low toxicity to living bodies, especially with respect to the compounds of Examples 12, 13 and 29. Therefore, it is clear that the formulation containing an effective amount of the compound of the present invention is preferable as a pharmaceutical.

An effective amount of a compound of the present invention or a salt thereof is a general method well known in the art such as a method of extrapolating to a human by establishing a dose-response curve in a suitable animal model or a non-human primate, or as determined by a clinical therapeutic test. Can be determined using.

Preferred dosages of the medicament, antiviral agent, and anti-HIV agent of the present invention depend on various factors such as the severity of the disease, the weight and age of the individual, and the half-life in circulation, but these can be easily determined by those skilled in the art.

The medicine of the present invention can be administered by various methods such as intravenous injection, oral administration and inhalation. Carriers, diluents and excipients for drugs can be easily determined by those skilled in the art depending on the clinical use of the drug, and if necessary, disintegrants, binders (including liposomes), surfactants, emulsifiers, buffers, solubilizers or preservatives, etc. The adjuvant of is added, and can also be formulated in liquid, emulsion, or suspension.

As described above, the compound of the present invention has a high antiviral activity and a low cytotoxic effect. Thus, the novel compounds of the present invention are optimal as antiviral agents.

In addition, since the novel compounds of the present invention have low anticoagulant action and low toxicity to a living body, preparations containing an effective amount thereof are preferable as pharmaceuticals. The low anticoagulant effect is especially useful as an anti-HIV agent, considering the bleeding tendency in HIV patients.

Claims (25)

The fatty portion is bonded by glycosidic linkage to the anomer carbon position of the nonuloic acid residue portion or by an amide bond or ester bond to the 1 position of the nonneuronic acid residue portion, and the nonneuronic acid residue portion A compound consisting of a monosaccharide-fat or a salt thereof, wherein all hydroxyl groups are sulfated. The compound or salt thereof according to claim 1, wherein the nonneuronic acid moiety consists of sialic acid or 2-ketone-3-dioxy-D-glycero-2-nonneuronic acid (KDN). The method of claim 2, wherein the sialic acid residue moiety or the linkage of the 2-keto-3-dioxy-D-glycero-2-nonneuronic acid (KDN) residue moiety to the lipid moiety is O- at the 2-position of the moiety moiety. A compound or a salt thereof, characterized in that it is an amide bond or an ester bond in the glycosidic bond or S-glycosidic bond or one-position of its moiety. The compound or salt thereof according to claim 3, wherein the fat is a chain-type fat, and the chain-type fat has a branched structure. The compound or a salt thereof according to claim 4, wherein the branch is branched at the 2 position of the main chain of the fatty portion. A compound or a salt thereof according to claim 5, wherein the fatty moiety consists of two chains by the branching. The compound or a salt thereof according to claim 6, wherein the fatty moiety has an alkyl group having 1 to 4 atoms forming a skeleton at the position of the branch. 8. A compound according to claim 7, or a salt thereof, wherein the total number of atoms forming the skeleton of the lipid is from 22 to 60. The compound or salt thereof according to claim 8, wherein the branched chain comprises an unsaturated bond between carbons. The compound or salt thereof according to claim 8, wherein the branched chain is straight chain. The compound or salt thereof according to claim 8, wherein the branched chains each comprise an ester bond or an ether bond. The compound or salt thereof according to claim 11, wherein the ester bond or ether bond is present at 1 or 2 positions of the branched chain. 9. A compound according to claim 8 or a salt thereof, wherein the number of atoms forming a skeleton per branched chain is 10 to 28. The compound or a salt thereof according to claim 13, wherein the number of atoms forming a skeleton per branched chain is 18 to 26. The compound or a salt thereof according to claim 14, wherein the number of atoms forming a skeleton per branched chain is 24. The compound or salt thereof according to claim 15, wherein the branched chains are each the same length. 17. The compound or salt thereof according to claim 16, wherein the branched chains are each the same. 18. The compound or salt thereof according to claim 17, wherein the branched chain has an ester bond or an ether bond at one or two positions of the branched chain. 19. The compound or salt thereof according to claim 18, wherein the branched chain is straight chain. The compound of claim 1, wherein the compound is sodium [2,2-bis (docosyl oxymethyl) propyl 5-acetamido-3,5-dideoxy-4,7,8,9 tetra-0- (sodium jade Sulphonyl) -D-glycero-α-D-galacto-2-nonurophyllanoside] onate or acid form thereof, or a salt thereof. 21. A compound or a salt thereof according to claim 20, wherein a cation is bound to neutralize carboxylic acid or sulfonic acid in the compound and not to deactivate the activity. The compound or salt thereof according to claim 21, wherein the compound to which the cation is bound is a potassium salt. Human immunodeficiency virus (HIV), Perrin immunodeficiency virus (FIV), and Perrin Lucemia virus (FeLV), which contain a pharmaceutically effective amount of the compound according to any one of claims 1 to 21. A pharmaceutical composition for treating viral diseases that mediates herpes simplex II virus (HSV II), parainfluenza virus, or respiratory syntactic virus (RSV). An antiviral agent comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 21. An anti-HIV agent comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 21.