KR100187302B1 - Lipid-a analogs having immunoactivating and anti-tumor activity - Google Patents

Abstract

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Description

Lipid A homologue with immunological and antitumor activity

The present invention provides a series of novel monosaccharide compounds that are homologues of known Lipid A, which have immune and antitumor activity. The present invention also provides methods for preparing these novel compounds, as well as methods for treating, preventing, diagnosing and maintaining patients suffering from immunodeficiency diseases and disorders and for inhibiting tumor growth and compositions using these materials.

The outermost layer of Gram-negative bacterial cell walls obtained from enteric bacterial species, such as Escherichia coli, contains toxic components (endotoxins) that are not secreted out of the bacteria. In addition to endotoxin activity, these endotoxins exhibit several biological activities: for example, immunoadjuvant, they activate macrophages, induce mitosis, cause fever, and cause tumor necrosis. do ; It also enhances the production of antibodies and induces the production of TNF (tumor necrosis factor), both of which play an important role in the immune system of animals, including humans. Therefore, there is considerable interest as precursors of drugs that are important in the treatment, prevention, maintenance or diagnosis of diseases and disorders caused or resulting from a deficiency of the immune system in humans and other animals.

Previously, endotoxins contained lipopolysaccharides, and it was found that there is a site now known as lipid A in the middle of this endotoxin activity. In addition, the monosaccharides known as Lipid X and Lipid Y, which are lipid A biosynthetic precursors, are E. coli. It could be isolated from E. coli mutants and found that, although weak, they exhibited similar activity to Lipid A.

As a result, various derivatives of the non-reducing sugar moieties of Lipid A monosaccharide, Lipid X, Lipid Y, and Lipid A are being synthesized and their activity is being investigated (Imoto et al., Tetrahedron Lett., 26, 1545 (1985) or Kiso et al., Carbohydrate Research, 162, 127 (1987)].

However, since these derivatives are bacterial endotoxins known per se, their use as a drug still has various problems including induction of lethal toxicity, pyrogenic activity, leukopenia and autoimmune diseases. Therefore, there is a need for compounds of that type that possess the desired activity and do not have the toxicity problems of the naturally occurring compounds.

Several attempts have been made to provide compounds that meet these requirements. For example, Lipid X, which has immune stimulating activity, is described in WO 84/04526 and is useful as a regulator of bactericidal resistance, enhances immune response, prevents endotoxin shock and treats malignant tumors and inflammation. Various saccharide derivatives used are described in British Patent 2 211 503. However, among the known compounds so far, the most excellent activity is GLA-60, which is described in J. Carbohydrate Chem., 6 (4), 625-638 (1987) and Carbohydrate Research, 162, 127-140 (1987).

It is now a homologue of Lipid A monosaccharides, and at worst, has the above-mentioned form of activity comparable to GLA-60, and in some cases is substantially superior to the activity of GLA-60, and thus probably to date. A series of saccharide derivatives have been found which are the best active compounds among the phosphorus compounds. The compounds of the present invention are characterized by the presence of at least one halogen atom, preferably a fluorine atom, at one or more specific selection sites in the molecule with the compounds of the prior art.

It is therefore an object of the present invention to provide a new series of compounds having activity of the lipid A form.

It is another object of the present invention to provide methods and compositions for the treatment, prevention, diagnosis and maintenance of a patient suffering from a disease or disorder resulting from a tumor or deficiency of the immune system using the compounds of the invention.

According to the present invention, this object can be carried out by providing the following novel compounds of the general formula (I) and salts thereof and their esters when containing a carboxyl group.

의 기를 나타내며; R²및 R³는 각각 탄소수 6 내지 20인 지방족 카르복실아실기로 구성된 군으로부터 선택되며, 이실기는 치환되지 않았거나 또는 아래에 정의한 바와 같은 치환체 (a)로 구성된 군으로부터 선택된 하나 이상의 치환체를 갖고 있으며; R⁴는 히드록시기, 앙래에 정의한 바와 같은 보호된 히드록시기, 또는 식

의 기를 나타내며, R¹및 R⁴의 적어도 하나는 식

의 기를 나타내고; R⁵는 히드록시, 아래에 정의한 바와 같은 보호된 히드록시기, 또는 불소원자를 나타내며, R¹및 R⁵의 적어도 하나가 불소원자를 나타내는 경우를 제외하고는 다음과 같다 : R²및 R³의 적어도 하나는 (i) 하나 이상의 할로겐 치환체 및 (ii) 할로겐 원자, 히드록시기 및 탄소수 6 내지 20인 지방족 카르복실 아실기로 구성된 군으로부터 선택된 하나 이상의 치환체를 갖는, 탄소수 6 내지 20인 치환된 지방족 카르복실 아실기를 나타내고, 또는 R²및 R³의 적어도 하나는 탄소수 6 내지 20인 하나 이상의 할로겐-치환 지방족 카르복실 아실옥시기로 치환된, 탄소수 6 내지 20인 치환된 지방족 아실기를 나타낸다; 보호된 히드록시기는 탄소수 1 내지 20인 지방족 카르복실 아실옥시기 ; 탄소수 2 내지 6인 할로겐화 카르복실 아실옥시기 ; 알콕시 부분은 탄소수 1 내지 6이며 아실 부분은 탄소수 2내지 6인 알콕시-치환 카르복실 아실옥시기 ; 방향족 부분은 탄소수 6내지 14이며 치환되지 않았거나 또는 아래에 정의한 바와 같은 치환체 (b)로 구성된 군으로부터 선택된 하나 이상의 치환체를 갖고 있는 카르보시클릭 방향족 카르복실 아실옥시기 ; 식 Het-O- 의 기 (Het는 질소, 산소 및 황원자로 구성된 군으로부터 선택된 1 내지 3 헤테로 원자의 5 또는 5원자 고리를 갖고 있는 헤테로시클릭기를 나타내며, 헤테로시클릭기는 치환되지 않았거나 또는 아래에 정의된 치환체 (c)로 구성된 군으로부터 선택된 하나 이상의 치환체를 갖고 있다.) ; R^aR^bR^cSi-O-의 기 (R^a, R^b및 R^c는 각각 탄소수 1 내지 6인 알킬기 및 탄소수 6 내지 10인 키르보시클릭 아릴기로 구성된 군으로부터 선택되며, 아릴기는 치환되지 않았거나 또는 아래에 정의된 치환체 (b)로 구성된 군으로부터 선택된 하나 이상의 치환체를 갖고 있다.) ; 두 개의 알콕시 부분이 같거나 또는 다르며 각각 탄소수 1 내지 6인 알콕시알콕시기 ; 아르알킬옥시기 (탄소수 1 내지 6인 알킬기는 1내지 3개의 아릴기로 치환되어 있으며, 아릴기는 치환되지 않았거나 또는 아래에 정의된 치환체 (b)로 구성된 군으로부터 선택된 하나 이상의 치환체를 갖고 있다) ; 알콕시 부분은 탄소수 1 내지 6인 알콕시카르보닐옥시기 ; 치환된 알콕시카르보닐옥시기(알콕시 부분은 탄소수 1 내지 6이며, 치환체는 아래에 정의한 치환체 (d)로 구성된 군으로부터 선택된다.) ; 알케닐 부분이 탄소수 2 내지 6인 알케닐옥시기 ; 탄소수 2 내지 6인 알케닐옥시기 ; 아실 부분은 탄소수 1 내지 6이며, 상기 아실 부분이 다른 상태로는 치환되지 않았거나 또는 하나 이상의 히드록시 치환체를 갖고 있는 카르복시-치환 지방족 카르복실 아실옥시기 ; 아실기는 탄소수 1 내지 6인 카르복실아실기인 아실옥시메톡시카르보닐옥시기 ; 아릴 부분은 탄소수 6 내지 14의 고리이며, 치환되지 않았거나 또는 아래에 정의된 치환체 (b)로 구성된 군으로부터 선택된 하나 이상의 치환체를 갖고 있는 (아릴셀레닐) 에톡시기 ; 각각의 알콕시 부분이 탄소수 1 내지 6인 알콕시알콕시메톡시기 ; 알콕시 부분은 탄소수 1 내지 6이며, 하나 하나이상의 할로겐 원자로 치환된, 하나, 둘 또는 세 개의 할로알콕시 치환체로 치환된 메톡시기 ; 에틸 부분이 하나 이상의 할로겐 원자로 치환된 할로에톡시기 ; 및 아르알킬옥시카르보닐옥시기 (아르알킬 부분은 1 내지 3개의 아릴기로 치환되어 있는 탄소수 1 내지 6개의 알킬기로 구성되며, 상기 아릴기는 치환되지 않았거나 또는 아래에 정의한 치환체 (b)로 구성된 군으로부터 선택된 하나 이상의 치환체를 갖고 있다)로 구성된 군으로부터 선택되며 ;[Wherein R ¹ is a hydroxy group, a protected hydroxy group, a fluorine atom or a formula as defined below

Represents a group of; R ² and R ³ are each selected from the group consisting of aliphatic carboxyacyl groups having 6 to 20 carbon atoms, the diyl group having one or more substituents unsubstituted or selected from the group consisting of substituents (a) as defined below; ; R ⁴ is a hydroxy group, a protected hydroxy group as defined in Anglai, or a formula

Wherein at least one of R ¹ and R ⁴ is

Represents a group of; R ⁵ represents hydroxy, a protected hydroxy group as defined below, or a fluorine atom, except that at least one of R ¹ and R ⁵ represents a fluorine atom: at least of R ² and R ³ One is a substituted aliphatic carboxyl acyl group having from 6 to 20 carbon atoms having (i) at least one halogen substituent and (ii) at least one substituent selected from the group consisting of halogen atoms, hydroxyl groups and aliphatic carboxyl acyl groups having 6 to 20 carbon atoms. Or at least one of R ² and R ³ represents a substituted aliphatic acyl group having 6 to 20 carbon atoms, substituted with one or more halogen-substituted aliphatic carboxyl acyloxy groups having 6 to 20 carbon atoms; The protected hydroxy group is an aliphatic carboxyl acyloxy group having 1 to 20 carbon atoms; Halogenated carboxyl acyloxy group having 2 to 6 carbon atoms; An alkoxy moiety having 1 to 6 carbon atoms and an acyl moiety having 2 to 6 alkoxy-substituted carboxyl acyloxy groups; The aromatic moiety is a carbocyclic aromatic carboxyl acyloxy group having 6 to 14 carbon atoms, which is unsubstituted or has one or more substituents selected from the group consisting of substituents (b) as defined below; Group of the formula Het-O- (Het represents a heterocyclic group having 5 or 5 membered rings of 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, wherein the heterocyclic group is unsubstituted or It has one or more substituents selected from the group consisting of substituents (c) as defined in; The groups of R ^a R ^b R ^c Si-O- (R ^a , R ^b and R ^c are each selected from the group consisting of alkyl groups having 1 to 6 carbon atoms and kybocyclic aryl groups having 6 to 10 carbon atoms, with the aryl group being unsubstituted Or at least one substituent selected from the group consisting of substituents (b) as defined below); An alkoxyalkoxy group having two alkoxy moieties which are the same or different and each having 1 to 6 carbon atoms; Aralkyloxy groups (alkyl groups having 1 to 6 carbon atoms are substituted with 1 to 3 aryl groups, the aryl group being unsubstituted or having one or more substituents selected from the group consisting of substituents (b) defined below); The alkoxy part is an alkoxycarbonyloxy group having 1 to 6 carbon atoms; Substituted alkoxycarbonyloxy group (alkoxy moiety has 1 to 6 carbon atoms, and the substituent is selected from the group consisting of substituents (d) as defined below); Alkenyloxy group whose alkenyl part is C2-C6; Alkenyloxy groups having 2 to 6 carbon atoms; An acyl moiety having 1 to 6 carbon atoms and a carboxy-substituted aliphatic carboxyl acyloxy group in which the acyl moiety is unsubstituted or has one or more hydroxy substituents; An acyl group is an acyloxy methoxycarbonyloxy group which is a carboxyl acyl group having 1 to 6 carbon atoms; The aryl moiety is a ring having 6 to 14 carbon atoms and has an unsubstituted or (aryl selenyl) ethoxy group having at least one substituent selected from the group consisting of substituents (b) defined below; An alkoxyalkoxy methoxy group having each alkoxy moiety of 1 to 6 carbon atoms; The alkoxy moiety has 1 to 6 carbon atoms and is substituted with one, two or three haloalkoxy substituents substituted with one or more halogen atoms; Haloethoxy groups in which the ethyl moiety is substituted with one or more halogen atoms; And an aralkyloxycarbonyloxy group (the aralkyl moiety consists of an alkyl group having 1 to 6 carbon atoms substituted with 1 to 3 aryl groups, wherein the aryl group is unsubstituted or consists of substituents (b) as defined below) Has one or more substituents selected from;

Substituent (a):

Halogen atom; An aryl group having 6 to 14 carbon atoms which is unsubstituted or has one or more substituents selected from the group consisting of substituents (b) defined below; An alkyl group having 1 to 6 carbon atoms is substituted with 1 to 3 aryl groups, and the aryl group is unsubstituted or an aralkyl group having one or more substituents selected from the group consisting of substituents (b) defined below; Hydroxyl group; Aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms; And a halogen-substituted aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms;

Substituent (b):

Halogen atom; An alkyl group having 1 to 6 carbon atoms; Halogen-substituted alkyl group having 1 to 6 carbon atoms; An alkoxy group having 1 to 6 carbon atoms; Nitro group; Alkoxycarbonyl group whose alkoxy part is C1-C6; An aryl group having 6 to 14 carbon atoms and having at least one substituent selected from the group consisting of a substituent (b) as defined herein, in addition to an unsubstituted or aryl group; Cyano group; An alkylenedioxy group having 1 to 4 carbon atoms; Divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms; A group of the formula -NR ^d R ^e (R ^d and R ^e are each selected from the group consisting of a hydrogen atom and an alkyl group having 1 to 6 carbon atoms); Haloalkoxy carbonyl groups having an alkoxy moiety of 1 to 6 carbon atoms; The aralkyl moiety is substituted with an aryl group having 1 to 3 carbon atoms, the aryl group being unsubstituted or consisting of an alkyl group having 1 to 6 carbon atoms having one or more substituents selected from the group consisting of substituents (b) as defined below Aralkyloxycarbonyl group; Groups of the formula -CO-NR ^d R ^e (where Rd and Re are as defined above); And aliphatic acyl groups having 1 to 20 carbon atoms;

Substituent (c):

Halogen atom; An alkyl group having 1 to 6 carbon atoms; Halogen-substituted alkyl groups having 1 to 6 carbon atoms; An alkoxy group having 1 to 6 carbon atoms; An aryl group having 6 to 14 carbon atoms which is unsubstituted or has at least one substituent selected from the group consisting of substituents (b) defined herein in addition to the aryl group; And oxygen atom;

Substituent (d):

Halogen atom; Groups of the formula R ^a R ^b R ^c Si-O- (R ^a , R ^b and R ^c are as defined above); And alkinoyl groups having 1 to 6 carbon atoms.

The present invention also provides a composition for treating, preventing, diagnosing and maintaining a patient suffering from or suffering from a disease or disorder resulting from a tumor or immune system deficiency, the composition comprising a pharmaceutically acceptable carrier, diluent or excipient. Effective amounts of one or more compounds of formula (I) or pharmaceutically acceptable salts thereof mixed together.

The present invention also provides a method of treating, preventing, diagnosing and maintaining an animal suffering from a disease or disorder resulting from a tumor or immune system deficiency, which method comprises one or more compounds of formula (I) or a pharmaceutically acceptable A salt thereof is a method of administering an effective amount to an animal, preferably a mammal, which may or may not be human.

In the following description referring to the group to be substituted, the number of substituents is not otherwise limited, and the number is limited only by the number of substitutable positions and steric hindrance. In this case, although not limited, generally 1 to 5 substituents (depending on the number of substitutable positions) are preferred and 1 to 3 are more preferred.

In the compounds of the present invention, R ¹ , R ⁴ or R ⁵ represent a protected hydroxy group and the protecting group is selected from the group consisting of the following groups:

[Aliphatic carboxyacyl group having 1 to 20 carbon atoms, more preferably 2 to 20 carbon atoms, most preferably 6 to 20 carbon atoms,

For example: alkylcarbonyl groups (formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, tridecanoyl, tetradecanoyl, palmitoyl And stearoyl group); Alkenylcarbonyl groups (acryloyl, methacryloyl and 2-methyl-2-butenoyl groups [particularly (E) -2-methyl-2-butenoyl isomer]); And alkynylcarbonyl groups (propiolyl groups); In the case of an unsaturated group, the minimum carbon number is 3;

The aliphatic acyl moiety may be any of the acyl groups exemplified above having 2 to 6 carbon atoms and is substituted with at least one halogen atom (eg chlorine, bromine, fluorine or iodine), preferably with 1 to 3 halogen atoms, Halogenated aliphatic carboxyacyl group having 2 to 6 carbon atoms; For example, chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl groups;

The alkoxy moiety has 1 to 6 carbon atoms and the acyl moiety has 2 to 6 alkoxy-substituted carboxyl acyl groups; There may be more than one alkoxy substituent but one substituent is preferred; Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy and hexyloxy groups, and examples of acyl groups are acetyl and propionyl , Butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl groups; Examples of alkoxy-substituted acyl groups include methoxyacetyl, ethoxyacetyl, propoxyacetyl, 3-methoxypropionyl, 4-methoxybutyryl, 5-methoxyvaleryl, 6-methoxyhexanoyl, 3- Ethoxypropionyl, 4-ethoxybutyryl, 5-ethoxyvaleryl, 6-ethoxyhelanoyl and 6-hexyloxyhelanoyl;

The aromatic moiety is a ring having 6 to 14 carbon atoms and is unsubstituted or at least one substituent selected from the group consisting of substituents (b) as defined above and exemplified below, preferably 1 to 4, more preferably 1 to 3 Carbocyclic aromatic carboxyacyl group which has a substituent of; Examples of the acyl group include unsubstituted groups (benzoyl, α-naphthoyl and β-naphthoyl groups); Halogen substituent (2-bromobenzoyl and 4-chlorobenzoyl group); Alkyl substituent (2,4,6-trimethylbenzoyl and 4-toluoyl group); Alkoxy substituent (4-anizoyl group); Nitro substituents (4-nitrobenzoyl and 2-nitrobenzoyl groups); Alkoxycarbonyl substituent (2- (methoxycarbonyl) benzoyl group); And an aryl substituent (4-phenylbenzoyl group);

Group of the formula Het- (Het represents a heterocyclic group having a 5 or 6 membered ring of 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and the heterocyclic group is unsubstituted or defined above One or more substituents selected from the group consisting of substituents (c) illustrated below, preferably only one substituent); Examples of unsubstituted groups include pyranyl, furyl, pyridyl, piperazinyl, piperidyl, tetrahydropyranyl (eg tetrahydropyran-2-yl), tetrahydrothiopyranyl (eg tetrahydrothio Pyran-2-yl), tetrahydofuranyl (eg tetrahydrofuran-2-yl) and tetrahydrothienyl (eg tetrahydrothien-2-yl) groups; Examples of substituted groups include 3-bromotetrahydropyran-2-yl, 4-methocitrahydropyran-4-yl and 4-methoxytetrahydrothien-4-yl groups; Among these, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuryl and tetrahydrothienyl groups and substituted equivalents are preferable;

Groups of formula R ^a R ^b R ^c Si- (R ^a , R ^b and R ^c are each alkyl groups having 1 to 6 carbon atoms (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl , Isopentyl, 2-methylbutyl, hexyl, isohexyl and 2-methylpentyl groups) and a carbocyclic aryl group (preferably a phenyl group) having 6 to 10 carbon atoms, wherein the aryl group is unsubstituted Or one or more substituents selected from the group consisting of the substituents (b) defined above and exemplified below (same as the aryl groups exemplified above); examples of substituted silyl groups include trialkylsilyl groups (eg trimethylsilyl Triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl groups) and 1 or 2 aryl groups and the corresponding 2 or 1 alkyl groups Substituted trisubstituted silyl groups (e.g. diphenylmethylsilyl, Diphenyl-t-butylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups);

Alkoxy and alkyl groups each having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms; Examples of the alkyl group are as shown above and examples of the alkoxy are the same as the alkoxy group exemplified in the alkoxy substituted acyl group; For example, an alkoxymethyl group (methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, pentyloxymethyl, isopentyloxymethyl, 2- Methylbutoxymethyl, hexyloxymethyl, isohexyloxymethyl and 2-methylpentyloxymethyl group); Alkoxyethyl groups (eg 1- and 2-methoxyethyl, 1- and 2-ethoxyethyl, 1- and 2-propoxyethyl, 1- and 2-isopropoxyethyl, 1- and 2-butoxyethyl , 1- and 2-isobutoxyethyl, 1- and 2-sec-butoxyethyl, 1- and 2-pentyloxyethyl, 1- and 2-isopentyloxyethyl, 1- and 2-methylbutoxyethyl, 1- and 2-hexyloxyethyl, 1- and 2-isohexyloxyethyl and 1- and 2- (2-methylpentyloxy) ethyl groups); And alkoxypropyl groups (1,1-dimethyl-1-methoxymethyl, methoxypropyl and 1-methyl-1-methoxyethyl group);

An alkyl group having 1 to 6 carbon atoms is substituted with an aryl group having 1 to 3, and the aryl group is unsubstituted or an aralkyl group having one or more substituents selected from the group consisting of the substituents (b) defined above and exemplified below; The aryl group is preferably substituted with 1 to 4, more preferably 1 to 3 substituents; For example, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthryl Methyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanophenyldiphenylmethyl, bis (2-nitrophenyl) methyl and piperonyl groups;

An alkoxycarbonyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms in the alkoxy moiety; For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyl Oxycarbonyl, isopentyloxycarbonyl, 2-methylbutoxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl and 2-methylpentyloxycarbonyl group;

Substituted alkoxy having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and a substituent selected from the group consisting of substituents (d) as defined above and exemplified below, preferably substituted with a halogen atom or a silyl group Carbonyl group; In principle, there is no limit to the number of substituents except when the number of positions that can be substituted is specified, but in general, one to three substituents are preferable. The alkoxycarbonyl moiety can be any of the unsubstituted alkoxy carbonyl groups exemplified above, examples of the substituted group include 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl group;

Alkenyloxycarbonyl groups having 2 to 6 carbon atoms, preferably 2 to 4, more preferably 2 or 3 carbon atoms; For example, there are vinyloxycarbonyl and allyloxycarbonyl group;

Alkenyl groups having 2 to 6 carbon atoms, especially 2 to 4 carbon atoms, such as vinyl and allyl groups; A carboxy-substituted aliphatic carboxyl acyl group having 1 to 6 carbon atoms (or 3 to 6 carbon atoms if unsaturated) in the acyl moiety and substituted only with a carboxy group or also having one or more hydroxy substituents; Examples of the acyl group include acyl groups having 1 to 6 carbon atoms as illustrated below, and specific examples of substituted groups include 3-carboxypropionyl, 3-carboxy-3-hydroxypropionyl and 3-carboxycryloyl group There is;

An acyl group is an acyloxy methoxycarbonyl group which is a carboxyl acyl group having 1 to 6 carbon atoms; The acyl moiety may be any of acyl groups having 1 to 6 carbon atoms as illustrated below; Specific examples of such a group include pivaloyloxymethoxycarbonyl group;

The aralkyl moiety contains an alkyl group having 1 to 6 carbon atoms and substituted with 1 to 3 aryl groups, wherein the aryl group is unsubstituted or at least one selected from the group consisting of substituents (b) as defined above and exemplified below An aralkyloxycarbonyl group having a substituent, preferably having a 1 or 2 lower alkoxy or nitro substituent; Aralkyl moieties of such groups are as exemplified above, examples of such aralkyloxycarbonyl groups are benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2- Nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups.

Each carbon number of the alkoxy moiety is 1 to 6, preferably 1 to 4, each being the same or different, and the total carbon number in the two alkoxy moieties is preferably not more than 7, more preferably no more than 4 an alkoxyalkoxy methyl group; Examples of the alkoxy group are as described above, and examples of the alkoxyalkoxymethyl group include 2-methoxyethoxymethyl and 2-ethoxyethoxymethyl group;

1, 2 or 3, preferably 1 or 2 haloalkoxy substituents having 1 to 6 carbon atoms and substituted with one or more halogen atoms (e.g., chlorine, fluorine, bromine or iodine atoms, preferably chlorine atoms) A methyl group substituted with; The number of halogen substituents is not limited except that the number of substitutable positions is limited, but in general, it is preferable to have 1 to 3 halogen substituents in each alkoxy group. Examples of such groups include 2,2,2, -trichloroethoxymethyl and bis (2-chloroethoxy) methyl groups;

Haloethyl groups in which the ethyl moiety is substituted with one or more halogen atoms (eg, chlorine, fluorine, bromine or iodine atoms, preferably chlorine or bromine atoms); There is no limitation on the number of halogen substituents except in the case where the number of positions which can be substituted is limited, but generally it is preferable to have 1 to 3 halogen substituents. Examples of such groups include 2,2,2-trichloroethyl groups;

The aryl group is a carbocyclic aryl group having 6 to 14 carbon atoms, and the aryl group is unsubstituted or has one or more substituents selected from the group consisting of the substituents (b) defined above and exemplified below (eg, aryl The group is as exemplified above, and a substituted or preferably unsubstituted phenyl group is preferable) arylselenylethyl group; An example of such a preferred group is a 2- (phenylcerenyl) ethyl group.

If R ² or R ³ represents an aliphatic carboxyl acyl group having 6 to 20 carbon atoms, then the acyl group has one or more substituents selected from the group consisting of substituents (a) which are unsubstituted or defined above and detailed below; Acyl groups are straight or branched groups, and examples of unsubstituted groups are hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, 4-methyldecanoyl, 9-methyldecanoyl, 4- Ethylnonanoyl, 4,8-dimethylnonanoyl, dodecanoyl (lauroyl), tridecanoyl, tetradecanoyl (myristoyl), pentadecanoyl, hexadecanoyl (palmitoyl), heptadeca Noyl, 2-methylhexadecanoyl, 15-methylhexadecanoyl, 14,14-dimethylpentadecanoyl, octadecanoyl (stearoyl), 16-methylheptadecanoyl, nonadecanoyl, 2-methyloctadeca There are noil and icosanoyl groups. Among them, a linear or branched aliphatic acyl group having 10 to 16 carbon atoms is preferable, and an even number of carbon atoms in this range, that is, 10, 12, 14 or 16 is more preferable.

If the substituent (a) is an aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms or a halogen-substituted aliphatic carboxyacyloxy group having 6 to 20 carbon atoms, the acyloxy group corresponds to the acyl group exemplified above with respect to R ² and R ³ . It may be an acyloxy group. In the case of halogen substituents, the halogen substituents may be fluorine, chlorine, bromine or iodine atoms but the preferred halogen substituents are fluorine atoms.

If the substituent (a) is a halogen atom, it may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom, more preferably a fluorine atom.

If substituent (a) is an aryl group, it is a ring having 6 to 14 carbon atoms and is a carbocyclic group which may be unsubstituted or may have one or more substituents (b) as defined above and exemplified below. When the group is substituted, there is no specific limit to the number of substituents except when the number of positions that can be substituted is limited (5 for phenyl group and 7 for naphthyl group), but generally 1 to 4 desirable. Examples of unsubstituted groups are phenyl, α-naphthyl and β-naphthyl groups. Examples of substituted groups include halogen-substituted aryl groups (2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl , 3-bromophenyl, 4-bromophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3 , 5-dibromophenyl, 2,5-dibromophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,3,6-trifluorophenyl, 2,3,4-trifluoro Rophenyl, 3,4,5-trifluorophenyl, 2,5,6-trifluorophenyl, 2,4,6-trifluorophenyl, 2,3,6-tribromophenyl, 2,3 , 4-tribromophenyl, 3,4,5-tribromophenyl, 2,5,6-trichlorophenyl, 2,4,6-trichlorophenyl, 1-fluoro-β-naphthyl, 2 -Fluoro-α-naphthyl, 3-fluoro-α-naphthyl, 1-chloro-β-naphthyl, 2-chloro-α-naphthyl, 3-bromo-α-naphthyl, 3,8 -Difluoro-α-naphthyl, 2,3-difluoro-α-naphthyl, 7,8-difluoro-α- Propyl, 5,6-difluoro-α-naphthyl, 3,8-dichloro-α-naphthyl, 2,3-dichloro-α-naphthyl, 4,8-dibromo-α-naphthyl, 5,6-dibromo-α-naphthyl, 2,3,6-trifluoro-α-naphthyl ,, 2,3,4-trifluoro-α-naphthyl, 3,4,5- Trifluoro-α-naphthyl, 4,5,6-trifluoro-α-naphthyl and 2,4,8-trifluoro-α-naphthyl groups); Aryl groups substituted with one or more haloalkyl groups (2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trichloromethylphenyl, 3-dichloromethylphenyl 4-trichloromethylphenyl, 2-tri Libromomethylphenyl, 3-dibromomethylphenyl, 4-dibromomethylphenyl, 3,5-bis (trifluoromethyl) phenyl, 2,5-bis (trifluoromethyl) phenyl, 2,6-bis ( Trifluoromethyl) phenyl, 2,4-bis (trifluoromethyl) phenyl, 3,5-bis (tribromomethyl) phenyl, 2,5-bis (dibromomethyl) phenyl, 2,6- Bis (dichloromethyl) phenyl, 2,4-bis (dichloromethyl) phenyl, 2,3,6-tris (trifluoromethyl) phenyl, 2,3,4-tris (trifluoromethyl) phenyl, 3, 4,5-tris (trifluoromethyl) phenyl, 2,5,6-tris (trifluoromethyl) phenyl, 2,4,6-tris (trifluoromethyl) phenyl, 2,3,6-tris (Tribromomethyl) phenyl, 2,3,4-tris (dibromethyl) phenyl, 3,4,5-tris (tribromomethyl) phenyl, 2,5,6-tris (dichloromethyl) phenyl, 2,4,6-tris (dichloromethyl) phenyl, 1-trifluoromethyl-β- Naphthyl, 2-trifluoromethyl-α-naphthyl, 3-trifluoromethyl-α-naphthyl, 1-trichloromethyl-β-naphthyl, 2-dichloromethyl-α-naphthyl, 3- Tribromomethyl-α-naphthyl, 3,8-bis (trifluoromethyl) -α-naphthyl, 2,3-bis (trifluoromethyl) -α-naphthyl, 4,8-bis ( Trifluoromethyl) -α-naphthyl, 5,6-bis (trifluoromethyl) -α-naphthyl, 3,8-bis (trichloromethyl) -α-naphthyl, 2,3-bis ( Dichloromethyl) -α-naphthyl, 4,8-bis (dibromomethyl) -α-naphthyl, 5,6-bis (tribromomethyl) -α-naphthyl, 2,3,6-tris (Trifluoromethyl) -α-naphthyl ,, 2,3,4-tris (trifluoromethyl) -α-naphthyl, 3,4,5-tris (trifluoromethyl) -α-naphthyl , 4,5,6-tris (trifluoromethyl) -α-naphthyl and 2,4,8-tris ( Trifluoromethyl) -α-naphthyl, group); Aryl groups substituted with one or more alkylies (2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl , 3,5-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,4-dimethylphenyl, 3,5-dibutylphenyl, 2,5-dipentylphenyl, 2,6-di Propylmethylphenyl, 2,4-dipropylphenyl, 2,3,6-trimethylphenyl, 2,3,4-trimethylphenyl, 3,4,5-trimethylphenyl, 2,5,6-trimethylphenyl, 2,4 , 6-trimethylphenyl, 2,3,6-tributylphenyl, 2,3,4-tripentylphenyl, 3,4,5-tributylphenyl, 2,5,6-tripropylmethylphenyl, 2,4, 6-tripropylphenyl, 1-methyl-β-naphthyl, 2-methyl-α-naphthyl, 3-methyl-α-naphthyl, 1-ethyl-β-naphthyl, 2-propyl-α-naph Tyl, 3-butyl-α-naphthyl, 3,8-dimethyl-α-naphthyl, 2,3-dimethyl-α-naphthyl, 4,8-dimethyl-α-naphthyl, 5,6-dimethyl- α-naphthyl, 3,8-diethyl-α-naphthyl, 2,3-dipropyl-α-naphthyl, 4,8-dipentyl-α-naphthyl, 5,6-dibu Tyl-α-naphthyl, 2,3,6-trimethyl-α-naphthyl, 2,3,4-trimethyl-α-naphthyl, 3,4,5-trimethyl-α-naphthyl, 4,5, 6-trimethyl-α-naphthyl and 2,4,8-trimethyl-α-naphthyl groups); Aryl groups substituted with one or more amino groups (2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 3,5-diaminophenyl, 2,5-diaminophenyl, 2,6-diaminophenyl, 2, 4-diaminophenyl, 2,3,6-triaminophenyl, 2,3,4-triaminophenyl, 3,4,5-triaminophenyl, 2,5,6-triaminophenyl, 2,4, 6-triaminophenyl, 1-amino-β-naphthyl, 2-amino-α-naphthyl, 3-amino-α-naphthyl, 3,8-diamino-α-naphthyl, 2,3-dia Mino-α-naphthyl, 4,8-diamino-α-naphthyl, 5,6-diamino-α-naphthyl, 2,3,6-triamino-α-naphthyl, 2,3,4 -Triamino-α-naphthyl, 3,4,5-triamino-α-naphthyl, 4,5,6-triamino-α-naphthyl and 2,4,8-triamino-α-naphthyl groups ); Aryl groups substituted with one or more nitro groups (2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-dinitrophenyl, 2,5-dinitrophenyl, 2,6-dinitrophenyl, 2, 4-dinitrophenyl, 2,3,6-trinitrophenyl, 2,3,4-trinitrophenyl, 3,4,5-trinitrophenyl, 2,5,6-trinitrophenyl, 2,4,6-trinitrophenyl , 1-nitro-β-naphthyl, 2-nitro-α-naphthyl, 3-nitro-α-naphthyl, 3,8-dinitro-α-naphthyl, 2,3-dinitro-α-naph Teal, 4,8-dinitro-α-naphthyl, 5,6-dinitro-α-naphthyl, 2,3,6-trinitro-α-naphthyl, 2,3,4-trinitro-α-naph Tetra, 3,4,5-trinitro-α-naphthyl, 4,5,6-trinitro-α-naphthyl and 2,4,8-trinitro-α-naphthyl groups); Aryl groups substituted with one or more cyano groups (2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3,5-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyano Phenyl, 2,4-dicyanophenyl, 2,3,6-tricyanophenyl, 2,3,4-tricyanophenyl, 3,4,5-tricyanophenyl, 2,5,6-tricyanophenyl, 2,4,6-tricyanophenyl, 1-cyano-β-naphthyl, 2-cyano-α-naphthyl, 3-cyano-α-naphthyl, 3,8-dicyano-α-naph Teal, 2,3-dicyano-α-naphthyl, 4,8-dicyano-α-naphthyl, 5,6-dicyano-α-naphthyl, 2,3,6-tricyano-α-naph Teal, 2,3,4-tricyano-α-naphthyl, 3,4,5-tricyano-α-naphthyl, 4,5,6-tricyano-α-naphthyl and 2,4,8- Tricyano-α-naphthyl group); Aryl groups substituted with one or more aliphatic acyl groups (2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 3,5-diacetylphenyl, 2,5-diacetylphenyl, 2,6-diacetylphenyl, 2 , 4-diacetylphenyl, 2,3,6-tripropionylphenyl, 2,3,4-tripropionylphenyl, 3,4,5-tripropionylphenyl, 2,5,6-tributyrylphenyl , 2,4,6-tributyrylphenyl, 1-acetyl-β-naphthyl, 2-acetyl-α-naphthyl, 3-acetyl-α-naphthyl, 3,8-diacetyl-α-naphthyl , 2,3, -dipropionyl-α-naphthyl, 4,8-dibutyryl-α-naphthyl, 5,6-dibutyryl-α-naphthyl, 2,3,6-triacetyl- α-naphthyl, 2,3,4-triacetyl-α-naphthyl, 3,4,5-tripropionyl-α-naphthyl, 4,5,6-tributyryl-α-naphthyl and 2 , 4,8-tributyryl-α-naphthyl group); Aryl groups substituted with one or more carboxy groups (2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3,5-dicarboxyphenyl, 2,5-dicarboxyphenyl, 2,6-dicarboxyphenyl and 2, 4-dicarboxyphenyl group); Aryl groups substituted with one or more carbamoyl groups (2-carbamoylphenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, 3,5-dicarbamoylphenyl, 2,5-dicarbamoylphenyl, 2,6-dicarbamoylphenyl and 2,4-dicarbamoylphenyl group); And aryl groups (3,4-methylenedioxyphenyl groups) substituted with alkylenedioxy groups.

If the substituent (a) is an aralkyl group, the alkyl portion has 1 to 6 carbon atoms, more preferably 1 to 4, even more preferably 1 to 3, and also 1 to 3, more preferably one aryl group. It is. When there is more than one aryl group they may be the same or different.

Preferred aryl groups are as listed above, preferred alkyl groups are as exemplified above but more preferred are methyl, ethyl and propyl groups, most preferred are methyl and ethyl groups. Specific examples of such aralkyl groups are as follows: unsubstituted groups (α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 1 -Phenylethyl, 2-phenylethyl (phenethyl), 2- (α-naphthyl) ethyl, 2- (β-naphthyl) ethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1- (α- or β-naphthyl) propyl, 2- (α- or β-naphthyl) propyl, 3- (α- or β-naphthyl) propyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenyl Butyl, 4-phenylbutyl, 1- (α- or β-naphthyl) butyl, 2- (α- or β-naphthyl) butyl, 3- (α- or β-naphthyl) butyl, 4- (α Or β-naphthyl) butyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1- (α- or β-naphthyl) pentyl, 2- ( α- or β-naphthyl) pentyl, 3- (α- or β-naphthyl) pentyl, 4- (α- or β-naphthyl) pentyl, 5- (α- or β-naphthyl) pentyl, 1 -Phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5- Nylhexyl, 6-phenylhexyl, 1- (α- or β-naphthyl) hexyl, 2- (α- or β-naphthyl) hexyl, 3- (α- or β-naphthyl) hexyl, 4- ( α- or β-naphthyl) hexyl, 5- (α- or β-naphthyl) hexyl and 6- (α- or β-naphthyl) hexyl groups), groups substituted with one or more halogen atoms (2-fluoro Benzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3,5 -Difluorobenzyl, 2,5-difluorophenethyl, 2,6-difluorobenzyl, 2,4-difluorophenethyl, 3,5-dibromobenzyl, 2,5-dibro Mofenethyl, 2,6-dichlorobenzyl, 2,4-dichlorophenethyl, 2,3,6-trifluorobenzyl, 2,3,4-trifluorophenethyl, 3,4,5-trifluoro Benzyl, 2,5,6, -trifluoropentyl, 2,4,6-trifluorobenzyl, 2,3,6-tribromophenethyl, 2,3,4-tribromobenzyl, 3, 4,5-tribromophenethyl, 2,5,6-trichlorobenzyl, 2,4,6-trickle Lofenethyl, (1-fluoro-β-naphthyl) methyl, 2- (2-fluoro-α-naphthyl) ethyl, (3-fluoro-α- or β-naphthyl) methyl, 2- ( 1-chloro-β-naphthyl) ethyl, (2-chloro-α-naphthyl) methyl, 2- (3-bromo-α- or β-naphthyl) ethyl, (3,8-difluoro- α- or β-naphthyl) methyl, 2- (2,3-difluoro-α-naphthyl) ethyl, (4,8-difluoro-α- or β-naphthyl) methyl, 2- ( 5,6-difluoro-α- or β-naphthyl) ethyl, (3,8-dichloro-α- or β-naphthyl) methyl, 2- (2,3-dichloro-α-naphthyl) ethyl , (4,8-dibromo-α- or β-naphthyl) methyl, 2- (5,6-dibromo-α- or β-naphthyl) ethyl, (2,3,6-trifluoro Rho-α-naphthyl) methyl, 2- (2,3,4-trifluoro-α- or β-naphthyl) ethyl, (3,4,5-trifluoro-α- or β-naphthyl ) Methyl, 2- (4,5,6-trifluoro-α- or β-naphthyl) ethyl, (2,4,8-trifluoro-α- or β-naphthyl) methyl, bis (2 -Fluorophenyl) methyl, α- (3-fluorophenyl) Vagina, bis (4-fluorophenyl) methyl, α- (4-fluorophenyl) benzyl, bis (2-chlorophenyl) methyl, bis (3-chlorophenyl) methyl, bis (4-chlorophenyl) methyl, α- (4-chlorophenyl) benzyl, α- (2-bromophenyl) benzyl, α- (3-bromophenyl) benzyl, bis (4-bromophenyl) methyl, bis (3,5-difluoro Rophenyl) methyl, bis (2,5-difluorophenyl) methyl, bis (2,6-difluorophenyl) methyl, α- (2,4-difluorophenyl) benzyl, bis (3,5 -Dibromophenyl) methyl, α- (2,5-dibromophenyl) benzyl, α- (2,6-dichlorophenyl) benzyl, bis (2,4-dichlorophenyl) methyl and bis (2,3 , 6-trifluorophenyl) methyl group); Aralkyl groups substituted with one or more haloalkyl groups (2-trifluoromethylbenzyl, 3-trifluoromethylphenethyl, 4-trifluoromethylbenzyl, 2-trichloromethylphenethyl, 3-dichloromethylbenzyl, 4 -Trichloromethylphenethyl, 2-tribromomethylbenzyl, 3-dibromomethylphenethyl, 4-dibromomethylbenzyl, 3,5-bis (trifluoromethyl) phenethyl, 2,5- Bis (trifluoromethyl) benzyl, 2,6-bis (trifluoromethyl) phenethyl, 2,4-bis (trifluoromethyl) benzyl, 3,5-bis (tribromomethyl) phenethyl, 2,5-bis (dibromomethyl) benzyl, 2,6-bis (dichloromethyl) phenethyl, 2,4-bis (dichloromethyl) benzyl, 2,3,6-tris (trifluoromethyl) phen Netyl, 2,3,4-tris (trifluoromethyl) benzyl, 3,4,5-tris (trifluoromethyl) phenethyl, 2,5,6-tris (trifluoromethyl) benzyl, 2, 4,6-tris (trifluoromethyl) phenethyl, 2,3,6-tris (tribromomethyl) benzyl, 2,3 , 4-tris (dibromomethyl) phenethyl, 3,4,5-tris (tribromomethyl) benzyl, 2,5,6-tris (dichloromethyl) phenethyl, 2,4,6-tris ( Dichloromethyl) benzyl, 2- (1-trifluoromethyl-β-naphthyl) ethyl, (2-trifluoromethyl-α-naphthyl) methyl, 2- (3-trifluoromethyl-α- or β-naphthyl) ethyl, (1-trichloromethyl-α- or β-naphthyl) methyl, 2- (2-dichloromethyl) -α-naphthyl) ethyl, (3-tribromomethyl-α- Or β-naphthyl) methyl, 2- [3,8-bis (trifluoroolmethyl) -α- or β-naphthyl] ethyl, [2,3-bis (trifluoromethyl) -α-naphthyl ] Methyl, 2- [4,8-bis (trifluoromethyl) -α- or β-naphthyl] ethyl, [5,6-bis (trifluoromethyl) -α- or β-naphthyl] methyl , 2- [3,8-bis (trichloromethyl) -α- or β-naphthyl] ethyl, [2,3-bis (dichloromethyl-α-naphthyl] methyl, 2- [4,8-bis (Dibromomethyl-α- or β-naphthyl] ethyl, [5,6-bis (tribromomethyl) -α- Is β-naphthyl] methyl, 2- [2,3,6-tris (trifluoromethyl) -α- or β-naphthyl] ethyl, [2,3,4-tris (trifluoromethyl-α -Naphthyl] methyl, 2- [3,4,5-tris (trifluoromethyl) -α- or β-naphthyl] ethyl, [4,5,6-tris (trifluoromethyl) -α- Or β-naphthyl] methyl, [2,4,8-tris (trifluoromethyl-α-naphthyl] methyl, bis (4-trifluoromethylphenyl) methyl, α- (4-trifluoromethylphenyl) Benzyl, bis (2-trichloromethylphenyl) methyl, bis (3-trichloromethylphenyl) methyl, bis (4-trichloromethylphenyl) methyl, α- (2-tribromomethylphenyl) benzyl, α- (3-t Libromomethylphenyl) benzyl, bis (4-tribromomethylphenyl) methyl, bis [3,5-bis (trifluoromethyl) phenyl] methyl, bis [2,5-bis (trifluoromethyl) phenyl] methyl , Bis [2,6-bis (trifluorophenyl) phenyl] methyl, α- [2,4-bis (trifluoromethyl) phenyl] benzyl, bis [3,5-bis (tribromo Methyl) phenyl] methyl, α- [2,5-bis (tribromomethyl) phenyl] benzyl, α- [2,6-bis (trichloromethyl) phenyl] benzyl, bis [2,4-bis (trichloro Romethyl) phenyl] methyl and bis [2,3,6-tris (trifluoromethyl) phenyl] methyl group); Aralkyl groups substituted with one or more alkylies (2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methylphenethyl, 4-methylphenethyl, 2-ethylbenzyl, 3-propylphenethyl, 4-ethyl Benzyl, 2-burylphenethyl, 3-pentylbenzyl, 4-pentylphenethyl, 3,5-dimethylbenzyl, 2,5-dimethylphenethyl, 2,6-dimethylbenzyl, 2,4-dimethylphenethyl, 3 , 5-dibutylbenzyl, 2,5-dipentylphenethyl, 2,6-dipropylbenzyl, 2,4-dipropylphenethyl, 2,3,6-trimethylbenzyl, 2,3,4-trimethylphenethyl , 3,4,5-trimethylbenzyl, 2,4,6-trimethylbenzyl, 2,5,6-trimethylphenethyl, 2,3,6-tributylphenethyl, 2,3,4-tripentylbenzyl, 3,4,5-tributylphenethyl, 2,5,6-tripropylbenzyl, 2,4,6-tripropylphenethyl, (1-methyl-β-naphthyl) methyl, 2- (2-methyl -α-naphthyl) ethyl, (3-methyl-α- or β-naphthyl) methyl, 2- (1-ethyl-β-naphthyl) ethyl, (2-propyl-α-naphthyl) methyl, 2 -(3-butyl-α- or β-naphthyl) ethyl, (3,8-dimethyl-α- or β-naphthyl) methyl, 2- (2,3-dimethyl- -Naphthyl) ethyl, (4,8-dimethyl-1-α- or β-naphthyl) methyl, 2- (5,6-dimethyl-α- or β-naphthyl) ethyl, (3,8-di Ethyl-α- or β-naphthyl) methyl, (2,3-dipropyl-α-naphthyl) methyl, 2- (4,8-dipentyl-α- or β-naphthyl) ethyl, (5, 6-dibutyl-α- or β-naphthyl) methyl, (2,3,6-trimethyl-α- or β-naphthyl) methyl, 2- (2,3,4-trimethyl-α- or β- Naphthyl) ethyl, (3,4,5-trimethyl-1- (α- or β-naphthyl)) methyl, (4,5,6-trimethyl- (α- or β-naphthyl)) methyl, ( 2,4,8-trimethyl-1- (α- or β-naphthyl)) methyl, bis (2-methylphenyl) methyl, α- (3-methylphenyl) benzyl, bis (4-methylphenyl) methyl, α- ( 4-methylphenyl) benzyl, bis (2-ethylphenyl) methyl, bis (3-ethylphenyl) methyl, bis (4-ethylphenyl) methyl, α- (2-propylphenyl) benzyl, α- (3-propylphenyl ) Benzyl, bis (4-propylphenyl) methyl, bis (3,5-dimethylphenyl) methyl, bis (2,5-dimethylphenyl) methyl, bis (2,6-dimethylphenyl) methyl, α- (2, 4-dimethylphenyl) Jill, Bis (3,5-dipropenylphenyl) methyl, α- (2,5-dipropylphenyl) benzyl, α- (2,6-diethylphenyl) benzyl, bis (2,4-diethylphenyl) Methyl and bis (2,3,6-trimethylphenyl) methyl group); Aralkyl groups substituted with one or more amino groups (2-aminophenethyl, 3-aminobenzyl, 4-aminophenethyl, 3,5-diaminobenzyl, 2,5-diaminophenethyl, 2,6-diaminobenzyl , 2,4-diaminophenethyl, 2,3,6-triaminobenzyl, 2,3,4-triaminophenethyl, 3,4,5-triaminobenzyl, 2,5,6-triaminophen Netyl, 2,4,6-triaminobenzyl, (1-amino-β-naphthyl) methyl, 2- (2-amino-α-naphthyl) ethyl, (3-amino-α- or β-naphthyl ) Methyl, (3,8-diamino-α- or β-naphthyl) methyl, 2- (2,3-diamino-1- (α- or β-naphthyl)) ethyl, (4,8- Diamino-α- or β-naphthyl) methyl, (5,6-diamino-1- (α- or β-naphthyl)) methyl, 2- (2,3,6-triamino-α-naph Ethyl), (2,3,4-triamino-αnaphthyl) methyl, (3,4,5-triamino-α- or β-naphthyl) methyl, 2- (4,5,6-tri Amino-α- or β-naphthyl) ethyl, (2,4,8-triamino-α-naphthyl) methyl, bis (2-aminophenyl) methyl, α- (3-aminophenyl ) Benzyl, bis (4-aminophenyl) methyl, α- (4-aminophenyl) benzyl, bis (3,5-diaminophenyl) methyl, bis (2,5-diaminophenyl) methyl, bis (2, 6-diaminophenyl) methyl, α- (2,4-diaminophenyl) benzyl and bis (2,3,6-triaminophenyl) methyl group; an aralkyl group substituted with one or more nitro groups (2-nitrophenethyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-nitrophenethyl, 3,5-dinitrobenzyl, 2,5-dinitrophenethyl, 2,6-dinitrobenzyl, 2,4-dinitrophenethyl, 2,3,6-trinitrobenzyl, 2,3,4-trinitrophenethyl, 3,4,5-trinitrobenzyl, 2,5,6-trinitrophennityl, 2,4,6-trinitrobenzyl, Nitro-β-naphthyl) methyl, (2-nitro-α-naphthyl) ethyl, (3-nitro-α- or β-naphthyl) methyl, (3,8-dinitro-α- or β-naph Methyl), 2- (2,3-dinitro-α-naphthyl) ethyl, (4,8-dinitro-α- or β-naphthyl) methyl, (5,6-dinitro-α- or β-naphthyl) methyl, 2- (2,3,6-trinitro-α- Is β-naphthyl) ethyl, (2,3,4-trinitro-α-naphthyl) methyl, (3,4,5-trinitro-α- or β-naphthyl) methyl, 2- (4,5, 6-trinitro-α- or β-naphthyl) ethyl, (2,4,8-trinitro-α-naphthyl) methyl, bis (2-nitrophenyl) methyl, α- (3-nitrophenyl) benzyl, bis (4-nitrophenyl) methyl, α- (4-nitrophenyl) benzyl, bis (3,5-dinitrophenyl) methyl, bis (2,5-dinitrophenyl) methyl, bis (2,6-dinitro Phenyl) methyl, α- (2,4-dinitrophenyl) benzyl and bis (2,3,6-trinitrophenyl) methyl group); Aralkyl groups substituted with one or more cyano groups (2-cyanophenethyl, 3-cyanobenzyl, 4-cyanobenzyl, 4-cyanophenyldiphenylmethyl, 4-cyanophenethyl, 3,5-dicyanobenzyl , 2,5-dicyanophenethyl, 2,6-dicyanobenzyl, 2,4-dicyanophenethyl, 2,3,6-tricyanobenzyl, 2,3,4-tricyanofetetyl, 3,4 , 5-tricyanobenzyl, 2,5,6-tricyanophenethyl, 2,4,6-tricyanobenzyl, (1-cyano-β-naphthyl) methyl, (3-cyano-α- or β -Naphthyl) methyl, (3,8-dicyano-α- or β-naphthyl) methyl, 2- (2,3-dicyano-α-naphthyl) ethyl, (4,8-dicyano-α Or β-naphthyl) methyl, (5,6-dicyano-α- or β-naphthyl) methyl, 2- (2,3,6-tricyano-α-naphthyl) ethyl, (2,3 , 4-tricyano-α-naphthyl) methyl, (3,4,5-tricyano-α- or β-naphthyl) methyl, 2- (4,5,6-tricyano-α- or β- Naphthyl) ethyl, (2,4,8-tricyano-α-naphthyl) methyl, bis (2-cyanophenyl) methyl, α- (3-cyanophenyl) Benzyl, bis (4-cyanophenyl) methyl, α- (4-cyanophenyl) benzyl, bis (3,5-dicyanophenyl) methyl, bis (2,5-dicyanophenyl) methyl, bis (2 , 6-dicyanophenyl) methyl, α- (2,4-dicyanophenyl) benzyl and bis (2,3,6-tricyanophenyl) methyl group); Aralkyl groups substituted with one or more aliphatic acyl groups (2-acetylphenethyl, 3-acetylbenzyl, 4-acetylphenethyl, 3,5-diacetylbenzyl, 2,5-diacetylphenethyl, 2,6-diacetyl Benzyl, 2,4-diacetylphenethyl, 2,3,6-tripropionylbenzyl, 2,3,4-tripropionylphenethyl, 3,4,5-tripropionylbenzyl, 2,5,6 -Tributyrylphenethyl, 2,4,6-tributyrylbenzyl, (1-acetyl-β-naphthyl) methyl, 2- (2-acetyl-α-naphthyl) ethyl, (3-acetyl-α- Or β-naphthyl) methyl, (3,8-diacetyl-1- (α- or β-naphthyl) methyl, 2- (2,3-dipropionyl-α-naphthyl) ethyl, (4, 8-dibutyryl-α- or β-naphthyl) methyl, (5,6-dibutyryl-α- or β-naphthyl) methyl, 2- (2,3,6-triacetyl-α- or β-naphthyl) ethyl, (2,3,4-triacetyl-α- or β-naphthyl) methyl, (3,4,5-tripropionyl-α- or β-naphthyl) methyl, 2- (4,5,6-tributyryl-1- (α- or β-naphthyl)) ethyl, (2,4,8-tributyryl-α-naphthyl) methyl, bis (2-acetylphenyl) methyl, α- (3-acetylphenyl) benzyl, bis (4-acetylphenyl) methyl, α- (4-acetylphenyl) benzyl, bis (2-propionylphenyl) methyl, bis (3 -Propionylphenyl) methyl, bis (4-propionylphenyl) methyl, α- (2-butyrylphenyl) benzyl, α- (3-butyrylphenyl) benzyl, bis (4-butyrylphenyl) methyl, bis (3,5-diacetylphenyl) metal, bis (2,5-diacetylphenyl) methyl, bis (2,6-diacetylphenyl) methyl, α- (2,4-diacetylphenyl) benzyl, bis ( 3,5-dibutyrylphenyl) methyl, α- (2,5-dibutylphenyl) benzyl, α- (2,6-dipropionylphenyl) benzyl, bis (2,4-dipropionylphenyl) methyl And bis (2,3,6-triacetylphenyl) methyl group; aralkyl groups substituted with one or more carboxy groups (2-carboxyphenethyl, 3-carboxybenzyl, 4-carboxyphenethyl, 3,5-dicarboxybenzyl, 2,5-dicarboxyphenethyl, 2,6-dicarboxybenzyl, 2,4-dicarboxyphenethyl, bis (2-carboxyphenyl) methyl, α- (3-carboxyphenyl) ben , Bis (4-carboxyphenyl) metal, α- (4-carboxyphenyl) benzyl, bis (3,5-dicarboxyphenyl) methyl, bis (2,5-dicarboxyphenyl) methyl, bis (2,6- Dicarboxyphenyl) methyl, α- (2,4-dicarboxyphenyl) benzyl and bis (2,3,6-tricarboxyphenyl) methyl group); Aralkyl groups substituted with one or more carbamoyl groups (2-carbamoylbenzyl, 3-carbamoylphenethyl, 4-carbamoylbenzyl, 3,5-dicarbamoylfetetyl, 2,5-dicarbomoyl Benzyl, 2,6-dicarbamoylphenethyl, 2,4-dicarbamoylbenzyl, bis (2-carbamoylphenyl) methyl, α- (3-carbamoylphenyl) benzyl, bis (4-carba Moylphenyl) methyl, α- (4-carbamoylphenyl) benzyl, bis (3,5-dicarbamoylphenyl) methyl, bis (2,5-dicarbamoylphenyl) methyl, bis (2,6-dica Arbamoylphenyl) methyl, α- (2,4-dicarbamoylphenyl) benzyl and bis (2,3,6-tricarbamoylphenyl) methyl group; and aralkyl groups substituted with alkylenedioxy groups (3,4- Methylenedioxybenzyl (piperonyl), 3,4-methylenedioxyphenethyl, bis (3,4-methylenedioxyphenyl) methyl and 3,4-methylenedioxyphenyl) benzyl group). Of these, unsubstituted aralkyl groups and alkoxy-substituted aralkyl groups are preferred, more preferred are benzyl groups and alkoxy-substituted benzyl groups, and most preferred are benzyl and 4-methoxy benzyl groups.

Examples of groups and atoms belonging to substituent (b) are as follows:

[Halogen atoms (chlorine, fluorine, bromine and iodine, fluorine or chlorine atoms are preferable;

Alkyl groups having 1 to 6 carbon atoms (metal, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, hexyl, isohexyl, 2-methyl Pentyl, 4-methylpentyl, 3-methylpentyl, 3,3-dimethylbutyl, 2,2 dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl and 2,3- Dimethylbutyl group); Halogen-substituted alkyl groups having 1 to 6 carbon atoms (alkyl groups can be any of those exemplified above and alkylie can have 1 to 5 halogen substituents (if there are sufficient positions to substitute). Methyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoromethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl and 2,2-dibromoethyl group); Alkoxy groups having 1 to 6 carbon atoms (methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, Neopentyloxy, hexyloxy, isohexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1 -Dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy and 2,3-dimethylbutoxy group); Nitro group; Alkoxycarbonyl groups having 1 to 6 carbon atoms of the alkoxy moiety (methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-part Methoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, 2-methylbutoxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, isohexyloxycarbonyl, 4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2- Dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl and 2,3-dimethylbutoxycarbonyl group); An aryl group having the one or more substituents selected from the group consisting of a ring having 6 to 14 carbon atoms which is unsubstituted or other than an aryl group as defined above (as exemplified in the above substituent (a)); Cyano group; Alkylenedioxy groups having 1 to 4 carbon atoms (methylenedioxy group, ethylenedioxy group, and propylenedioxy group); Divalent aliphatic hydrocarbon groups having 1 to 4 carbon atoms (methylene, dimethylene, propylene and trimethylene groups);

Groups of NR ^d R ^e (R ^d and R ^e are each selected from the group consisting of hydrogen and alkyl groups having 1 to 6, preferably 1 to 4, e.g. amino, methylamino, ethylamino, propylamino, Isopropylamino, butylamino, isobutylamino, sec-butylamino, t-butylamino, pentylamino hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylanino, methyletheramino, methylpropylamino , Methyl isopropylamino, methylbutylamino, dibutylamino, diisobutylamino, methylisobutylamino, methyl-sec-butylamino, methyl-t-butylamino, ethylpropylamino and ethylbutylamino groups);

Haloalkoxycarbonyl groups having 1 to 6 carbon atoms in the alkoxy moiety (trifluoromethoxycarbonyl, trichloromethoxycarbonyl, difluoromethoxycarbonyl, dichloromethoxycarbonyl, dibromomethoxycarbonyl, fluoromethoxycarbon Carbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-chloroethoxycarbonyl, 2-fluoro Oxycarbonyl and 2,2-dibromoethoxycarbonyl group);

Aralkyloxycarbonyl groups (aralkyl moieties have alkyl groups having 1 to 6 carbon atoms, are substituted with 1 to 3 aryl groups, and aryl groups are unsubstituted or substituted as defined above with respect to hydroxy protecting groups) (b) has one or more substituents selected from the group consisting of;

Groups of the formula —CO—NR ^d R ^e (R ^d and R ^e are as defined above, eg carbamoyl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, Butylcarbamoyl, isobutylcarbamoyl, sec-butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarba Moyl, diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl, methylethylcarbamoyl, methylpropylcarbamoyl, methylisopropylcarbamoyl, methylbutylcarbamoyl, methylisobutyl Carbamoyl, methyl-sec-butylcarbamoyl, methyl-t-butylcarbamoyl, ethylpropylcarbamoyl and ethylbutylcarbamoyl groups); And aliphatic acyl groups having 1 to 20 carbon atoms (as exemplified in the above hydroxy protecting group).

Examples of the various groups and atoms belonging to substituents (c) and (d) are as indicated in the corresponding groups and atoms belonging to substituents (b).

In the compound of this invention, the following are preferable;

[(A: R ¹ and R ⁴ one represents a hydroxy group, a protected hydroxy group as defined above, or the formula -OP (O) (OH) ₂ , and the other represents the formula -OP (O) (OH) ₂ One of R ² and R ³ is an aliphatic acyl group having 6 to 20 carbon atoms (having 0 or one or more halogen substituents and having a hydroxy group, an aliphatic carboxyacyloxy group having 6 to 20 carbon atoms and a halogen having 6 to 20 carbon atoms). A substituted or aliphatic carboxyacyloxy group having 0 or 1 substituent selected from the group consisting of an aliphatic carboxyl acyl group having 6 to 20 carbon atoms ((i) having at least one halogen substituent and having a hydroxy group and a carbon number Having one substituent selected from the group consisting of aliphatic carboxyl acyloxy groups having 6 to 20, or (ii) halogen-substituted aliphatic carboxyl acyl having 6 to 20 carbon atoms Having at least one oxy group and having at least one substituent selected from the group consisting of halogen atoms, hydroxy groups and aliphatic carboxyl acyloxy groups having 6 to 20 carbon atoms; and R ⁵ represents a hydroxy group or a protection as defined above Hydroxy group.

의 기를 나타낸다.](B): one of R ¹ and R ⁵ represents a hydroxy group or a protected hydroxy group as defined above and the other represents a fluorine atom; R ² and R ³ are each selected from the group consisting of aliphatic carboxyacyl groups having 6 to 20 carbon atoms, and the acyl group has one or more substituents selected from the group consisting of unsubstituted or defined substituents (a). ; And R ⁴ is an expression

Represents a group.]

More preferred are:

[(C): Compound in which the glucopyran moiety in (A) and (B) above has a D configuration

Even more preferred are the following compounds:

의 기를 나타내고, 다른 하나는 히드록시 또는

₂의 기를 나타낸다.[(D): One of R ¹ and R ⁴ is an expression

Group, the other being hydroxy or

The group of ₂ is represented.

(E): one of R ² and R ³ is an aliphatic acyl group having 10 to 16 carbon atoms (with one or more halogen substituents and 0 or 1 substituent selected from the group consisting of a hydroxy group and an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms) The other represents an aliphatic carboxyl acyl group having 10 to 16 carbon atoms (having at least one substituent selected from the group consisting of a halogen atom, a hydroxy group and an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms). .

(F): R ² represents an aliphatic acyl group having 10 to 16 carbon atoms, and has one or more halogen substituents and 0 or 1 substituents selected from the group consisting of a hydroxyl group and an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms.

(G): R ⁵ represents a hydrogen atom or a carboxy-substituted aliphatic carboxyl acyloxy group having 1 to 6 carbon atoms in the acyl moiety and a carboxyl substituent at the terminal away from the oxy group of the acyloxy group.

(H): R ¹ represents a hydroxy group or a protected hydroxy group as defined above.

(I): One of R ² and R ³ is an aliphatic carboxyacyl group having 12 to 16 carbon atoms or a halogen atom, a hydroxy group, an aliphatic carboxyl acyloxy group having 12 to 16 carbon atoms and a halogen-substituted aliphatic carbon having 12 to 16 carbon atoms. If a substituted aliphatic carboxyl acyl group having 12 to 16 carbon atoms having one or more substituents selected from the group consisting of carboxyl acyloxy groups, and only one hydroxy group and an acyloxy group are substituted, the other is a hydroxy group and an aliphatic carbon having 12 to 16 carbon atoms A substituted aliphatic carboxyacyl group having 12 to 16 carbon atoms having 0 or 1 substituents and one or more halogen substituents selected from the group consisting of cyclic acyloxy groups.

(J): As defined above in (B), R ⁵ is a fluorine atom.

(K): as defined in (B), wherein (R ¹ represents a hydroxy group or a protected hydroxy group as defined above; one of R ² and R ³ is an aliphatic carboxyl acyl group having 12 to 16 carbon atoms Or a substituted aliphatic carboxyl acyl group having 12 to 16 carbon atoms having at least one substituent selected from the group consisting of a halogen atom, a hydroxy group and an aliphatic carboxyl acyloxy group having 12 to 16 carbon atoms, and only one hydroxy group and an acyloxy group are substituted The other represents a substituted aliphatic carboxyl acyl group having 0 or 1 substituents and at least one halogen substituent selected from the group consisting of a hydroxy group and an aliphatic carboxyl acyloxy group having 12 to 16 carbon atoms.

R ⁴ represents a group of the formula -OP (O) (OH) 2; And R ⁵ represents a fluorine atom or a hydroxyl group.]

(L): as defined in the above (B), R ¹ represents a hydroxy group.

(M): One of R ² and R ³ is an aliphatic acyl group having 10 to 16 carbon atoms (with one or more halogen substituents and 0 or 1 selected from the group consisting of a hydroxy group and an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms) And an aliphatic carboxyl acyl group having one or more substituents selected from the group consisting of a halogen atom, a hydroxy group and an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms.

의 기를 나타내며 ; 및 R⁵는 불소원자 또는 히드록시기를 나타낸다.(N): R ¹ represents a hydroxy group; One of R ² and R ³ represents an aliphatic acyl group having 10 to 16 carbon atoms (having 0 or 1 substituents and at least one halogen substituent selected from the group consisting of a hydroxy group and an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms). And the other represents an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms having at least one substituent selected from the group consisting of a halogen atom, a hydroxy group and an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms. R ⁴ is an expression

Represents a group of; And R ⁵ represents a fluorine atom or a hydroxyl group.

의 기를 나타낸다. R²및 R³는 각각 탄소수 6 내지 20인 지방족 카르복실 아실기로 구성된 군으로부터 선택한 것이며 아실기는 치환되지 않았거나 또는 하기에 정의된 치환체(a')로 구성된 군으로부터 선택한 하나 이상의 치환체를 갖는다 ; R⁴는 히드록시기 또는 식

의 기를 나타내며, R¹및 R⁴의 적어도 하나는 식

의 기를 나타낸다 ; R⁵는 히드록시기 또는 불소원자를 나타낸다 ; R¹및 R⁵의 적어도 하나가 불소원자를 나타내고, R²및 R³의 적어도 하나가 탄소수 6 내지 20인 치환된 지방족 카르복실 아실기 ((i) 하나 이상의 할로겐 치환체 및 (ii) 할로겐 원자, 히드록시기 및 탄소수 6 내지 20인 지방족 카르복실 아실옥시기로 구성된 군으로부터 선택한 하나 이상의 치환체를 갖고 있다)를 나타내거나 또는 R²및 R³의 적어도 하나는, 탄소수 6 내지 20인 하나 이상의 할로겐-치환 지방족 카르복실 아실옥시기로 치환된, 탄소수 6 내지 20인 치환된 지방족 아실기를 나타내는 경우를 제외한다.(O): R ¹ is a hydroxy group, a fluorine atom

Represents a group. R ² and R ³ are each selected from the group consisting of aliphatic carboxyl acyl groups having 6 to 20 carbon atoms and the acyl group has one or more substituents unsubstituted or selected from the group consisting of substituents (a ') defined below; R ⁴ is a hydroxy group or formula

Wherein at least one of R ¹ and R ⁴ is

Represents a group of; R ⁵ represents a hydroxy group or a fluorine atom; At least one of R ¹ and R ⁵ represents a fluorine atom and at least one of R ² and R ³ has 6 to 20 carbon atoms with substituted aliphatic carboxyl acyl groups ((i) one or more halogen substituents and (ii) halogen atoms, At least one substituent selected from the group consisting of a hydroxy group and an aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms), or at least one of R ² and R ³ is at least one halogen-substituted aliphatic carbon having 6 to 20 carbon atoms Except for the case where a substituted aliphatic acyl group having 6 to 20 carbon atoms is substituted with a cyclic acyloxy group.

Substituent (a '):

Halogen atom; Hydroxyl group; Aliphatic carboxyacyloxy group having 6 to 20 carbon atoms; And a halogen-substituted aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms.

의 기를 나타내고, 다른 하나는 식의 기를 나타낸다 ; R²및 R³중의 하나는 탄소수 6 내지 20인 지방족 카르복실 아실기 (0 또는 하나 이상의 할로겐 치환체를 갖고 있으며, 히드록시기, 탄소수 6 내지 20인 지방족 카르복실 아실옥시기 및 탄소수 6 내지 20인 할로겐-치환 지방족 카르복실 아실옥시기로 구성된 군으로부터 선택한 0 또는 1개의 치환체를 갖고 있다)를 나타내며, 다른 하나는 탄소수 6 내지 20인 지방족 카르복실 아실기((i) 하나 이상의 할로겐 치환체를 갖고 있으며 히드록시기 및 탄소수 6 내지 20인 지방족 카르복실 아실옥시기로 구성된 군으로부터 선택된 1개의 치환체를 갖고 있거나, 또는 (ii) 탄소수 6 내지 20인 할로겐-치환 지방족 카르복실 아실옥시기를 하나 이상 가지고 있으며 할로겐 원자, 히드록시기 및 탄소수 6 내지 20인 지방족 카르복실 아실옥시기로 구성된 군으로부터 선택한 0 또는 1개의 치환체를 갖고 있다)를 나타낸다 ; R5는 히드록시기를 나타낸다.(P): One of R ¹ and R ⁴ is a hydroxy group or formula

Where the other is Represents a group of; One of R ² and R ³ is an aliphatic carboxyl acyl group having 6 to 20 carbon atoms (having 0 or one or more halogen substituents and having a hydroxy group, an aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms and a halogen having 6 to 20 carbon atoms). Having 0 or 1 substituent selected from the group consisting of substituted aliphatic carboxyl acyloxy groups), and the other has an aliphatic carboxyl acyl group having 6 to 20 carbon atoms ((i) having one or more halogen substituents and having a hydroxy group and a carbon number Having one substituent selected from the group consisting of aliphatic carboxyl acyloxy groups having from 6 to 20, or (ii) having at least one halogen-substituted aliphatic carboxyl acyloxy group having from 6 to 20 carbon atoms and having a halogen atom, a hydroxy group and a carbon number of 6 0 selected from the group consisting of aliphatic carboxyl acyloxy groups having from 20 to 20 or It has one substituent); R5 represents a hydroxyl group.

의 기를 나타낸다.](Q): One of R ¹ and R ⁵ represents a hydroxy group and the other represents a fluorine atom. R ² and R ³ are each a group selected from the group consisting of aliphatic carboxyl acyl groups having 6 to 20 carbon atoms, the acyl group being unsubstituted or at least one substituent selected from the group consisting of substituents (a ') as defined in (P). Have; And R ⁴ is an expression

Represents a group.]

Certain compounds of the present invention may contain carboxyl groups and therefore may form esters, which is also a form of the present invention. If the resulting compounds are used for therapeutic purposes, there is no restriction on the nature of these esters, and pharmaceutically acceptable, as is known in the art, as compared to compounds corresponding to formula (I), ie free acids It does not exhibit reduced activity (or unacceptable reduced activity) or increased toxicity (or unacceptable increased toxicity). However, if this compound is used for non-therapeutic purposes, for example as an intermediate in the manufacture of other compounds, the nature of the esters should be chosen in consideration of the reaction, even without these limitations. Examples of suitable esters capable of substituting hydrogen atoms of the carboxyl groups are as follows:

[C ₁ -C ₂₀ alkyl group, more preferably C ₁ -C ₆ alkyl group (as exemplified in the substituent (b)) and higher alkyl groups known in the art: Yes. Heptyl, 1-methylhexyl, 2-methylhexyl, 5-methylhexyl, 3-ethylpentyl, octyl, 2-methylheptyl, 5-methylheptyl, 2-ethylhexyl, 2-ethyl-3-methylpentyl, 3- Ethyl-2-methylpentyl, nonyl, 2-methyloctyl, 7-methyloctyl, 4-ethylheptyl, 3-ethyl-2-methylhexyl, 2-ethyl-1-methylhexyl, decyl, 2-methylnonyl, 8 -Methylnonyl, 5-ethyloctyl, 3-ethyl-2-methylheptyl, 3,3-diethylhexyl, undecyl, 2-methyldecyl, 9-methyldecyl, 4-ethylnonyl, 3,5-dimethylnonyl , 3-propyloctyl, 5-ethyl-4-methyloctyl, dodecyl, 1-methylundecyl, 10-methylundecyl, 3-ethyldecyl, 5-propylnonyl, 3,5-diethyloctyl, tridecyl , 11-methyldodecyl, 7-ethylundecyl, 4-propyldecyl, 5-ethyl-3-methyldecyl, 3-pentyloctyl, tetradecyl, 12-methyltridecyl, 8-ethyldodecyl, 6-propyl Undecyl, 4-butyldecyl, 2-pentylnonyl, pentadecyl, 13-methyltetradecyl, 10-ethyltridecyl, 7-propyldodecyl, 5-ethyl-3-methyldodecyl, 4-pentyldecyl, hexa Decyl, 14-methylpenta Decyl, 6-ethyltedecyl, 4-propyltridecyl, 2-butyldodecyl heptadecyl 15-methylhexadecyl, 7-ethylpentadecyl, 3-propyltedecyl, 5-pentyldodecyl, octadecyl, 16- Methylheptadecyl, 5-propylpentadecyl, nonadecyl, 17-methyloctadecyl, 4-ethylheptadecyl, ecosil, 18-methylnonadecyl and 3-ethyloctadecyl. But most preferred are methyl, ethyl and t-butyl groups; C ₃ -C ₇ cycloalkyl group: Yes. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl groups; Aralkyl group (the carbon number of the aromatic group is C ₆ to C ₁₄ and has one or more substituents selected from the group consisting of unsubstituted or exemplified substituents (b) above); Yes. Benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) Ethyl, benzhydryl (eg diphenylmethyl), triphenylmethyl, bis (o-nitrophenyl) methyl, 9-anthrylmethyl, 2,4,6-trimethylbenzyl, 4-bromobenzyl, 2-nitro Benzyl, 4-nitrobenzyl, 4-methoxybenzyl and piperonyl groups; Alkenyl groups having 2 to 6 carbon atoms (unsubstituted or having one or more substituents selected from the group consisting of halogen atoms); Examples of unsubstituted groups are as in Substituent (b) above and preferred groups are allyl, 2-chloroallyl and 2-methylallyl groups;

C ₁ -C ₆ , preferably C ₁ -C ₄ halogenated alkyl groups (the alkyl moiety is the same as the alkyl group shown in the above substituent (b), and the halogen atom is chlorine, fluorine, bromine or iodine); Yes. 2,2,2-trichloroethyl, 2-haloethyl (eg 2-chloroethyl, 2-fluoroethyl, 2-bromoethyl or 2-iodineethyl), 2,2-dibromoethyl and 2 , 2,2-tribromoethyl group;

A substituted silylalkyl group (alkyl moiety is the same as the alkyl group shown in substituent (b), etc., wherein the silyl group is at least one selected from the group consisting of C ₁ -C ₆ alkyl groups and unsubstituted or substituents as exemplified in substituent (b) Has up to 3 substituents selected from the group consisting of phenyl groups having substituents); 2-trimethylsilylethyl group; Phenyl group (unsubstituted or preferably substituted with one or more C ₁ -C ₄ alkyl or acylamino groups); Yes. Phenyl, tolyl and benzamidophenyl groups; Phenacyl groups (unsubstituted or have one or more substituents selected from the group consisting of substituents (b) as defined and exemplified above): Phenacyl group or p-bromophenacyl group; Cyclic and cyclic terphenyl groups; Yes. Geranyl, neryl, linalyl, pictyl, menthyl (particularly m- and p-menthyl), dialysis, caryl, pinanyl, bornyl, norcaryl, norpinanyl, norbornyl, mentenyl, campenyl and nord Bornenyl group; Terphenylcarbonyloxyalkyl and terphenyloxycarbonyloxyalkyl groups (terphenyl groups are as exemplified above, with cyclic terphenyl groups being preferred): Yes. 1- (menthyloxycarbonyloxy) ethyl, 1- (menthylcarbonyloxy) ethyl, menthyloxycarbonyloxymethyl, menthylcarbonyloxymethyl, 1- (3-pinanyloxycarbonyloxy) ethyl, 1- (3-pinanylcarbonyloxy) ethyl, 3-pinanyloxycarbonyloxymethyl and 3-pinanylcarbonyloxymethyl groups; Alkoxymethyl group (alkoxy moiety is C ₁ -C ₆ , preferably C ₁ -C ₄ and may be substituted with one unsubstituted alkoxy group): Yes. Methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and methoxyethoxymethyl groups; Aliphatic acyloxymethyl group (acyl group is preferably an alkinoyl group, more preferably a C ₂ to C ₆ alkanoyl group): Yes. Acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl and pivaloyloxymethyl groups; Higher aliphatic acyloxyalkyl groups (acyl groups are preferably alkanoyl groups, more preferably C ₂ to C ₆ alkanoyl groups and alkyl moieties C ₂ to C ₆ , preferably C ₂ to C ₄ ). 1-pivaloyloxyethyl, 1-acetoxyethyl, 1-isobutyryloxyethyl, 1-pivaloyloxypropyl, 2-methyl-1-pivaloyloxypropyl, 2-pivaloyloxypropyl, 1-isobutyryloxyethyl, 1-isobutyryloxypropyl, 1-acetoxypropyl, 1-acetoxy-2-methylpropyl, 1-propionyloxyethyl, 1-propionyloxypropyl, 2-acetoxy Propyl and 1-butyryloxyethyl group; Cycloalkyl-substituted aliphatic acyloxyalkyl groups (acyl groups are preferably alkanoyl groups, more preferably C ₂ to C ₆ alkanoyl groups, cycloalkyl substituents are C ₃ to C ₇ , and alkyl moieties are C ₁ to C ₆ alkyl groups , Preferably a C ₁ to C ₄ alkyl group). (Cyclohexylacetoxy) methyl, 1- (cyclohexylacetoxy) ethyl, 1- (cyclohexylacetoxy) propyl, 2-methyl-1- (cyclohexylacetoxy) propyl, (cyclopentylacetoxy) methyl, 1- (cyclopentylacetoxy) ethyl, 1- (cyclopentylacetoxy) propyl, and 2-methyl-1- (cyclopentylacetoxy) propyl groups;

Alkoxycarbonyloxyalkyl groups, in particular 1- (alkoxycarbonyloxy) ethyl groups, (alkoxy moieties are C ₁ -C ₁₀ , preferably C ₁ -C ₆ , more preferably C ₁ -C ₄ and the alkyl moiety is C ₁ -C ₆ , preferably C ₁ -C ₄ ): Yes. 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-butoxycarbonyloxyethyl, 1-isobutoxy Carbonyloxyethyl, 1-sec-butoxycarbonyloxyethyl, 1-t-butoxycarbonyloxyethyl, 1- (1-ethylpropoxycarbonyloxy) ethyl and 1- (1, 1-dipropyl butoxycarbonyloxy) ethyl groups, and other alkoxycarbonylalkyl group (alkoxy and alkyl groups are both C ₁ ~C _6, preferably C ₁ ~C _4): example. 2-methyl-1- (isopropoxycarbonyloxy) propyl, 2- (isopropoxycarbonyloxy) propyl, isopropoxycarbonyloxymethyl, t-butoxycarbonyloxymethyl, methoxycarbonyloxy Methyl and ethoxycarbonyloxymethyl groups; Cycloalkylcarbonyloxyalkyl and cycloalkyloxycarbonyloxyalkyl groups (cycloalkyl groups are C ₃ to C ₁₀ , preferably C ₃ to C ₇ , mono or polycyclic and one or more (preferably only one) C ₁ ~C ₄ alkyl group is optionally substituted with (eg selected from the above-exemplified alkyl group), and the alkyl group is C ₁ ~C _6, more preferably one selected from the C ₁ ~C ₄ alkyl group (the alkyl group exemplified in the ) And most preferred is methyl, ethyl or propyl). 1-methylcyclohexylcarbonyloxymethyl, 1-methylcyclohexyloxycarbonyloxymethyl, cyclopentaloxycarbonyloxymethyl, cyclopentylcarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1 -Cyclohexylcarbonyloxyethyl, 1-cyclopentyloxycarbonyloxyethyl, 1-cyclopentylcarbonyloxyethyl, 1-cycloheptyloxycarbonyloxyethyl, 1-cycloheptylcarbonyloxyethyl, 1-methylcyclo Pentylcarbonyloxymethyl, 1-methylcyclopentyloxycarbonyloxymethyl, 2-methyl-1- (1-methylcyclohexylcarbonyloxy) propyl, 1- (1-methylcyclohexylcarbonyloxy) propyl, 2 -(1-methylcyclohexylcarbonyloxy) propyl, 1- (cyclohexylcarbonyloxy) propyl, 2- (cyclohexylcarbonyloxy) propyl, 2-methyl-1- (1-methylcyclopentylcarbonyloxy ) Propyl, 1- (1-methylcyclopentylcarbonyloxy) propyl, 2- (1-methylcyclopentylcarbon Nyloxy) propyl, 1- (cyclopentylcarbonyloxy) propyl, 2- (cyclopentylcarbonyloxy) propyl, 1- (1-methylcyclopentylcarbonyloxy) ethyl, 1- (1-methylcyclopentylcarbon Carbonyloxy) propyl, adamantyloxycarbonyloxymethyl, adamantylcarbonyloxymethyl, 1-adamantyloxycarbonyloxyethyl and 1-adamantylcarbonyloxyethyl group; Cycloalkylalkoxycarbonyloxyalkyl groups (alkoxy groups have one cycloalkyl substituent and the cycloalkyl substituent is C ₃ -C ₁₀ , preferably C ₃ -C ₇ and is mono- or polycyclic): Yes. Cyclopropylmethoxycarbonyloxymethyl, cyclobutylmethoxycarbonyloxymethyl, cyclopentylmethoxycarbonyloxymethyl, cyclohexylmethoxycarbonyloxymethyl, 1- (cyclopropylmethoxycarbonyloxy) ethyl, 1 -(Cyclobutylmethoxycarbonyloxy) ethyl, 1- (cyclopentylmethoxycarbonyloxy) ethyl and 1- (cyclohexylmethoxycarbonyloxy) ethyl group; The (5-alkyl- or 5-phenyl-2-oxo-1,3-dioxolen-4-yl) alkyl group (each alkyl group (which may be the same or different) may be C ₁ -C ₆ , preferably C ₁ -C ₄ and the phenyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of substituents (b)). (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-isopropyl- 2-oxo-1,3-dioxolen-4-yl) methyl, (5-t-butyl-2-oxo-1,3-dioxolen-4-yl) methyl and 1- (5-methyl-2- Oxo-1,3-dioxolen-4-yl) ethyl group; And other groups, in particular groups which can be easily removed in vivo. Phthalidyl, indanyl and 2-oxo-4,5,6,7-tetrahydro-1,3-benzodioxolen-4-yl groups]

Among the above groups, groups which can be easily removed in particular are preferred, and most preferred are aliphatic acyloxymethyl group, higher aliphatic acyloxyalkyl group, cycloalkyl-aliphatic acyloxyalkyl group, alkoxycarbonyloxyalkyl group, cycloalkylcarbonyl Oxyalkyl group and cycloalkylalkoxycarbonyloxyalkyl group.

Compounds of formula (I) also form salts with the following cations:

[Metal atoms, in particular alkali metal atoms (eg sodium and potassium atoms), alkaline earth metal atoms (eg calcium atoms), and other atoms (eg iron, magnesium, aluminum and cobalt atoms); ammonium groups; trialkylamine derivatives Cations (e.g. triethylamine or trimethylamine) or cations of other organic base induction (e.g. procaine, dibenzylamine, phenethylamine, 2-phenylethylbenzylamine, ethanolamine, diethanolamine, polyhydroxy Alkylamines or N-methylglucosamines; and basic amino acids (eg lysine, arginine, ornithine or histidine)]

Among the above, alkali metal salts or inorganic acid salts are preferable.

Compounds of the invention have one or more asymmetric carbon atoms in the molecule and can form optical isomers having (R) -configuration or (S) -configuration. Although these are represented in one molecular formula, the present invention includes all compounds including individual compounds, isolated isomers and racemates thereof. Each isomer can be prepared directly using the stereospecific synthesis method, while once a mixture of isomers is prepared, each isomer can be obtained by conventional separation methods.

Specific examples of the present invention are shown in the following formulas (I-1) to (I-3), and substituents are as defined in Tables 1 to 3, respectively. [In other words, Table 1 relates to Formula (I-1), Table 2 relates to Formula (I-2), and Table 3 relates to Formula (I-3).]

(I-1)

Equation I-2

Equation I-3

Among the compounds mentioned above, the following compounds are preferable.

1-8, 1-16, 1-21, 1-22, 1-52, 1-54, 1-59, 1-65, 1-72, 1-74, 1-105, 1-106, 1- 107, 1-110, 1-111, 1-112, 1-115, 1-116, 1-117, 1-120, 1-121, 1-122, 1-125, 1-126, 2-3, 2-4, 2-9, 2-14, 2-15, 2-19, 2-36, 2-38, 2-59, 2-66, 2-72, 2-78, 2-84, 2- 87, 2-91, 2-93, 2-96, 2-97, 2-98, 2-99, 2-101, 2-102, 2-103, 2-104, 2-106, 2-107, 2-108, 2-111, 2-112, 2-113, 2-116, 2-117, 3-2, 3-4, 3-6, 3-8, 3-10, 3-12, 3- 14, 3-16, 3-30, 3-32, 3-36, 3-42, 3-44, 3-46, 3-52, 3-54, 3-56, 3-62, 3-64, 3-66, 3-72, 3-74, 3-76, 3-85, 3-89, 3-92, 3-97, 3-103, 3-114, 3-122, 3-123, 3- 124, 3-125, 3-133, 3-143, 3-144, 3-156, 3-157, 3-158, 3-163, 3-167 and 3-176. More preferred compound numbers are 1-21, 1-54, 1-74, 1-105, 1-110, 1-115, 1-120, 1-125, 1-126, 2-14, 2-38, 2-59, 2-66, 2-72, 2-78, 2-84, 2-96, 2-101, 2-106, 2-111, 2-116, 2-117, 3-2, 3- 4, 3-6, 3-42, 3-52, 3-56, 3-72, 3-74, 3-76, 3-114, 3-123, 3-156 and 3-159.

The number of the most preferred compounds is as follows:

2-38. 2-deoxy-2- (2'-fluoro-3'-hydroxytetradecanoylamino) -3-0- [3- (tetradecanoyloxy) tedecanoyl] glucopyranosyl-4-phosphate ;

2-66. 2-deoxy-2- (3'-hydroxytetradecanoylamino) -3-0- [3- (2,2-difluorotetradecanoyloxy) tetradecanoyl] glucopyranosyl-4- Phosphate, especially 2-deoxy-2-[(3'R) -3'-hydroxytetradecanoylamino] -3-0-[(3R) -3- (2,2-difluorotetradeca Noyloxy) tetradecanoyl] -D-glucopyranosyl-4-phosphate isomer; 2-84. 2-deoxy-2- (3'-hydroxytetradecanoylamino) -3-0- [2,2-difluoro-3-tetradecanoyloxy) tetradecanoyl] glucopyranosyl-4- Phosphate; 2-96. 2-deoxy-2- (2 ', 2'-difluoro-3'-hydroxytetradecanoylamino) -3-0- (3-tetradecanoyloxytetradecanoyl) glucopyranosyl-4- Phosphate, especially 2-deoxy-2-[(R) -2 ', 2'-difluoro-3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradeca Noyloxytetradecanoyl] -D-glucopyranosyl-4-phosphate and 2-deoxy-2-[(S) -2 ', 2'-difluoro-3'-hydroxytetradecanoylamino]- 3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranosyl-4-phosphate isomer; 2-101. 2-deoxy-2- (2 ', 2'-difluoro-3'-hydroxytetradecanoylamino) -3-0- (3-dodecanoyloxytetradecanoyl) glucopyranosyl-4- Phosphate; 2-106. 2-deoxy-2- (2 ', 2'-difluoro-3'-hydroxytetradecanoylamino) -3-0- (2,2-difluoro-3-tetradecanoyloxytetedeca Noyl) glucopyranosyl-4-phosphate; 2-111. 2-deoxy-2- (2 ', 2'-difluoro-3'-hydroxytetradecanoylamino) -3-0- (2,2-difluoro-3-dodecanoyloxytetedeca Noyl) glucopyranosyl-4-phosphate; 3-2. 2,6-dideoxy-6-fluoro-2- (3'-hydroxytetradecanoylamino) -3-0- (3-tetradecanoyloxytetradecanoyl) glucopyranosyl-4-phosphate, in particular 2,6-dideoxy-6-fluoro-2-[(R) -3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranosyl-4-phosphate isomer; 3-72. 2,6-dideoxy-6-fluoro-2- (3'-hydroxytetradecanoylamino) -3-0- (2,2-difluoro-3-tetradecanoyloxytedecanoyl) gluco Pyranosyl-4-phosphate; And 3-125. 2,6-dideoxy-6-fluoro-2- (2,2-difluoro-3'-hydroxytetradecanoylamino) -3-0- (3-tetradecanoyloxytetradecanoyl) Copyranosyl-4-phosphate.

Isomers of the D-configuration are preferred for all compounds, including those listed above, preferred more preferred and most preferred.

The compounds of the present invention are prepared by a variety of methods known to those of skill in the art for preparing this type of compound, and any such known method can be used and constitutes the present invention. In general, however, it can be prepared as follows:

[(a) A compound of formula (II) is reacted with a compound of formula (III) to prepare a compound of formula (IV), removing the protecting group if desired and removing R ¹ , R ² ′, R ³ ′, R ⁴ And optionally substituted at least one group represented by R ⁵ ′ with any group represented by R ¹ , R ² , R ³ , R ⁴ and R ⁵ as defined in formula (I) above, optionally esterifying the product or Produces a salt.

Formula II

(In the above formula, R ^1, and one R4 represents a hydroxyl group, and one case of the case of R ¹ is represents a protected hydroxy group or a fluorine atom, R ⁴ is formula -OP (= O) (OH) 2 It represents a group or a protected hydroxy group; R ² and R ³ are the group and hydroxy consisting of groups represented in R ² and R ³ respectively would select from or amino protecting group, in the group represented by R ² and R ³ the reactor is protected and R5 represents a protected hydroxyl group or fluorine atom.

Formula III

(Wherein each R ¹⁰ is each selected from the group consisting of a phosphate protecting group and X represents a halogen atom.)

Formula IV

(Wherein one or both of R ¹ and R ⁴ represent the formula -OP (= O) (OR ¹⁰ ) ₂ , R ¹⁰ is as defined above and only one is formula -OP (= O) (OR ¹⁰ ₂ ), the other represents a protected hydroxy group or fluorine element in the case of R ¹ , or a protected hydroxy group in the case of R ⁴ ; and R ² , R ³ and R ⁵ are as defined above. same.)]

More specifically, the compounds of the present invention may be prepared by the reactions shown in the following Schemes A to E according to the compounds to be prepared.

Scheme A:

[Step A1-Step A2]

[Step A3]

[Step A4-Step A5]

[Step A6]

[Steps A7-A8]

[Step A9]

Scheme B:

[Step B1]

[Step B2-Step B3]

Scheme C:

[Step C1-Step C2]

[Step C3]

[Step C4]

[Step C5]

Scheme D:

[Step D1-Step D2]

[Step D3]

[Step D4]

Scheme E:

[Step E1-Step E2]

[Step E3]

[Step E4]

In the above formulas, R ² and R ^{3 are} as defined above; R ^2a and R ^3a are the same as or different from each other, and each mean any one of the R ² and R ³ groups defined above, provided that any reactive group is optionally protected; R ⁶ is an amino-protecting group, for example, an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an aralkyloxycarbonyl group, a silyl group or an aralkyl group as illustrated above, and a trifluoroacetyl group desirable ; R ⁷ and R ¹¹ are the same or different from each other and are the hydroxy-protecting groups as defined for R ¹ , R ⁴ and R ⁵ , respectively; R ⁸ and R ⁹ are the same as or different from each other, and each has a straight or branched chain alkyl group having 1 to 6 carbon atoms (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, iso Pentyl, 2-methylbutyl, neopentyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 1,3-dimethylbutyl or 2,3-dimethylbutyl group) or aryl groups of 5 to 12, preferably 6 to 10, carbon atoms (e.g. unsubstituted or 1 to 4 substituents on the ring) Phenyl or naphthyl group which may have an amino group, a nitro group, a cyano group, a carboxyl group (which may be esterified with a lower alkyl group, a halogenated lower alkyl group, or an aralkyl group exemplified above) Barmoyl group, halogen atom, lower alkyl group, halogenated lower alkyl group (for example, triple Oromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl , 2-chloroethyl, 2-fluoroethyl and 2,2-dibromoethyl groups) and aliphatic acyl groups as exemplified above, preferably halogen atoms or halogenated lower alkyl groups; And

R1 ⁰ and R ¹² are the same as or different from each other, and are each a protecting group for a phosphoryl group or a phosphono group, for example, an aryl group or an aralkyl group exemplified above.

In step A1 of Scheme A, glucoseamine hydrochloride of formula (v) is reacted with an acid corresponding to aminoprotecting group R ⁶ or a reactive derivative of such acid. The type of reagent selected will of course depend on the type of group R ⁶ desired to be introduced, and in the case of the preferred trifluoroacetyl group, the reagent will be trifluoroacetic acid or a reactive derivative thereof. If the reagent is a free acid such as trifluoroacetic acid, the reaction is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC). If the reagent is an acid anhydride such as trifluoroacetic anhydride, the reaction is carried out with an organic base such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino ) Pyridine (DMAP), N, N-dimethylaniline, 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), 1,4-diazabicyclo [2,2,2] Preference is given to performing in the presence of octane (DABCO) or 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU). In addition, when the reagent is an active ester, for example trifluoroacetate such as ethyltrifluoroacetate, the reaction is preferably carried out in the presence of any one of the above organic bases. The reaction of this step affords the amide of formula VI.

The reaction is generally preferably carried out in the presence of a solvent. There is no particular limitation on the type of solvent used as long as the starting material can be dissolved to some extent without adversely affecting the reaction and the reagent used. Examples of suitable solvents include halogenated hydrocarbons, in particular halogenated aliphatic hydrocarbons such as methylenechloride and chloroform, ethers (eg diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane); Alcohols (eg methanol, ethanol, propanol, isopropanol, butanol, isobutanol and isoamyl alcohol); Amides, especially fatty acid amides such as dimethylformamide, dimethylacetoamide and hexamethylphosphortriamide; And sulfoxides such as dimethyl sulfoxide.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is generally convenient to carry out the reaction at a temperature of from 0 to 100 ° C., preferably at room temperature. The time required for the reaction can also vary over a wide range, and many factors will depend on the type, in particular the reaction temperature, the reagents and solvents used. However, 0.1 to 24 hours will usually be sufficient when the reaction is carried out under the above-illustrated preferred conditions.

In step A2 of Scheme A, the glucoside bond is an amide of formula (VI) in the presence of an acid catalyst of formula R ⁷ OH, wherein R ⁷ is methanol, ethanol, benzyl alcohol or allyl alcohol as defined above. Reaction with an alcohol of to form a compound of formula (VII).

The alcohol of the general formula R ⁷ OH serving as the reaction solvent is preferably used in excess. The acid used as a catalyst acts as an acid and there is no particular limitation as long as it does not adversely affect the reaction and the reagent. Preferred acids are inorganic acids such as hydrochloric acid or sulfuric acid and organic acids, in particular euphonic acid such as p-toluenesulfonic acid. These acids can be used in a hydrated state as needed.

Such reactions can also occur over a wide temperature range, and the exact reaction temperature is not critical to the present invention. It is generally convenient to carry out the reaction at 0 to 200 ° C., preferably at the circulation temperature of the reaction medium. The time required for the reaction can also vary over a wide range and will depend on many factors, especially the reaction temperature and the type of reagent and solvent used. However, when the reaction is carried out under the preferred conditions outlined above, 0.1 to 24 hours will usually be sufficient.

In step A3 of Scheme A, the diols of general formula (VII) prepared above are prepared in groups 4- and 6-positions of the general formula R ⁸ R ⁹ C, for example isopropylidene, benzylidene or ethyl Introduce a protector group to protect it; This reaction is carried out in the presence of a solvent and a catalyst to prepare a compound of formula (VIII).

It does not limit the kind of reagent used in the protection step of this diol. Usually any reagent used for diol protection can equally be used here. Preferred examples include aldehyde derivatives such as benzaldehyde; Ketone derivatives such as acetone; And dimethoxy compounds such as 2,2-dimethoxypropane or benzaldehyde dimethylacetal.

There is no particular limitation on the type of solvent used unless adversely affecting the reaction or the reagent used. Examples of suitable solvents include halogenated hydrocarbons, in particular halogenated aliphatic hydrocarbons (eg methylene chloride or chloroform); Ethers (eg dioxane or tetrahydrofuran); Aliphatic hydrocarbons (eg hexane or pentane); Aromatic hydrocarbons (eg benzene or toluene); Esters such as ethyl acetate; And polar solvents (eg amides such as dimethylformamide and ketones such as acetone).

The type of catalyst used is not particularly limited so long as it does not adversely affect the reaction or reagents, and any acids commonly used in this type of reaction may equally be used here. Examples include organic acids, in particular eutechonic acids and their salts such as p-toluenesulfonic acid, camphorsulfonic acid and pyridium p-toluenesulfonate; Inorganic catalysts such as hydrochloric acid; And Lewis acids such as zinc chloride, aluminum chloride, and tin tin chloride.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. In general, it is convenient to carry out the reaction at a temperature of 0-100 ° C. The time required for the reaction may also vary over a wide range and many factors will depend, in particular, on the reaction temperature and the type of reagent and solvent used. However, when the reaction is carried out under the preferred conditions outlined above, 0.1 to 24 hours will usually be sufficient.

In step A4 of Scheme A, the R ⁶ group of the compound of formula (VIII) is removed to prepare a compound of formula (IX).

Many reactions can be used to remove such protecting groups, and the type of reaction will depend, for example, on the type of protecting group as illustrated below.

For example, when a silyl group is used as the R ⁶ group, such a group can generally be removed by treating the compound of formula (VIII) as a compound which generates fluorine anion, for example tetrabutylammonium fluoride. The reaction is preferably carried out in the presence of a solvent. The type of solvent used is not particularly limited as long as it does not adversely affect the reaction or the reagent used. Examples of suitable solvents are ethers such as tetrahydrofuran and dioxane.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. In general, it is convenient to carry out the reaction at a temperature of approximately room temperature. The time required for the reaction can also vary over a wide range and will depend on many factors, in particular on the reaction temperature and the type of reagent. However, when the reaction is carried out under the preferred conditions outlined above, from 10 minutes to 18 hours is usually sufficient.

When the R ⁶ group is an aliphatic acyl group, aromatic acyl group or alkoxycarbonyl, the compound of formula (VIII) can be removed by treatment or reduction with a base in the presence of an aqueous solvent to remove such groups. The type of base used in this reaction is not particularly limited as long as it does not affect other parts of the molecule, and any base commonly used in this type of reaction may equally be used here.

Examples of suitable bases include alkali metal carbonates such as sodium carbonate or potassium carbonate; Alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; And concentrated methanol ammonia. This reaction is preferably carried out in the presence of a solvent. The type of solvent used is not limited so long as it does not adversely affect the reaction or the reagent contained therein, and any solvent usually used in the hydrolysis reaction may be used. Examples of suitable solvents are water, mixtures of water and organic solvents, for example alcohols (eg methanol, ethanol or cropanol) or ethers (eg tetrahydrofuran or dioxane).

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. In general, it is convenient to carry out the reaction at a temperature of 0 to 150 ° C in order to prevent side reactions. The time required for the reaction can also vary over a wide range and will depend on many factors, in particular on the reaction temperature and the type of reagent used. However, when the reaction is carried out under the preferred conditions outlined above, 1 to 10 hours will usually be sufficient.

Removal of R ⁶ groups via reduction can be carried out in a conventional manner using a reducing agent such as sodium borohydride.

If the R ⁶ group is an aralkyl group or an aralkyloxycarbonyl group, the removal of this group is preferably carried out by catalytic reduction at ambient temperature using a catalyst such as platinum or palladium-on-carbon. This reaction is preferably carried out in the presence of a solvent. The type of solvent used is not particularly limited as long as it does not adversely affect the reaction or the reagent contained therein. Examples of suitable solvents include alcohols such as methanol, ethanol or isopropanol; Ethers such as diethyl ether, tetrahydrofuran or dioxane; Aromatic hydrocarbons such as toluene, xylene or benzene; Aliphatic hydrocarbons such as hexane or cyclohexane; Esters such as ethyl acetate or propyl acetate; Fatty acids such as acetic acid; And mixtures of one or more of these organic solvents with water. Any catalyst commonly used in the reduction reaction can be used here, with preferred examples being palladium-on-carbon, rannickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate There is.

The reaction pressure is not critical but is usually 1 to 10 atmospheres.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. In general, it is convenient to carry out the reaction at a temperature of 0-100 ° C. The time required for the reaction may also vary over a wide range and will depend on many factors, in particular on the reaction temperature, the type of catalyst and the type of reagent. However, if the reaction is carried out under the conditions outlined above roughly, 5 minutes to 24 hours will usually be sufficient.

Even when the R ⁶ group is an alkenyloxycarbonyl group, these groups can usually be removed under the same conditions as the removal conditions used when the R ⁶ group is an aliphatic acyl group, aromatic acyl group or lower alkoxycarbonyl group. Note that when the R ⁶ group is an allyloxycarbonyl group, it is particularly eliminated using palladium and triphenylphosphine or with nickeltetracarbonyl, since this reaction involves minimal side reactions.

In step A5 of Scheme A, the amino moiety at the 2-position of the compound of formula (IX) is acylation of one of the following acylating agents, preferably with 1.0 to 1.1 equivalents, to formula (X) To prepare a compound.

Acylation results in the formation of such amino moieties in the presence of a condensation agent (e.g., dicyclohexylcarbodiimide (DCC) or carbonyldiimidazole) in the form of a general formula R ^2a OH, wherein R ^2a is as defined above. Reacted with an acid, or R ^2a Y wherein R ^2a is as defined above and Y is a leaving group, e.g., a group of the formula OR ^2a , a halogen atom (e.g. chlorine, bro or iodine) Aliphatic acyloxy groups (e.g. alkylcarbonyloxy groups such as acetoxy or propionyloxy groups, halogenated alkylcarbonyloxy groups such as chloroacetoxy, dichloroacetoxy, trichloroacetoxy or trifluoroacetoxy groups, Lower alkoxyalkylcarbonyloxy groups such as oxyacetoxy groups, or unsaturated alkylcarbonyloxy groups such as (E) -2-methyl-2-butenoyloxy groups), aromatic acyloxy groups (e.g. aryl such as benzoyloxy groups) Carbonyl A halogenated arylcarbonyloxy group such as a period, 2-bromo-benzoyloxy or 4-chlorobenzoyloxy group, a lower alkylated arylcarbonyloxy group such as 2,4,6-trimethylbenzoyloxy or 4-toluoyloxy group, Lower alkoxylated arylcarbonyloxy groups such as 4-anizoyloxy groups, nitrated arylcarbonyloxy groups such as 4-nitrobenzoyloxy groups or 2-nitrobenzoyloxy groups, and trihalomethoxy groups (e.g. trichloromethoxy) Lower alkanesulfonyloxy groups (e.g. methanesulfonyloxy or ethanesulfonyloxy groups), halogenated lower alkanesulfonyloxy groups (e.g. trifluoromethanesulfonyloxy or pentafluoroethanesulfonyloxy groups), arylsulfo Reaction with an activating acylating agent of a niloxy group (e.g., benzenesulfonyloxy or p-toluenesulfonyloxy group) The reaction is preferably carried out in a solvent in the presence of a base.

The type of solvent used is not particularly limited as long as it does not adversely affect the reaction or the reagent contained therein. Examples of suitable solvents include halogenated hydrocarbons, in particular halogenated aliphatic hydrocarbons such as methylene chloride, chloroform or carbon tetrachloride; Ethers such as diethyl ether, dioxane or tetrahydrofuran; Aliphatic hydrocarbons such as hexane; Aromatic hydrocarbons such as benzene or toluene; Esters such as ethyl acetate; And polar solvents such as sulfoxides such as dimethyl sulfoxide and amides such as dimethylformamide.

There is no particular limitation on the type of base used, and any base commonly used in this type of reaction can equally be used here. Preferred examples of the organic base include triethylamine, pyridine, DBU, DBN, N, N-dimethylaniline, N, N-diethylaniline and N, N-dimethylaminopyridine.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. Generally it is convenient to carry out the reaction at a temperature of from 0 to 100 ° C, preferably from 20 to 50 ° C. The time required for the reaction may also vary over a wide range and will depend on many factors, in particular on the reaction temperature and the type of reagent and solvent used. However, 0.1 to 24 hours will usually be sufficient when the reaction is carried out under the above-illustrated preferred conditions.

In step A6 of Scheme A, the hydroxy moiety at the 3-position of the compound of formula (XI) is modified with a group R ^3a to obtain a compound of formula (XI). This reaction is essentially carried out under the same reaction conditions using the same reagents used for the acylation of the amino moieties in step A5.

In step A ⁷ of Scheme A, the protecting group R ⁷ at the 1-position of the compound of formula (XI) is removed to prepare a compound of formula (XII).

The reaction to remove such protecting groups will, of course, depend on the nature of the protecting group itself, and any reaction known in the art to remove protecting groups in this type of compound can equally be used here.

For example, if the R ⁷ group is a silyl group, an aralkyloxycarbonyl group, an aralkyl group, an aliphatic acyl group, an aromatic acyl group, an alkoxycarbonyl group, an alkoxymethyl group or a substituted ethyl group, the removal thereof is the same as when the R ⁶ group is removed in step A4. Is carried out in a manner.

If the R ⁷ group is a tetrahydropyranyl group, tetrahydrofuranyl group, tetrahydrothiopyranyl group, tetrahydrothienyl group or vinyl group, it can generally be removed by treating the compound of general formula (XI) with an acid in a solvent. There is no particular limitation on the type of acid used, and preferred examples are hydrochloric acid, yellow sand, p-toluenesulfonic acid and acetic acid.

The reaction is generally carried out in the presence of a solvent and is preferred. There is no particular limitation on the type of solvent used unless adversely affecting the reaction or the reagent used. Examples of preferred solvents are organic solvents such as alcohols (eg methanol or ethanol), ethers (eg tetrahydrofuran or dioxane) and mixtures of one or more such organic solvents with water.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. In general, it is convenient to carry out the reaction at 0 to 50 ° C. The time required for the reaction can also vary over a wide range and will depend on many factors, in particular the reaction temperature and the type of reagent to be used. However, from 10 minutes to 18 hours will usually be sufficient when the reaction is carried out under the above-illustrated preferred conditions.

If the R ⁷ group is an alkenyloxycarbonyl group, it can be removed by treatment with a base under the same conditions as the removal reaction in the case where R ⁷ is an aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group. It should be noted that when the R ⁷ group is an allyloxycarbonyl group, it is conveniently removed with palladium and triphenylphosphine or nickel tetracarbonyl, since this reaction involves minimal side reactions.

If the R ⁷ group is an allyl group, it can be preferably removed by reacting the compound of formula (XI) in a solvent in the presence of a catalyst and transfers the double bond to convert the group to the enolether form and immediately pyridine-iodine-water or Inorganic acids such as concentrated hydrochloric acid or sulfuric acid are added.

The reaction is generally carried out in the presence of a solvent and is preferred. There is no particular limitation on the type of solvent used unless adversely affecting the reaction or the reagent used. Examples of preferred solvents include halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons (eg methylene chloride, chloroform or carbon tetrachloride); Ethers (eg diethyl ether, dioxane or tetrahydrofuran); Aliphatic hydrocarbons (eg hexane); Aromatic hydrocarbons (eg benzene or toluene); Esters (eg ethyl acetate); And polar solvents (eg sulfoxides such as dimethyl sulfoxide and fatty acid amides such as dimethylformamide).

Examples of catalysts used herein include known catalysts capable of moving double bonds, such as palladium catalysts (eg palladium chloride and palladium acetate), rhodium catalysts (eg 1,5-cyclooctadiene-bis [ Methyldiphenylphosphine] rhodium hexafluorophosphate and rhodium acetate) and iridium catalysts (eg 1,5-cyclooctadiene-bis [methyldiphenylphosphine] iridium hexafluorophosphate).

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. In general, it is convenient to carry out the 0-100 ° C. thermal reaction. The time required for the reaction can also vary over a wide range and will depend on many factors, in particular on the reaction temperature, the type of reagent, catalyst and solvent used. However, 1 to 5 hours will usually be sufficient when the reaction is carried out under the conditions outlined above roughly.

A compound of formula (XIII) is prepared by phosphorylating the hydroxy group at the 1-position of the compound of formula (XII) obtained in step A8 of Scheme A.

The phosphorylation reaction can be carried out by forming an anion with a base in a solvent and then reacting the anion with a phosphorylating agent.

There is no particular limitation on the type of solvent used unless adversely affecting the reaction or the reagent used. Examples of suitable solvents include ethers (eg diethyl ether, dioxane or tetrahydrofuran); And halogenated aliphatic hydrocarbons (eg methylene chloride).

If an anion can be formed, there is no particular limitation on the kind of base used, and any base commonly used in this type of reaction can equally be used here. Preferred examples include lithium compounds (eg butyllithium and phenyllithium); And organic bases (eg DBU, DBN, DMAP, triethylamine and pyridine).

The phosphorylating agent can be any reagent commonly used in phosphorylation reactions, for example dibenzyl chlorophosphate or diphenyl chlorophosphate.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. In general, it is convenient to carry out the reaction at a temperature of -78 to 50 ° C, preferably -78 to room temperature. The time required for the reaction may also vary over a wide range and will depend on many factors, in particular on the reaction temperature and the type of reagent and solvent used. However, 10 minutes to 24 hours will usually be sufficient when the reaction is carried out under the above-illustrated preferred conditions.

In step A9 of Scheme A, the protecting group of the compound of formula (XIII) is removed to produce the compound of formula (XIV), if desired, any protecting group present in the compound or the protecting group represented by R ^3a may also be removed. .

The type of reaction used to remove the protecting groups of the phosphoric acid residues and hydroxy-protecting groups will in principle depend on the type of protecting group, and the desired removal reaction can be carried out in any order.

If desired, the protecting group of the phosphate residue can be removed simultaneously with the removal of the hydroxy-protecting group. However, the protecting group R ¹⁰ of the phosphoric acid moiety is preferably removed last for ease of handling.

For example, if the R ¹⁰ group is an aralkyl group, such as a benzyl group, then all protecting groups, including those in which the hydroxyl group of R ^2a and / or R ^3a have a protecting group, are selected from the palladium-on-carbon catalyst at -78 ° C to 25 ° C. It can be removed at one time by catalytic reduction in the presence. If R ¹⁰ is also an aryl group such as a phenyl group, removal of the protecting group can be carried out by catalytic reduction in the presence of a palladium-on-carbon catalyst and then by catalytic reduction in the presence of a platinum oxide catalyst.

In the case of a protecting group containing an R ⁸ group or an R ⁹ group (in the case of acetonide) it can be optionally removed by purification using silica gel chromatography. However, solvents (e.g. aqueous acetic acid, ethers (e.g. tetrahydrofuran or dioxane)) or alcohols (e.g. ethanol or ethanol) are generally used at 0 to 100 DEG C using a catalyst such as dilute hydrochloric acid, dilute sulfuric acid or Methanol)) can more conveniently remove the protecting group.

To obtain a water-soluble phosphate, the general formula (XIV) compound is first washed with an inorganic acid (e.g. diluted hydrochloric acid) diluted with water, dissolved in a solvent (e.g. chloroform) and then a base is added.

Schemes B-E illustrate a process for producing different or intermediate products through different routes.

In step B1 of Scheme B, the hydroxy group at the 3-position of the compound of formula (VIII) prepared in step A3 is acylated with a group R ^3a to prepare a compound of formula (XV). Acylation is essentially the same reaction as described in step A5 and can be carried out under the same reagents and reaction conditions.

In step B2 of Scheme B, the general formula (XVI) compound is prepared by removing the protecting group R ⁶ of the amino group at the 2-position of the compound of formula (XV) in the same manner as described in step A4.

In step B3 of Scheme B, the compound of formula (XI) is prepared by modifying the amino group at the 2-position of the compound of formula (XVI) with the group R ^2a by the method as described in step A5.

The compound of formula (XI) thus obtained is carried out according to the method described in steps A7 to A9 to prepare a compound corresponding to the compound of formula (XIV).

In step C1 of Scheme C, a compound of formula (XVII) is prepared by removing the hydroxy groups at the 4- and 6- positions of the compound of formula (XI). This is done in a similar manner as described in step A9.

In step C2 of Scheme C, the hydroxy group at the 6-position of the compound of formula (XVII) is protected with a group R ¹¹ to prepare a compound of formula (XVIII).

The general formula (XVIII) compound is a base (eg DBU, DBN, DMAP, DABCO, pyridine, triethylamine, iniline, Solvents using N, N-dimethylaniline or N, N-diethylaniline (e.g., halogenated hydrocarbons (e.g. methylenechloride, chloroform or carbon tetrachloride), ethers (diethyl ether, dioxane or tetrahydrofuran), aliphatic hydrocarbons (Eg hexane), aromatic hydrocarbons (eg benzene or toluene), esters (eg ethyl acetate), or polar solvents (eg dimethylsulfoxide, dimethylformamide or acetone); Or a compound of the general formula R ¹¹ Y in a solvent (e.g. acetone, tetrahydrofuran or dioxane) using an aqueous solution of a base (e.g. sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate) R ¹¹ and Y are as defined above.) Yes. Chloromethyl methyl ether, benzyl, chloromethyl ether, benzyl bromomethel ether, benzyl chloroformate or 2,2,2-trichloroethyl chloroformate).

In step C3 of Scheme C, the hydroxy group at the 4-position of the compound of formula (XVIII) is phosphorylated to prepare a compound of formula (XIX). This reaction is essentially the same reaction as described in step A8 and can be carried out using the same reagents and reaction conditions.

In step C4 of Scheme C, the protecting group of the compound of formula (XIX) is removed to make compound of formula (XX). In this step, the protecting groups R ⁷ and R ¹¹ of the hydroxyl group can be removed according to the method described in step A7. If a hydroxy-protecting group is present on R ^2a and / or R ^3a , the protecting group R ¹² removal of this protecting group and the phosphate residue can be carried out according to the method described in step A9. However, it is preferable to carry out under the condition that the protecting group R ¹² of the phosphate residue can be removed first after removing other protecting groups.

Optionally, in step C5 of Scheme C, according to the method described in step A7, optionally remove the protecting group of the hydroxy group in the 1-position of the general formula (XIX) compound, the compound produced according to the method of step A8 The hydroxyl group at the 1-position of is phosphorylated. If the hydroxy-protecting group R11 and / or the hydroxy-protecting group is present on R ^3a and / or R ^2a , the protecting group R ¹² of the phosphate residue is removed according to the security described in step A9 to prepare a general formula (XXI) compound. can do.

In step D1 of Scheme D, the hydroxyprotecting group R ⁷ at the 1-position of the compound of formula (XIX) is optionally removed to prepare a compound of formula (XXII). This reaction is essentially the same as the removal reaction described in step A7 of Scheme A and is carried out using the same reagents and reaction conditions.

In step D2 of Scheme D, a fluorinating agent is used to replace the hydroxy group at the 1-position of the compound of formula (XXII) with a fluorine atom to prepare a compound of formula (XXIII).

The reaction is preferably carried out in the presence of a solvent. There is no particular limitation on the type of solvent used, as long as it does not adversely affect the reaction and the reagents used and the starting materials are dissolved to at least some extent. Examples of suitable solvents include aliphatic hydrocarbons (eg hexane, heptane, ligroin or petroleum ether); Aromatic hydrocarbons (eg benzene, toluene or xylene); Halogenated hydrocarbons (eg methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene); Esters (eg ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate); Ethers (eg diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether); And ketones (eg acetone methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone).

The type of fluorinating agent used herein is not particularly important and any reagent typically used for the fluorination of alcohols can be used in this reaction. Preferred examples include compounds of the general formula (R ¹³ ) (R ¹⁴ ) NSF ₃ . [Wherein, R ¹³ and R ¹⁴ are the same or different and each represent a lower alkyl group (preferably methyl or ethyl group) as exemplified above, or both lower alkylene which may be optionally interrupted by an oxygen atom Group; Examples of lower alkylene groups include alkylene having 1 to 6 carbon atoms, such as methylene, methylmethylene, ethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene and 3-methyltrimethylene , 3-pentamethylene and hexamethylene groups, and tetramethylene or pentamethylene groups are preferable. Dialkylaminosulfurtrifluoride is preferred.

The reaction can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. In general, it is convenient to carry out the reaction at -20 to 120 ° C, preferably 0 to 100 ° C. The time required for the reaction can also vary over a wide range and will depend on many factors, in particular the reaction temperature and the type of reagent used. However, 0.1 to 5 days will usually be sufficient when the reaction is carried out under the above-illustrated preferred conditions.

In step D3 of Scheme D, the protecting group R ¹¹ of hydroxy at the 6-position of the compound of formula (XXIII) is removed to prepare a compound of formula (XXIV), and if desired, to groups R ^2a and / or R ^3a . Remove the protecting group of the hydro unit. This step is essentially the same as the reaction described in step A7 and is carried out using the same reagents and reaction conditions.

In step D4 of Scheme D, the protecting group of the phosphate residue of the compound of formula (XXIV) is removed to prepare a compound of formula (XXV). This reaction is essentially the same as described in Scheme A step A9 and is carried out using the same reagents and reaction conditions.

In step E1 of Scheme E, the protecting group R11 of the hydroxy group at position 6- of formula (XIX) is optionally removed to prepare a compound of formula (XXVI). This reaction is essentially the same as described in Scheme A, step A7, and is carried out using the same reagents and reaction conditions.

In step E2 of Scheme E, the hydroxy group at the 6-position of the compound of formula (XXVI) is converted to a fluorine atom to prepare a compound of formula (XXVII). This reaction is essentially the same as the fluorination reaction described in step D2 of Scheme D and is carried out using the same reagents and reaction conditions.

In step E3 of Scheme E, the hydroxy protecting group R ⁷ at the 1-position of the compound of formula (XXVII) is optionally removed to prepare a compound of formula (XXVIII). This step is the same as the reaction described in step A7 and is carried out using the same reagents and reaction conditions.

In step E4 of Scheme E, the phosphate residue protecting group of the compound of formula (XXVIII) is removed to prepare a compound of formula (XXIX). If desired, any of the hydroxy-protectors in the R ^2a and / or R ^3a groups can be removed according to the method described in step A9 of Scheme A.

[Biological activity]

It has now been found that the compounds of the present invention have no deleterious toxicity of lipid A, have activity of lipid A type and are associated with natural products or compounds derived from such natural products. This activity is shown by the following experiment.

[Quantitative analysis of [ ¹⁴ C] -prostaglandin D2 released from cultured cells]

The cell used is a murine cell line J774.1 such as a macrophage. Inoculate approximately 5 × 10 ⁵ cells per well into each 12-well dish with 1 ml culture medium containing Ham F-12 supplemented with 10% newborn calf serum.

Cells are incubated overnight at 37 ° C., then incubated for 18 hours at 37 ° C. with [14 C] -arachidonic acid and labeled at ¹⁴ C. Wash three times with 0.5 ml culture medium maintained at 37 ℃. One of the compounds under test is then added to each well by 10 μmol and the cells are further incubated at 37 ° C. for 12 hours. The culture medium is harvested and centrifuged at 10,000 x G for 5 minutes. The solution was acidified to pH 3.0 by adding 0.1N aqueous hydrochloric acid solution, and the prostaglandin D2 released into the medium was extracted using a mixture of chloroform and methanol 2: 1 by volume. The resulting mixture is analyzed by thin membrane chromatography (TLC) using chloroform, ethyl acetate, methanol, acetic acid and water in a 70: 30: 8: 1: 0.5 volume ratio as the developing solution. The prostaglandin D2 labeled with the radioactive element is located by autoradiography. The part showing the radioactivity is scraped off the TLC plate and counted with a suntilization counter to measure the amount of prostaglandin D2 produced. The amount of prostaglandin inspired by the test compound is a measure of the activity of the compound, such as lipid A. References Zoeller et al., J. Biol. Chem., 262, No. 35, pp 17212-17220 (1987).

Several compounds of the present invention were tested and these are shown in Table 4 below with reference to the following Example No. for which the compounds were prepared. In addition, the known compound GLA-60, which is considered to be the most active among the presently known compounds of this type, is tested. As the number of counts per minute, the results are shown in Table 4 below.

As can be seen from the above results, the compounds of the present invention have a much better activity than GLA-60, and the compounds of the present invention tested above show an important degree of activity, even at the worst.

Therefore, the compounds of the present invention are expected to be useful for the treatment, prevention, maintenance and diagnosis of various diseases and disorders, including a deficiency of the immune system and tumor conditions. The compounds may also play a role in inhibiting AIDS.

The compounds of the present invention can be administered to humans or other patients via any route and, if desired, to facilitate administration, absorption, migration or acceptance of the patient or therapist to the active site, as is known in the art. Or may be formulated with conventional additives, excipients, diluents or such other agents. For example, oral administration in the form of tablets, capsules, granules, powders or syrups; Or parenterally in the form of injections or suppositories. Such pharmaceutical preparations may be prepared by conventional means using additives such as excipients, binders, disintegrants, lubricants, stabilizers or copulating agents. Dosage may depend on several factors, including the condition, age and weight of the patient as well as the type and severity of the disease or disorder to be treated. In general, however, the daily dose of an adult patient is on the order of 0.01-50 mg / kg, which can be administered at one time or dividedly.

The invention will be further illustrated by the following non-limiting examples, which illustrate the preparation of various compounds of the invention.

Example 1

2-deoxy-2-[(3'R) -3'hydroxytetradecanoylamino] -3-0-[(2RS, 3SR) -2-fluoro-3-hydroxytedecanoyl] -α -D-glucopyranosyl-1-phosphate

[1 (a) N-trifluoroacetylglucosamine]

160 g (0.742 mole) of D-(+)-glucosamine hydrogen chloride is dissolved in 2200 ml of methanol (99.6% purity) and 187.9 g (1.86 moles) of triethylamine are added to the resulting solution. 115.9 g of ethyl trifluoroacetate was added dropwise to the resulting mixture under ice cooling, and the mixture was stirred overnight at room temperature. Thereafter, the mixture was concentrated by evaporation under reduced pressure, and benzene (250 ml twice) and ethyl acetate (250 ml) were added repeatedly to the residue, concentrated by evaporation under reduced pressure, and finally sufficiently dried in a sufficient vacuum. . The entire resulting trifluoroacetyl compound is used in the next step (b) without purification.

[1 (b) Allyl 2-deoxy-2-trifluoroacetylamino-D-glucopyranoside]

To the crude trifluoroacetyl compound obtained as described in Example 1 (a) is added 1850 ml of a 2% w / w hydrochloric acid solution dissolved in allyl alcohol and the mixture is heated at reflux for 30 minutes. The mixture is then cooled to about 50 ° C. with ice water and filtered through Celite (tradename), a filter aid. The filtrate is concentrated by evaporation under reduced pressure and dried sufficiently in vacuo. The resulting crude allylether compound is used in next step 1 (c) without purification.

[1 (c) Allyl 2-deoxy-2-trifluoroacetylamino-4,6-0-isopropylidene-D-glucopyranoside]

The entire crude allylether compound obtained as described in Example 1 (b) is dissolved in 740 ml of dimethylformamide and 370 ml of 2,2-dimethoxypropane is added to the resulting solution. 7.5 g of pyridinium p-toluene sulfonate are then added and the mixture is stirred overnight at room temperature. The mixture is then concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The precipitate is filtered off and the filtrate is washed in order of saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution; Thereafter, anhydrous magnesium sulfate is dried. The dried material is filtered using Celite filter aid and activated charcoal, and the filtrate is concentrated by evaporation under reduced pressure. The residue was taken up in a silica gel chromatography column (eluent: a mixture of cyclohexane and ethyl acetate in a 3: 2 volume ratio), separated and purified, and 80.5 g of the title compound having an α-ether bond in the 1-position and 1 77.3 g of the title compound having the β-ether bond in the -position are obtained. Both α-compounds and β-compounds can be used for the subsequent reaction of step 1 (d).

α-allyl compound:

Mass spectrum m / z: 356 (M ⁺ + 1), 340, 298, 282, 256, 240, 222, 211, 193, 168, 126, 109, 101

β-allyl compound:

Mass spectrum m / z: 356 (M ⁺ + 1), 340, 298, 280, 240, 222, 211, 193, 168, 155, 145, 126, 114, 101

[1 (d) Allyl 2-deoxy-2-amino-4,6-0-isopropylidene-β-D-glucopyranoside]

10 g of the trifluoroacetyl compound obtained as described in Example 1 (c) above was dissolved in 200 ml of ethanol (99.5% purity), and 100 ml of 1N aqueous sodium hydroxide solution was added to the resulting solution. The mixture is heated at reflux for 4 hours. The mixture is then concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with water and aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was removed by evaporation under reduced pressure. The residue in the oil phase is put into a silica gel chromatography column (eluent: ethyl acetate) and purified to give 6.6 g (yield 90.5%) of the title compound.

NMR Spectrum (CDCI ₃ , 60 MHz)

δ ppm:

1.43 (3 H, s);

1.52 (3H, s);

2.40 (3H, broad singlet);

2.6-4.6 (9H, m);

5.05-6.35 (3H, m).

Elemental Analysis C ₁₂ H ₂₁ NO ₅ (Molecular Weight 259.3)

Calculated: C, 55.58%; H, 8. 16%; N, 5.40%.

Found: C, 55.37%; H, 8.05%; N, 5.40%.

[1 (e) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxytetradecanoylamino] -4,6-0-isopropylidene-β-D-glucopyranoside]

5 g (19.3 mmol) of the compound obtained as described in Example 1 (d) above were dissolved in 150 ml of methylene chloride, and then 6.8 g of (R) -3-benzyl-oxytetradecanoic acid was added to the resulting solution. Then, 4.79 g of N, N'-dicyclohexylcarbodiimide is added and stirred at room temperature for 1 hour. The mixture is then filtered, the filtrate is concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. It is filtered and ethyl acetate is removed by evaporation under reduced pressure. The residue is purified by silica gel column chromatography (eluent 1: 1 mixture of cyclohexane and ethyl acetate) to afford 5.33 g (yield 48%) of the title compound.

IR absorption spectrum (KBr) υ _max cm ^-1 :

3510, 3280, 1643, 1550

NMR Spectrum (CDCI ₃ , 270 MHz) δppm:

0.88 (3H, t, J = 6.9 Hz);

1.20-1.41 (18H, m);

1.45 (3 H, s);

1.52 (3H, s);

1.56-1.70 (2H, m);

2.43 (1H, doublet of doublets, J = 6.9 15.4 Hz);

2.56 (1H, doublet of doublets, J = 3.7 15.0 Hz);

3.19-3.29 (1 H, m);

3.46-3.63 (2H, m);

3.75-3.94 (5H, m);

4.18-4.24 (1 H, m);

4.36 (1H, doublet, J = 2.6 Hz);

4.45-4.62 (3H, m);

5.12-5.26 (2H, m);

5.70-5.88 (1 H, m);

6.72 (1H, doublet, J = 5.9 Hz);

7.30-7.37 (5H, m).

[1 (f) Allyl2-deoxy-2-[(3'R) -3'-benzyloxytetradecanoylamino] -3-0-[(2RS, 3SR) -2-fluoro-3- ( Benzyloxycarbonyloxy) tetradecanoyl] -4,6-0-isopropylidene-β-D-glucopyranoside]

1 g (1.74 mmol) of N-acyl compound obtained as described in Example 1 (e) was dissolved in 80 ml of methylene chloride and 828 mg of (+)-syn-2-fluoro-3 in the resulting solution. Benzyloxycarbonyltetracanoic acid is added; To the resulting mixture, 359 mg of N, N'-dicyclohexylcarbodiimide and 255 mg of 4-dimethylaminopyridine are added sequentially, and the mixture is stirred at room temperature for 1 hour. The mixture is then filtered, concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed in order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. It is then filtered and the ethyl acetate is removed by evaporation under reduced pressure. The residue was taken up in silica gel column chromatography (eluent 5: 1 volume ratio of cyclohexane and ethyl acetate mixture) to yield 1.22 g (yield 73.6%) of the title compound.

Elemental _{analysis: C 55 H 84 FNO 11 ·} H 2O ( molecular weight 972.3)

Calculated: C, 67.94%; H, 8.96%; N, 1.44%; F, 1.95%.

Found: C, 67.79%; H, 8.98%; N, 1.40%; F, 1.96%.

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3290, 1750, 1655.

NMR Spectrum (CDCI ₃ , 60 MHz)

δppm:

0.66-2.43 (57H, m);

3.12 = 6.53 17H, m [including 4.98 (2H, s)]};

7.28 (10 H, s).

[1 (g) 2-deoxy-2-[(3'R) -3'-benzyloxytetradecanoylamino] -3-0-[(2RS, 3SR) -2-fluoro-3- (benzyl Oxycarbonyloxy) -tetradecanoyl] -4,6-0-isopropylidene-D-glucopyranose]

380 mg of the compound obtained as described in Example 1 (f) above was dissolved in 20 ml of dry tetrahydrofuran, and 17 mg (5% mole) of 1,5-cyclooctadiene-bis [methyldi in the resulting solution Phenylphosphine] iridium hexafluorophosphate is added.

The reaction vessel is first purged with nitrogen followed by hydrogen. As soon as the color of the liquid changes from red to colorless, the atmosphere of the reaction vessel is replaced with nitrogen. After stirring the mixture for 3 hours at room temperature, 2 ml of water, 200 mg of iodine and 0.2 ml of pyridine are added, and the mixture is further stirred at room temperature for 30 minutes. Thereafter, the mixture is concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The reaction mixture was washed in the order of 5% w / v aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and then the mixture was dried over anhydrous magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The resulting residue is taken up in silica gel column chromatography (eluent 3: 3 volume ratio of cyclohexane and ethyl acetate mixture) to give 280 mg (yield 76.9%) of the title compound.

NMR Spectrum (CDCI ₃ , 60 MHz)

δ ppm:

0.53-2.78 (58H, m);

3.48-5.43 11H, m [including 5.12 (2H, s)];

6.25 (1H, doublet, J = 8 Hz);

7.28-7.48 (10 H, m).

Elemental analysis: C ₅₂ H ₈₀ FNO ₁₁ (Molecular Weight 914.2)

Calculated value: C, 68.32%; H, 8. 82%; N, 1.53%; F, 2.08%

Found: C, 68.17%; H, 8.99%; N, 1.56%; F, 2.13%

[1 (h) 2-deoxy-2-[(3'R) -3'-hydroxytetradecanylamino] -3-0-[(2RS, 3SR) -2-fluoro-3-hydroxy Tetradecanoyl] -α-D-glucopyranosyl-1-phosphate]

550 mg of the compound obtained as described in Example 1 (g) above was dissolved in 20 ml of dry tetrahydrofuran, and 0.4 ml of butyllithium (1.6 dissolved in hexane at -78 ° C under nitrogen) was added to the resulting solution. M solution) is added slowly. After 2 minutes, 5 ml of dry tetrahydrofuran solution containing 231 mg of dibenzylphosphorochlorate is added dropwise to the mixture. After 5 minutes, 1 g of 10% w / w palladium-on-carbon is added to cause hydrogenation at the same temperature. After 15 minutes, the mixture is returned to room temperature at -78 ° C and stirred for 3 hours. Thereafter, it is filtered and tetrahydrofuran is removed by evaporation under reduced pressure. The residue was taken up in silica gel column chromatography (eluent: 5: 1 volume ratio of chloroform and methanol mixture) to yield 98 mg (yield 22.3%) of the title compound.

FAB mass spectrum, m / z: 728 [M, -H]

(FAB / MS is a fast atomic impact mass spectrum.)

Example 2

[2-deoxy-2 [(2'R, 3'S) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3-hydroxytetradecanoyl] -α-D-glucopyranosyl-1-phosphate

2 (a) allyl 2-deoxy-2-[(2'R, 3'S) and (2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -4,6-0-isopropylidene-β-D-glucopyranoside

200 ml of 10 g (38.56 mmol) allyl 2-deoxy-2-amino-4,6-0-isopropylidene-β-D-glucopyranoside [prepared as described in Example 1 (d)] Of methylene chloride, and 16.06 g of (+)-syn-2-fluoro-3- (benzyloxycarbonyloxy) tetradecanoic acid is added to the resulting solution. 9.55 g of N, N'-dicyclohexylcarbodiimide was added to the resulting mixture, followed by stirring at room temperature for 1 hour. The mixture is then filtered and concentrated by evaporation under reduced pressure and then diluted with ethyl acetate. The ethyl acetate layer was washed in order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. It is filtered and ethyl acetate is removed by evaporation under reduced pressure. The residue was purified by silica gel chromatography column (eluent: 2: 1 volume ratio of cyclohexane and ethyl acetate mixture), and 9.60 g (yield 39.0%) of (2'R, 3'S) isomer of 9.2 g of desired N-acyl compound and 9.67. g (yield 39.3%) of (2'S, 3'R) isomer of the desired N-acyl compound is obtained.

(2'R, 3'S) Compound

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (3H, t, J = 6.9 Hz);

1.18-1.43 (18H, m);

1.47 (3H, s);

1.53 (3 H, s);

1.67-1.98 (2H, m)

3.15-3.24 (1H, m);

3.57-3.84 (5H, m);

3.91 (1H, doublet of doublets, J = 5.5 10.6 Hz);

4.02 (1H, doublet of doublets, J = 6.2 12.8 Hz);

4.23-4.30 (1 H, m);

4.39 (1H, doublet, J = 8.06 Hz);

4.94 (1H, doublet of doublets, J = 2.2 47.6 Hz);

5.14-5.28 (5H, m);

6.45 (1H, t, J = 5.4 Hz)

7.34-7. 41 (5H, m);

IR absorption spectrum (CDCI3) υ _max cm ^-1 :

1750, 1685, 1535.

Elemental Analysis C ₃₄ H ₅₂ FN _O9 (Molecular Weight 637.8)

Calculated: C, 64.03%; H, 8.22%; N, 2.20%; F, 2.98%

Found: C, 63.96%; H, 8. 44%; N, 2.59%; F, 2.97%

(2'S, 3'R) Compound

NMR Spectrum (CDCI ₃ , 270 MHz)

δppm:

0.88 (3H, t, J = 6.9 Hz);

1.18-1.43 (18H, m);

1.45 (3 H, s);

1.53 (3 H, s);

1.54-2.01 (2H, m);

3.30-3.36 (3H, m);

3.55 (1H, t, J = 9.5 Hz);

3.80 (1H, t, J = 10.3 Hz);

3.93 (1H, doublet of doublets, J = 5.5 11.0 Hz);

4.01-4.14 (2H, m);

4.27 (1H, doublet of doublets, J = 5.5 18.3 Hz);

4.87 (1H, doublet, J = 8.4 Hz);

4.91 (1H, doublet of doublets, J = 2.2 48.0 Hz);

5.09-5.3 (5H, m);

5.78-5.93 (1 H, m);

6.60 (1H, t, J = 5.1 Hz);

7.26-7. 38 (5H, m);

Elemental Analysis C ₃₄ H ₅₂ FNO ₉ (Molecular Weight 637.8):

Calculated: C, 64.03%; H, 8.22%; N, 2.20%; F, 2.98%

Found: C, 63.84%; H, 8.33%; N, 2.76%; F, 3.02%

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1750, 1685, 1535.

[2 (b) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3-benzyloxytetradecanoyl] -4,6-0-isopropylidene-β-D-glucopyranoside]

3.5 g (5.49 mmol) of the (2'R, 3'S) compound obtained as described in Example 2 (a) were dissolved in 150 ml of methylene chloride and 1.93 g of (R) -3-benzyl in the resulting solution. Oxytedecanoic acid is added. 0.7 g of 4-dimethylaminopyridine and 1.36 g of N, N'-dicyclohexylcarbodiimide were added to the resulting mixture, followed by stirring at room temperature for 1 hour. Then the mixture is filtered, concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed in the order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. It is filtered and ethyl acetate is removed by evaporation under reduced pressure. The residue was taken up in silica gel column chromatography (eluent 5: 1 volume ratio of cyclohexane and ethyl acetate mixtures) to yield 3.54 g (yield 67.6%) of the title compound.

NMR Spectrum (CDCI ₃ , 270 MHz) δppm:

0.88 (6H, t, J = 6.6 Hz);

1.25-1.73 (46H, m);

2.42-2.61 (2H, m);

3.35-3.42 (1 H, m);

3.56-4.08 (6H, m);

4.21-4.28 (1 H, m);

4.40-4.98 (4H, m);

5.07-5.36 (6H, m);

5.72-5.86 (1 H, m);

6.44-6.48 (1 H, m);

7.14-7.35 (10H, m);

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1743, 1695, 1530.

[2 (c) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R ) -3-benzyloxytetradecanoyl] -4,6-0-isopropylidene-D-glucopyranose]

All of the compounds prepared as described in Example 2 (b) above were treated in the same manner as described in Example 1 (g) to yield 2.69 g (yield 79.3%) of the title compound.

NMR Spectrum (CDCI ₃ , 270 MHz)

δppm:

0.88 (6H, t, J = 6.2 Hz);

1.23-1.73 (46H, m);

2.42-2.54 (3H, m);

3.60-4.02 (6H, m);

4.42 5.27 (9H, m);

7.16-7.46 (10 H, m).

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1745, 1685, 1535.

[2 (d) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3-hydroxy Loxytetradecanoyl] -α-D-glucopyranosyl-1-phosphate]

914 mg of the compound obtained as described in Example 2 (c) was treated in the same manner as described in Example 1 (h) to give 91 mg (11% yield) of the title compound.

FAB mass spectrum, m / z: 728 [M ⁻ H] ⁻

Example 3

[2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-hydroxytetradecanoylamido] -3-0-[(3R) -3-hydroxytedeca Noyl] -α-D-glucopyranosyl-1-phosphate

3 (a) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R ) -3- (benzyloxycarbonyloxy) tetradecanoyl] -4,6-0-isopropylidene-β-D-glucopyranoside]

3.5 g of allyl 2-deoxy-2- (2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino-4,6-0-isopropylitrate- β-D-glucopyranoside [prepared as described in Example 2 (a)], 2.0 g (R) -3 dissolved in 150 ml of methylene chloride in the same manner as in Example 2 (b) Reaction with benzyloxycarbonyloxytetradecanoic acid, 0.7 g of 4-dimethylaminopyridine and 1.36 g of N, N'-dicyclohexylcarbodiimide to yield 2.7 g (yield 49.3%) of the title compound.

3 (b) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R) -3- (benzyloxycarbonyloxy-tetradecanoyl] -4,6-0-isopropylidene-D-glucopyranose

All of the compounds obtained as described in Example 3 (a) were treated by the method as described in Example 1 (g) to yield 1.75 g (yield 67.5%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.81-2.34 (52H, m);

2.47-2.78 (2H, m);

3.00 (1 H, broad singlet);

3.45-5.51 {14H, m [including 5.12 (4H, s)]};

6.65 (1 H, broad singlet);

7.35 (10 H, s).

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1745, 1670, 1545.

[3 (c) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-hydroxytetradecanoylamido] -3-0-[(3R) -3- Hydroxytetradecanoyl) -α-D-glucopyranosyl-1-phosphate]

All of the compounds obtained as described in Example 3 (b) were treated by the method as described in Example 1 (h) to afford 190 mg (yield 29.3%) of the title compound.

Example 4

[2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-hydroxytetradecanoylamido] -3-0-[(3R) -3-hydroxytedeca Noyl] -α-D-glucopyranosyl-4-phosphate]

4 (a) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R ) -3- (benzyloxycarbonyloxy) tetradecanoyl) -4,6-0-isopropylidene-β-D-glucopyranoside

5.1 g of allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -4,6-0-isopropyl 2.9 g of riden-α-D-glucopyranoside [prepared as described in Example 2 (a)] was dissolved in 200 ml of methylene chloride in the same manner as described in Example 3 (a). 6.1 g (yield 77.9%) by reaction with (R) -3- (benzyloxycarbonyloxy) tetradecanoic acid, 1.0 g of 4-dimethylaminopyridine and 2.0 g of N, N'-dicyclohexylcarbodiimide To give the title compound.

NMR Spectrum (CDCI _3, 60 MHz)

δppm:

0.86-2.23 (52H, m);

2.45-2.84 (2H, m);

3.17-6.30 {19H, [including 5.12 (4H, s)]};

6.58 (1 H, broad singlet);

7.33 (10 H, s).

IR absorption spectrum (KBr) υ _max cm ^-1 ;

1745, 1671, 1545.

[4 (b) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3- (benzyloxycarbonyloxy) tetradecanoyl] -β-D-glucopyranoside]

5 g (5.24 mmol) of the compound obtained as described in Example 4 (a) are suspended in 50 ml of an aqueous 80% v / v acetic acid solution, and the suspension is stirred at 50 ° C. for 30 minutes. Thereafter, acetic acid is removed by evaporation under reduced pressure. The residue is purified by silica gel column chromatography (eluent 1: 1 mixture of cyclohexane and ethyl acetate) to yield 4.55 g (yield 94.8%) of the title compound.

NMR Spectrum (CDCI ₃ , 270 MHz)

δppm:

0.88 (6H, t, J = 6.9 Hz);

1.08-1.84 (40H, m);

2.47 (1H, doublet of doublets, J = 8.1 15.0 Hz);

2.58 (1H, doublet of doublets, J = 3.7 15.0 Hz);

3.26 (1 H, br);

3.40-3.45 (1 H, m);

3.61 (1H, t, J = 9.2 Hz);

3.75-3.94 (3H, m);

4.00-4.31 (2H, m);

4.63 (1H, doublet, J = 8.4 Hz);

4.82-5.28 (11 H, m);

5.75-5.88 (1 H, m);

6.00 (1H, doublet of doublets, J = 4.4 8.4 Hz);

7.33-7. 38 (10H, m);

Elemental analysis: C ₅₂ H ₈₀ FNO ₁₃ (Molecular Weight 958.2)

Calculated: C, 66.43%; H, 8.42%; N, 1.46%; F, 1.98%

Found: C, 66.48%; H, 8.72%; N, 1.60%; F, 1.96%

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1745, 1695, 1535.

[4 (c) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3- (benzyloxycarbonyloxy) tetradecanoyl] -6-0-benzyloxycarbonyl-β-D-glucopyranoside]

4.3 g (4.5 mmol) of the compound obtained as in Example 4 (b) are dissolved in 100 ml of methylene chloride and 822 mg of 4-dimethylaminopyridine is added to the resulting solution. 916 mg benzylchloroformate is added dropwise and the mixture is stirred at room temperature for 1 hour. The mixture is then concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed in the order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.

It is filtered and ethyl acetate is removed by evaporation under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent: 5: 1 volume ratio of cyclohexane and ethyl acetate mixtures) to afford 2.43 g (yield 49.6%) of the title compound.

NMR Spectrum (CDCI ₃ , 60 MHz)

δppm:

0.64-1.89 (46 H, m);

2.37-2.64 (2H, m);

3.09-6.20 {22H, m [including 5.09 (4H, s), 5.13 (2H, s)]};

6.49 (1 H, br);

7.32 (15 H, s).

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1745, 1695, 1533.

[4 (d) Allyl 2-deoxy-2-[[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0- [ (3R) -3- (benzyloxycarbonyloxy) tetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxycarbonyl-β-D-glucopyranoside]

2.2 g (2.01 mmol) of the compound obtained as in Example 4 (c) are dissolved in 30 ml of methylene chloride, and 1.47 g of 4-dimethylaminopyridine is added to the resulting solution. After 1.62 g of diphenylchlorophosphate is added dropwise, the mixture is stirred at room temperature for 1 hour. Thereafter, the mixture is concentrated by evaporation under reduced pressure and the ethyl acetate is diluted. The ethyl acetate layer was washed in the order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After filtration, ethyl acetate is removed by evaporation under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent: 3: 1 volume ratio of cyclohexane and ethyl acetate mixture) to afford 2.65 g (yield 99.3%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.64-2.05 (46H, m);

2.25-2.51 (2H, m);

3.00-6.15 {21H, m [including 5.08 (6H, s)]};

6.63 (1 H, br);

7.18-7.33 (25H, m).

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1747, 1690, 1590, 1530.

[4 (e) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R ) -3- (benzyloxycarbonyloxy) tetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxycarbonyl-D-glucopyranose]

2.50 g of the compound obtained as described in Example 4 (d) were treated in the same manner as described in Example 1 (g) to yield 1.68 g (yield 69.3%) of the title compound.

NMR Spectrum (CDCI ³ , 270MHz) δppm:

0.88 (6H, t, J = 6.2 Hz);

1.13-1.71 (40H, m);

2.37 (1H, doublet of doublets, J = 7.33 17.22 Hz);

2.55 (1H, doublet of doublets, J = 5.13 17.22 Hz);

3.61 (1 H, br);

3.83-3.90 (1 H, m);

4.16-4.37 (3H, m);

4.64-4.81 (2H, m);

4.96-5.28 (9H, m);

5.56 (1H, doublet of doublets, J = 9.2 11.0 Hz);

6.84 (1H, doublet of 3.3 7.7 Hz);

7.09-7.37 (25H, m);

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1743, 1685, 1590.

[4 (f) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3-hydroxy Loxytetradecanoyl] -D-glucopyranosyl-4-phosphate]

1.3 g (1.01 mmol) of the compound obtained as described in Example 4 (e) were dissolved in 30 ml of tetrahydrofuran and 1 g of 10% w / w palladium-on-carbon was added to the resulting solution. Add. The catalytic reduction takes place under hydrogen atmosphere at room temperature for 3 hours. Thereafter, the reaction mixture is filtered, and 200 mg of platinum oxide is added to the filtrate to further perform catalytic reduction for 2 hours at room temperature. The reaction mixture is filtered and then tetrahydrofuran is removed by evaporation under reduced pressure. The residue was first purified by chromatography on a silica gel column using a 9: 1 volumetric chloroform and methanol mixture as eluent, followed by a 5: 1 volumetric chloroform and methanol mixture as eluent to give 490 mg (yield 66.3%). Obtain the title compound.

IR absorption spectrum (KBr) υ _max cm ^-1 :

1710, 1660.

FAB mass spectrum, m / z: 728 [M-H] −

Example 5

[2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3-hydroxytetradecanoyl ] -D-glucopyranosyl-4-phosphate

5 (a) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R ) -3-benzyloxytetradecanoyl] -4,6-0-isopropylidene-β-D-glucopyranoside]

4.5 g (7.06 mmol) allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -4,6- 0-isopropylidene-β-D-glucopyranoside [prepared as described in Example 2 (a)] is dissolved in 100 ml of tetrahydrofuran and 857 ml of triethylamine is added to the resulting solution. . 2.86 g of 3-benzyloxytetradecanoylchloride is added dropwise to the resulting mixture, and the mixture is stirred at room temperature for 1 hour. The mixture is then concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed in order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. It is filtered and ethyl acetate is removed by evaporation under reduced pressure. The residue is purified by silica gel column chromatography (eluent: 5: 1 volume ratio of cyclohexane and ethyl acetate mixture) to give 5.1 g (yield 75.7%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.65 to 2.08 {52H, m [including 1.43 (3H, s)]}

2.43 to 2.72 (2H, m);

3.05 to 6.21 {19H, m [including 4.48 (2H, s), 5.12 (2H, s)]};

6.31 to 6.67 (1H, m);

7.28 (5 H, s);

7.30 (5 H, s).

IR absorption spectrum (KBr) υ _max cm ^-1 :

1745, 1670, 1545, 1268, 1089.

[5 (b) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3-benzyloxytetradecanoyl] -β-D-glucopyranoside]

4.50 g of the compound obtained as described in Example 5 (a) were treated by the method as described in Example 4 (b) to yield 4.14 g (yield 96%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.62 to 2.18 (46H, m);

2.32 to 2.91 (4H, m);

3.20 to 4.25 (8H, m);

4.28 to 4.71 {3H, m [including 4.48 (2H, s)]};

4.86-6.19 (8H, m);

6.45 to 6.85 (1 H, m);

7.28 (5 H, s);

7.31 (5 H, s);

IR absorption spectrum (KBr) υ _max cm ^-1 :

1742, 1669, 1578, 1271.

[5 (c) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3-benzyloxytetradecanoyl] -6-0-benzyloxycarbonyl-β-D-glucopyranoside]

Compound 3.80 obtained as described in Example 5 (b) was treated in the same manner as described in Example 4 (c) to afford 2.85 g (yield 65.4%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.85 to 2.08 (46H, m);

2.41 to 2.64 (2H, m);

3.00 (1 H, broad singlet);

3.48 to 6.08 {21H, m [including 4.45 (2H, s), 5.15 (4H, s)]};

6.18 to 6.72 (1H, m);

7.26 to 7.56 (15 H, m).

IR absorption spectrum (KBr) υ _max cm ^-1 :

1750, 1727, 1676, 1548.

[5 (d) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-benzyloxycarbonyloxytetradecanoylamino] -3-0-[(3R) -3-benzyloxytetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxycarbonyl-β-D-glucopyranoside]

2.60 g of the compound obtained as described in Example 5 (c) were treated by the method as described in Example 4 (d) to afford 3.16 g (yield 99.5%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.72 to 1.87 (46H, m);

2.26 to 2.49 (2H, m);

3.45 to 6.05 {21H, m [including 4.30 (2H, s), 5.05 (4H, s)]};

6.18 to 6.50 (1H, m);

6.89-7.49 (25H, m);

IR absorption spectrum (KBr) υ _max cm ^-1 :

1743, 1679, 1541, 1494.

[5 (e) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R ) -3-benzyloxytetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxycarbonyl-D-glucopyranose]

2.80 g of the compound obtained as described in Example 5 (d) were treated by the method as described in Example 1 (g) to yield 1.8 g (yield 66.4%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.66 to 2.01 (46H, m);

2.16 to 2.56 (2H, m);

2.89 (1H, doublet, J = 5 Hz);

3.38 to 5.71 {16H, m [including 4.32 (2H, s), 5.10 (4H, s)]};

6.45 to 6.81 (1H, m);

7.08 to 7.45 (25H, m).

IR absorption spectrum (KBr) υ _max cm ^-1 :

1747, 1685, 1590.

[5 (f) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3-hydroxy Loxytetradecanoyl] -4-0-diphenylphosphoryl-D-glucopyranose]

880 mg (0.6 mmol) of the compound obtained as described in Example 5 (e) are dissolved in 30 ml of tetrahydrofuran and 1 g of 10% w / w palladium-on-carbon is added to the resulting solution. Allow the catalytic reduction to occur for 2 hours at room temperature under a hydrogen atmosphere and then filter the mixture. Tetrahydrofuran is removed from the filtrate by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: acetate) to give 340 mg (yield 56.2%) of the title compound.

Elemental analysis: C ₄₆ H ₇₃ FNO ₁₂ P (Molecular Weight 882.1)

Calculated: C, 62.64%; H, 8.34%; N, 1.59%; F, 2.15%; P, 3.51%.

Found: C, 62.89%; H, 8.24%; N, 1.47%; F, 2.15%; P, 3.41%.

5 (g) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3-hydroxy Tetradecanoyl] -D-glucopyranosyl-4-phosphate

490 mg (0.56 mmol) of the compound obtained as described in Example 5 (f) are dissolved in 30 ml of tetrahydrofuran and 80 g of platinum oxide is added to the resulting solution. The catalytic reduction takes place for 3 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered and then tetrahydrofuran was removed by evaporation under reduced pressure to yield 380 mg (yield 93.7%) of the title compound.

Elemental analysis: C ₃₄ H ₆₅ FNO ₁₂ P (Molecular Weight 729.9)

Calculated: C, 55.95%; H, 8.98%; N, 1.92%; F, 2.60%; P, 4.24%

Found: C, 55.84%; H, 9. 22%; N, 1.94%; F, 2.51%; P, 4.09%

FAB mass spectrum m / z: 728 [M-H] -502

Example 6

[2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetetecanoylyloxytetradecanoylamino] -3-0-tetradecanoyl-D-glucopyranosyl -4-phosphate

6 (a) allyl 2-deoxy-2-[(2'R, 3'S) and (2'S, 3'R) -2'-fluoro-3 '-(tetratecanoyloxy) tetradecanoylamino] -4,6-0-isopropylidene-β-D-glucopyranoside]

5.18 g (20 mmol) allyl 2-deoxy-2-amino-4,6-0-isopropylidene-β-D-glucopyranoside [prepared as described in Example 1 (d)] It is dissolved in 150 ml of methylene chloride and 9.93 (+)-syn-2-fluoro-3- (tetradecanoyloxy) tetradecanoic acid is added to the resulting solution. 4.95 g of N, N'-dicyclohexylcarbodiimide was added to the resulting mixture, followed by stirring at room temperature for 1 hour. The mixture is then filtered, concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed in the order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, and the residue was purified by chromatography on a silica column (eluent: 3: 1 volume ratio of cyclohexane and ethyl acetate) to give 5.65 g (yield 39.6%) of the title compound. The (2'R, 3'S) isomer is obtained, followed by 5.55 g (38.9% yield) of the (2'S, 3'R) isomer of the title compound.

(2'R, 3'S) Compound:

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (6H, t, J = 6.9 Hz);

1.20-1.38 (38H, m);

1.44 (3 H, s);

1.52 (3H, s);

1.60 to 1.84 (5H, m);

2.30 (2H, t);

3.23 to 3.33 (1H, m);

3.58 to 3.85 (4H, m);

3.93 (1H, doublet of doublets, J = 5.5 10.6 Hz);

4.07 (1H, doublet of doublets, J = 6.2 12.8 Hz);

4.30-4.37 (1H, m);

4.76 (1H, doublet, J = 7.7 Hz);

4.93 (1H, doublet of doublets, J = 2.9 48.0 Hz);

5.20 to 5.36 (3H, m);

5.79 to 5.94 (1 H, m);

6.44 (1H, t, J = 5.5 Hz).

IR absorption spectrum (CHCI3) υ _max cm ^-1 :

1735, 1680, 1535.

(2'S, 3'R) Compound

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (6H, t, J = 6.9 Hz);

1.20-1.38 (38H, m);

1.45 (3 H, s);

1.52 (3H, s);

1.56 to 1.76 (5H, m);

2.29 (2H, t);

3.30 to 3.41 (2H, m);

3.57 (1H, t, J = 9.2 Hz);

3.80 (1H, t, J = 10.6 Hz);

3.93 (1H, doublet of doublets, J = 5.5 11.0 Hz);

4.05-4.16 (2H, m);

4.29 to 4.36 (1H, m);

4.77 (1H, doublet, J = 8.1 Hz);

4.89 (1H, doublet of doublets, J = 2.2 48.0 Hz);

5.20 to 5.34 (3H, m);

5.80 to 5.89 (1 H, m);

6.52 (1H, t, J = 5.5 Hz).

IR absorption spectrum (CHCI3) υ _max cm ^-1 :

1735, 1680, 1535.

[6 (b) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(tetratecanoyloxy) tetradecanoylamino] -3-0-tetradeca Noyl-4,6-0-isopropylidene-D-glucopyranoside]

2 g (2.8 mmol) of the (2'R, 3'S) compound obtained as described in Example 6 (a) is dissolved in 30 ml of methylene chloride and 728 mg of tetradecanoyl chloride is added to the resulting solution. 313 mg of triethylamine is added to the resulting mixture, and the mixture is heated at room temperature for 1 hour. The mixture is then concentrated by distillation under reduced pressure and diluted with ethyl acetate. This was washed in order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The mixture is dried over anhydrous magnesium sulfate, filtered and the ethyl acetate is removed by evaporation under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent: 5: 1 volume ratio of cyclohexane and ethyl acetate mixture) to yield 1.35 g (52.1%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (9H, t, J = 6.6 Hz);

1.13 to 1.67 {70H, m [including 1.36 (3H, s), 1.46 (3H, s)]};

2.25 to 2.25 (4H, m);

3.32 to 3.41 (1H, m);

3.66 to 3.85 (3H, m);

3.95 (1H, doublet of doublets, J = 5.5 10.6 Hz);

4.05 (1H, doublet of doublets, J = 6.2 12.8 Hz);

4.26 to 4.34 (1H, m);

4.74 to 4.93 (2H, m);

5.16 to 5.29 (4H, m);

5.75 to 5.89 (1 H, m);

6.34 (1H, doublet of doublets, J = 4.4 8.8 Hz).

Elemental analysis: C ₅₄ H ₉₈ FNO ₉ (Molecular Weight, 924.4)

Calculated: C, 70.17%; H, 10.69%; N, 1.52%; F, 2.06%

Found: C, 70.41%; H, 10.58%; N, 1.47%; F, 1.99%

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1740, 1695.

Mass spectrum m / z:

924 (M ⁺ + 1), 909, 883, 867, 737, 724, 655, 638, 610, 526, 513, 452.

[6 (c) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetratecanoyloxytetradecanoylamino] -3-0-tetradecanoyl- β-D-glucopyranoside]

2.6 g of the compound obtained as described in Example 6 (b) were treated by the method as described in Example 4 (b) to give 2 g (yield 80.4%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.66-1.91 (74H, m);

2.09 to 2.55 (4H, m);

2.87 to 6.16 (15H, m);

6.54 (1 H, m).

IR absorption spectrum (KBr) υ _max cm ^-1 :

1739, 1668, 1553, 1468, 1175.

[6 (d) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetrahydrodecanoyloxytetradecanoylamino] -3-0-tetradecanoyl- 6-0-benzyloxycarbonyl-β-D-glucopyranoside]

1.9 g (2.15 mmol) of the compound obtained as described in Example 6 (c) are dissolved in 20 ml of methylene chloride and 550 mg of benzylchloroformate is added to the resulting solution. 327 mg of triethylamine is added to the resulting mixture, and the mixture is stirred at room temperature for 5 hours. The mixture is then concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed in the order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was removed by evaporation under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent: 3: 1 volume ratio of cyclohexane and ethyl acetate mixture) to give 660 mg (yield 30.2%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (9H, t, J = 6.9 Hz)

1.25-1.65 (66H, m);

2.25 to 2.36 (4H, m);

2.82 (1 H, s);

3.59 to 3.66 (2H, m);

4.03 (1H, doublet of doublets, J = 6.2 12.8 Hz);

4.27 (1H, doublet of doublets, J = 5.1 12.8 Hz);

4.42 to 4.52 (1H, m);

4.81 (1H, doublet of doublets, J = 3.7 47.6 Hz);

4.84 (1H, doublet, J = 8.1 Hz);

5.14-5.27 (6H, m);

5.76 to 5.89 (1 H, m);

6.37 (1H, doublet of doublets, J = 4.4 8.1 Hz);

7.34 to 7.40 (50 H, m).

IR absorption spectrum (KBr) υm _ax cm ^-1 :

1737, 1673, 1550, 1285.

[6 (e) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetedecanoylamino] -3-0-tetradecanoyl-4 -0-diphenylphosphoryl-6-0-benzyloxycarbonyl-β-D-glucopyranoside]

600 mg (0.589 mmol) of the compound obtained as described in Example 6 (d) is dissolved in 20 ml of methylene chloride and 474.8 mg of diphenylchlorophosphate is added to the resulting solution. 62.6 mg of triethylamine is added to the resulting mixture, which is then stirred at room temperature overnight. The mixture is then concentrated by evaporation under reduced pressure and the residue is diluted with ethyl acetate. The ethyl acetate layer was washed in the order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. It is filtered and ethyl acetate is removed by evaporation under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent 5: 1 volume ratio of cyclohexane and ethyl acetate mixtures) to yield 600 mg (81.4% yield) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (9H, t, J = 6.9 Hz);

1.05-1.73 (64H, m);

2.11 to 2.3 (4H, m);

3.46 to 3.56 (1H, m);

3.77 to 3.82 (1 H, m);

4.03 (1H, doublet of doublets, J = 6.2 12.8 Hz);

4.19-4.38 (3H, m);

4.63-4.89 (2H, m);

5.01 to 5.26 (6H, m);

5.64-5.87 (2H, m);

6.37 (1H, doublet of doublets, J = 4.4 7.7 Hz);

7.11-7.74 (15H, m).

Elemental analysis: C ₇₁ H ₁₀₉ FNO ₁₄ P (Molecular Weight, 1250.6)

Calculated: C, 68.19%; H, 8.79%; N, 1.12%; F, 1.52%; P, 2.48%

Found: C, 67.97%; H, 8.56%; N, 1.21%; F, 1.47%; P, 2.47%

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1743, 1690.

[6 (f) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-tetradecanoyl-4- 0-diphenylphosphoryl-6-0-benzyloxycarbonyl-D-glucopyranose]

600 mg of the compound obtained as described in Example 6 (e) was treated by the method as described in Example 1 (g) to give 490 mg (yield 84.3%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (9H, t, J = 7.0 Hz);

1.11 to 1.66 (64H, m);

2.11 to 2.29 (4H, m);

3.36 (1 H, s);

4.13 to 4.39 (4H, m);

4.71 to 5.56 (7H, m);

6.70 (1H, doublet of doublets, J = 3.3 8.1 Hz);

7.11 to 7.35 (15 H, m).

IR absorption spectrum (CHCI3) υ _max cm ^-1 :

1751, 1711, 1658.

[6 (g) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-tetradecanoyl-4- 0-diphenylphosphoryl-D-glucopyranose]

490 mg of the compound obtained as described in Example 6 (f) was treated by the method as described in Example 5 (f) to give 270 mg (yield 75.9%) of the title compound.

Elemental analysis: C ₆₀ H ₉₉ FNO ₁₂ P (Molecular Weight, 1076.4)

Calculated: C, 66.95%; H, 9. 27%; N, 1.30%; F, 1.76%; P, 2.88%

Found: C, 67.23%; H, 9. 27%; N, 1.35%; F, 1.91%; P, 2.81%

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

1735, 1685.

[6 (h) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-tetradecanoyl-D- Glucopyranosyl-4-phosphate]

230 mg of the compound obtained as described in Example 6 (g) is treated by the method as described in Example 5 (g) to give 190 mg (yield 96.2%) of the title compound.

FAB mass spectrum, m / z: 922 [M ⁻ H] ⁻

Example 7

[2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-tetradecanoyl-D-glucopyranosyl- 4-phosphate

7 (a) allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'- tetradecanoyloxytetradecanoylamino] -3-0-tetradecanoyl-4, 6-0-isopropylidene-β-D-glucopyranoside]

2.9 g (4.06 mmol) allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(tetradecanoyloxy) tetradecanoylamino] -4,6-0 Isopropylidene-β-D-glucopyranoside [prepared as described in Example 6 (a)] is dissolved in 30 ml of methylene chloride and 1.02 g of tetradecanoic acid is added to the resulting solution. 1 g of N, N'-dicyclohexylcarbodiimide is added to the resulting mixture and stirred at room temperature for 1 hour. However, when the reaction does not proceed, 50 mg of 4-dimethylaminopyridine is added and stirred for further 1 hour at room temperature. The mixture is then concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed in the order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. After filtration, the ethyl acetate was removed by evaporation under reduced pressure. The residue is purified by silica gel column chromatography (eluent: 5: 1 volume ratio of cyclohexane and ethyl acetate mixture) to afford 3.8 g of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.66 to 2.01 (79H, m);

2.05 to 2.61 (4H, m);

3.30 to 6.23 (14H, m);

6.85 (1 H, m).

IR absorption spectrum (KBr) υ _max cm ^-1 :

1741, 1666, 1544, 1468.

[7 (b) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'- tetradecanoyloxytetedecanoylamino] -3-0-tetradecanoyl-β -D-glucopyranoside]

3.8 g of the compound obtained as described in Example 7 (a) were treated in the same manner as described in Example 4 (b) to obtain 3.08 g (yield 84.7%) of the title compound.

IR absorption spectrum (KBr) υ _max cm ^-1 :

1736, 1671, 1553, 1467.

[7 (c) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'- tetradecanoyloxytetedecanoylamino] -3-0-tetradecanoyl-6 -0-benzyloxymethyl-β-D-glucopyranoside]

2.7 g (3.05 mmol) of the compound obtained as described in Example 7 (b) are dissolved in 50 ml of methylene chloride, and 0.525 g of benzylchloromethyl ether is added to the resulting solution.

0.355 g of tetramethylurea is added to the resulting mixture and heated under reflux for 6 hours. The methylene chloride is then removed by evaporation under reduced pressure. The residue is purified by silica gel column chromatography (eluent: 3: 1 volume ratio of cyclohexane and ethyl acetate mixture) to afford 2.08 g (yield 67.8%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (9H, t, J = 6.9 Hz);

1.20-1.73 (65H, m);

2.24 to 2.37 (4H, m);

3.47 to 3.51 (1H, m);

3.74 (1H, t, J = 9.5 Hz);

3.89-4.11 (4H, m);

4.26 to 4.33 (1H, m);

4.59 (1H, doublet, J = 8.4 Hz);

4.63 (2H, s);

4.79 (1H, doublet of doublets, J = 4.3 48.4 Hz);

4.81 (2H, s);

5.03 (1H, doublet of doublets, J = 9.2 10.6 Hz);

5.15 to 5.30 (3H, m);

5.80 to 5.88 (1H, m);

6.36 (1H, doublet of doublets, J = 4.4 9.2 Hz);

7.29 to 7.36 (5H, m).

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

3430, 1738, 1695.

Mass spectrum, m / z:

986, 928, 834, 775, 717, 596, 509, 456, 383, 354, 298, 285, 268.

[7 (d) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetedecanoylamino] -3-0-tetradecanoyl-4 -0-diphenylphosphoryl-6-0-benzyloxymethyl-β-D-glucopyranoside]

2.0 g of the compound obtained as described in Example 7 (c) are treated by the method as described in Example 6 (e) to afford 2.5 g of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (9H, t, J = 6.9 Hz);

1.10-1.68 (65H, m);

2.08 to 2.31 (3H, m);

3.65 to 3.69 (2H, m);

3.78 to 3.74 (1H, m);

4.03 to 4.11 (2H, m);

4.25 to 4.32 (1H, m);

4.50 to 4.85 (7H, m);

5.15 to 5.39 (4H, m);

5.76 to 5.83 (1H, m);

6.38 (1H, doublet, J = 4.8 9.2 Hz);

7.13 to 7.44 (15 H, m).

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

3430, 1740, 1695.

Mass spectrum m / z:

1014, 994, 758, 670, 580, 440, 322, 268.

[7 (e) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-tetradecanoyl-4- 0-diphenylphosphoryl-6-0-benzyloxymethyl-D-glucopyranose]

2.3 g of the compound obtained as described in Example 7 (d) were treated by the method as described in Example 1 (g) to afford 1.58 g (yield 71%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.63 to 2.42 (77 H, m);

3.55 to 5.78 {14H, m [including 4.54, (2H, s), 4.66 (2H, s)]};

6.70 (1 H, m);

7.00 to 7.53 (15 H, m).

[7 (f) 2-deoxy-2 [(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-tetradecanoyl-4-0 -Diphenylphosphoryl-D-glucopyranose]

1.44 g (1.2 mmol) of the compound obtained as described in Example 7 (e) is dissolved in 30 ml of methanol and 1 g of 10% w / w palladium-on-carbon is added to the resulting solution. The catalytic reduction is carried out at 40 to 45 ° C. for 3 hours under a hydrogen atmosphere. The mixture is then filtered and methanol is removed by evaporation under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent: 1: 1 volume ratio of cyclohexane and ethyl acetate mixture) to give 715 mg (yield 55.2%) of the title compound.

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

3440, 1740, 1690.

Elemental analysis: C ₆₀ H ₉₉ FNO ₁₂ P (Molecular Weight, 1076.4)

Calculated: C, 66.95%; H, 9. 27%; N, 1.30%; F, 1.76%; P, 2.88%

Found: C, 66.96%; H, 9. 30%; N, 1.17%; F, 1.74%; P, 2.81%

[7 (g) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-tetradecanoyl-D- Glucopyranosyl-4-phosphate]

550 mg of the compound obtained as described in Example 7 (f) is treated by the method as described in Example 5 (g) to give 420 mg (89% yield) of the title compound.

FAB mass spectrum m / z: 922 [M ⁻ H] ⁻

Example 8

[2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3- (tetradecanoyl jade Tetradecanoyl] -D-glucopyranosyl-4-phosphate

8 (a) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R ) -3- (tetradecanoyloxy group) tetradecanoyl] -4,6-0-isopropylidene-α-D-glucopyranoside]

33.1 g of allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -4,6-0-isopropyl Lyden-β-D-glucopyranoside [prepared as described in Example 2 (a)] was dissolved in 700 ml of methylene chloride, and 25.9 g of 3-tetradecanoyloxytetradecanoic acid was added to the resulting solution. Add. 7 g of 4-dimethylaminopyridine and 12.8 g of N, N'-dicyclohexylcarbodiimide are added to the resulting mixture, and the mixture is stirred at room temperature for 2 hours. The mixture is then filtered, concentrated by evaporation under reduced pressure and diluted with ethyl acetate. The ethyl acetate layer was washed in the order of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After filtration, ethyl acetate is removed by evaporation under reduced pressure. The residue is subjected to chromatography on a silica gel column (eluent: a 5: 1 volume ratio of cyclohexane and ethyl acetate mixture) to give 47.7 g (yield 85.5%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.86 to 0.90 (9H, m);

1.25 to 1.77 {68H, m [including 1.37 (3H, s) 1,48 (3H, s)]};

2.26 (2H, m);

2.49 (1H, doublet of doublets, J = 6.3 15.1 Hz);

2.62 (1H, doublet of doublets, J = 6.3 15.1 Hz);

3.70 to 3.86 (5H, m);

3.93 to 3.98 (1 H, m);

4.21 to 4.27 (1H, m);

4.63 (1H, doublet, J = 3.9 Hz);

4.90 (1H, doublet of doublets, J = 47.4 Hz);

5.09 to 5.21 (7H, m);

5.74 to 5.44 (1H, m);

6.63 (1H, doublet of doublets, J = 3.9 9.8 Hz);

7.26 to 7.36 (5H, m).

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

3440, 1745, 1695, 1530

Elemental Analysis: C ₆₂ H1 ₄ NFO ₁₂

Calculated: C, 69.30%; H, 9.76%; N, 1.30%; F, 1.77%

Found: C, 69.39%; H, 9.86%; N, 1.31%; F, 1.75%

[8 (b) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3- (tetradecanoyloxy) tetradecanoyl] -α-D-glucopyranoside]

46 g of the compound obtained as described in Example 8 (a) were treated by the method as described in Example 4 (b) to give 42 g (yield 94.8%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85 to 0.90 (9H, m);

1.04 to 1.78 (64H, m);

2.26 to 2.31 (2H, m);

2.47 to 2.59 (2H, m);

3.63 to 3.88 (5H, m);

3.96 to 4.02 (1H, m);

4.16 to 4.23 (1H, m);

4.66 (1H, doublet, J = 3.7 Hz);

4.89 (1H, doublet of doublets, J = 2.2 47.6 Hz);

5.09 to 5.21 (7H, m);

5.73 to 5.87 (1H, m);

6.66 (1H, doublet of doublets, J = 3.7 9.5 Hz);

7.26 to 7.37 (5H, m).

IR absorption spectrum (KBr) υ _max cm ^-1 :

1741, 1719, 1703, 1670, 1545, 1468.

Elemental Analysis C ₅₉ H ₁₀₀ NFO ₁₂ :

Calculated: C, 68.51%; H, 9.74%; N, 1.35%; F, 1.84%

Found: C, 68.62%; H, 9.70%; N, 1.55%; F, 1.80%

[8 (c) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3- (tetradecanoyloxy) tetradecanoyl] -6-0-benzyloxycarbonyl-α-D-glucopyranoside]

23.1 g of the compound obtained as described in Example 8 (b) is treated by the method as described in Example 4 (c) to give 10.6 g (yield 40.6%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85 to 0.90 (9H, m);

1.02 to 1.77 (62H, m);

2.25 to 2.31 (2H, m);

2.46 to 2.59 (2H, m);

3.31 (1H, doublet, J = 4.2 Hz);

3.61 (1H, t of d, J = 9.3 4.2 Hz);

3.76 to 3.86 (2H, m);

3.93 to 4.00 (1H, m);

4.16 to 4.24 (1H, m);

4.38-4.48 (1H, m);

4.88 (1H, doublet of doublets, J = 2.2 47.6 Hz);

5.07 to 5.19 (9H, m);

5.70 to 5.85 (1 H, m);

6.62 (1H, doublet of doublets, J = 3.7 9.5 Hz);

7.26 to 7.40 (10H, m);

IR absorption spectrum (KBr) υ _max cm ^-1 :

1747, 1738, 1724, 1712, 1678, 1547.

Elemental Analysis: C ₆₇ H ₁₀₆ NFO ₁₄ :

Calculated: C, 68.86%; H, 9. 14%; N, 1.20%; F, 1.63%

Found: C, 68.77%; H, 9. 18%; N, 1.42%; F, 1.64%

[8 (d) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3- (tetradecanoyloxy) tetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxycarbonyl-α-D-glucopyranoside]

10.47 g of the compound obtained as described in Example 8 (c) were treated in the same manner as described in Example 4 (d) to give 11.4 g (yield 91.3%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85 to 0.90 (9H, m);

1.03 to 1.80 (62H, m);

2.13 to 2.19 (2H, m);

2.33 (1H, doublet of doublets, J = 7.3 15.8 Hz);

2.42 (1H, doublet of doublets, J = 5.1 15.8 Hz);

3.75 to 3.82 (1 H, m);

3.89 to 4.02 (2H, m);

4.17 to 4.36 (3H, m);

4.64 (1H, doublet, J = 3.7 Hz);

4.72 (1H, doublet of doublets, J = 9.2 18.7 Hz);

4.85 to 5.22 (9H, m);

5.42 (1H, doublet of doublets, J = 9.2 11.0 Hz);

5.70 to 5.84 (1H, m);

6.56 (1H, doublet of doublets, J = 3,7 9.5 Hz);

7.12-7.75 (20H, m).

IR absorption spectrum (liquid film) υ _max cm ^-1 :

1750, 1690, 1590.

Elemental Analysis: C ₇₉ H ₁₁₅ NFO ₁₇ P:

Calculated: C, 67.74%; H, 8. 28%; N, 1.00%; F, 1.36%; P, 2.21%

Found: C, 68.77%; H, 9. 18%; N, 1.42%; F, 1.64%; P, 2.14%

[8 (e) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R ) -3- (tetradecanoyloxy) tetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxycarbonyl-D-glucopyranos]

1.4 g of the compound obtained as described in Example 8 (d) were treated by the method as described in Example 1 (g) to yield 0.77 g (yield 56.6%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85 to 0.90 (9H, m);

1.18-1.82 (62H, m);

2.12 to 2.18 (2H, m);

2.32 (1H, doublet of doublets, J = 7.3 15.8 Hz);

2.41 (1H, doublet of doublets, J = 5.5 15.8 Hz);

2.70 (1H, doublet of doublets, J = 1.5 4.8 Hz);

4.09 to 4.18 (3H, m);

4.29 to 4.34 (1H, m);

4.67 (1H, doublet of doublets, J = 9.2 18.7 Hz);

4.87 (1 H, m);

4.89 (1H, doublet of doublets, J = 1.8 47.3 Hz);

5.61 to 5.25 (6H, m);

5.46 (1H, doublet of doublets, J = 9.2 11.0 Hz);

6.63 (1H, doublet of doublets, J = 3.3 8.8 Hz);

7.12-77.3 (20H, m).

IR absorption spectrum (KBr) υ _max cm- ¹ :

1739, 1660, 1290, 1266, 1250, 1195.

Elemental analysis: C ₇₆ H1 ₁₁ FNO ₂₇ P:

Calculated: C, 67.09%; H, 8.22%; N, 1.03%; F, 1.40%; P, 2.28%

Found: C, 67.04%; H, 7.97%; N, 1.64%; F, 1.35%; P, 2.15%

[8 (f) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3- ( Tetradecanoyloxy) tetradecanoyl] -4-0-diphenylphosphoryl-D-glucopyranose]

6.5 g of the compound obtained as described in Example 8 (e) were treated by the method as described in Example 5 (f) to yield 4.89 g (yield 93.7%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.85 to 0.90 (9H, m);

1.18-1.80 (62H, m);

2.13 to 2.21 (2H, m);

2.37 to 2.39 (2H, m);

3.50 to 3.61 (4H, m);

3.97 to 4.06 (2H, m);

4.21 to 4.28 (1H, m);

4.65 to 4.83 (2H, m);

5.04-5.13 (1 H, m);

5.24 to 5.28 (2H, m);

5.49 to 5.57 (1 H, m);

6.80 to 6.85 (1 H, m);

7.14 to 7.38 (10H, m);

IR absorption spectrum (KBr) υ _max cm ^-1 :

1735, 1671, 1289, 1202, 1060.

Elemental Analysis: C ₆₀ H ₉₉ FNO ₁₃ P:

Calculated: C, 65.97%; H, 9. 13%; N, 1.28%; F, 1.74%; P, 2.84%

Found: C, 65.93%; H, 9.25%; N, 1.48%; F, 1.63%; P, 2.84%

[8 (g) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3- ( Tetradecanoyloxy) tetradecanoyl] -D-glucopyranosyl-4-phosphate]

4.59 g of the compound obtained as described in Example 8 (f) were treated by the method as described in Example 5 (g) to yield 3.9 g (yield 98.7%) of the title compound.

NMR spectrum (deuterium pyridine, 270MHz) δ ppm:

0.85 to 0.90 (9H, m);

1.03 to 2.15 (62H, m);

2.43 to 2.49 (2H, m);

3.08 to 3.25 (2H, m);

4.09 to 4.13 (1H, m);

4.52 to 4.56 (2H, m);

4.62 to 4.65 (1H, m);

4.99 to 5.08 (1H, m);

5.21 to 5.49 (2H, m);

5.63 to 5.74 (2H, m);

6.24 to 6.31 (1H, m);

8.03-8.72 (6H, m).

IR absorption spectrum (KBr) υ _max cm ^-1 :

1734, 1661, 1550, 1465, 1224, 1182, 1171, 1063.

Elemental analysis: C ₄₈ H ₉₁ FNO ₁₃ P:

Calculated: C, 61.32%; H, 9.76%; N, 1.49%; F, 2.02%; P, 3.29%

Found: C, 60.66%; H, 9.87%; N, 1.68%; F, 1.91%; P, 3.10%

Example 9

[2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-hydroxytetradecanoylamido] -3-0-[(3R) -3- (tetradecanoyl Oxy) tetradecanoyl] -D-glucopyranosyl-4-phosphate

9 (a) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R ) -3- (tetradecanoyloxy) tetradecanoyl] -4,6-0-isopropylidene-α-D-glucopyranoside]

1.1 g of allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -4,6-0-isopropyl Liden-α-D-glucopyranoside [Preparation was carried out as described in Example 2 (a) to give 1.36 g (73.8% yield) of the title compound as described in Example 8 (a). To obtain.

IR absorption spectrum (liquid film) υ _max cm ^-1 :

1740, 1685, 1530, 1460.

Elemental Analysis: C ₆₂ H ₁₀₄ FNO ₁₂ :

Calculated: C, 69.30%; H, 9.76%; N, 1.30%; F, 1.77%

Found: C, 68.94%; H, 9.58%; N, 1.26%; F, 1.76%

[9 (b) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3- (tetradecanoyloxy) tetradecanoyl] -α-D-glucopyranoside]

57.6 g of the compound obtained as described in Example 9 (a) were treated by the method as described in Example 4 (b) to give 42.6 g (yield 76.8%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.86 to 0.90 (9H, m);

1.25-1.76 (64H, m);

2.25 to 2.45 (4H, m);

3.64 to 3.76 (3H, m);

3.85 to 3.90 (2H, m);

3.95-4.00 (1H, m);

4.14 to 4.21 (2H, m);

4.84-5.32 (8H, m);

5.83 to 5.87 (1H, m);

7.07 to 7.10 (1H, m);

7.26 to 7.38 (5H, m).

Elemental Analysis: C ₅₉ H ₁₀₀ O ₁₂ NF:

Calculated: C, 68.51%; H, 9.74%; N, 1.35%; F, 1.84%

Found: C, 68.27%; H, 9.97%; N, 1.48%; F, 1.92%

[9 (c) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3- (tetradecanoyloxy) tetradecanoyl] -6-0-benzyloxycarbonyl-α-D-glucopyranoside]

0.83 g of the compound obtained as described in Example 9 (b) was treated by the method as described in Example 4 (c) to yield 0.6 g (yield 63.6%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.86 to 0.90 (9H, m);

1.25-1.76 (63H, m);

2.23 to 2.45 (4H, m);

3.63 to 3.65 (2H, m);

3.85 to 3.98 (2H, m);

4.11 to 4.19 (2H, m);

4.43-4.93 (2H, m);

4.89 (1H, doublet of doublets, J = 2.6 47.3 Hz);

4.93 (1H, doublet, J = 3.3 Hz);

5.01 to 5.30 (8H, m);

5.76 to 5.92 (1H, m);

7.03 to 7.07 (1H, m);

7.26 to 7.41 (10H, m);

IR absorption spectrum (liquid film) υ _max cm ^-1 :

1750, 1690.

Elemental analysis: C ₆₇ H ₁₀₆ O ₁₄ NF:

Calculated: C, 68.86%; H, 9. 14%; N, 1.20%; F, 1.63%

Found: C, 68.69%; H, 9. 21%; N, 1.40%; F, 1.63%

[9 (d) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( 3R) -3- (tetradecanoyloxy) tetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxycarbonyl-α-D-glucopyranoside]

30.5 g of the compound obtained as described in Example 9 (c) were treated in the same manner as described in Example 4 (d) to afford 31 g (yield 96%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85 to 0.90 (9H, m);

1.12 to 1.72 (62H, m);

2.06 to 2.12 (2H, m);

2.35 (1H, doublet of doublets, J = 7.7 17.6 Hz);

2.52 (1H, doublet of doublets, J = 5.5 17.6 Hz);

3.90 to 4.35 (6H, m);

4.73 (1H, doublet of doublets, J = 9.2 18.7 Hz);

4.89 (1H, doublet of doublets, J = 2.6 47.6 Hz);

4.95 (1H, doublet, J = 3.7 Hz);

5.04-5.29 (8H, m);

5.47 (1H, doublet of doublets, J = 9.2 11.0 Hz);

5.77 to 5.84 (1H, m);

6.81 (1H, doublet of doublets, J = 3.3 8.1 Hz);

7.11 to 7.37 (20H, m).

IR absorption spectrum (liquid film) υ _max cm _-1 :

1745, 1690, 1590, 1530.

Elemental analysis: C ₇₉ H ₁₁₅ O ₁₇ NFP:

Calculated: C, 67.74%; H, 8. 28%; N, 1.00%; F, 1.36%; P, 2.21%

Found: C, 67.37%; H, 8.25%; N, 0.87%; F, 1.31%; P, 2.27%

[9 (e) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3 '-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[(3R ) -3- (tetradecanoyloxy) tetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxycarbonyl-D-glucopyranos]

15 g of the compound obtained as described in Example 9 (d) were treated by the method as described in Example 1 (g) to give 11.6 g (yield 79.6%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85 to 0.90 (9H, m);

1.14 to 1.75 (62H, m);

2.08 to 2.13 (2H, m);

2.33 (1H, doublet of doublets, J = 7.7 16.9 Hz);

2.51 (1H, doublet of doublets, J = 4,8 16.9 Hz);

3.63 (1H, doublet of doublets, J = 1.1 4.03 Hz);

3.97 (1 H, m);

4.14 to 4.36 (3H, m);

4.66-4.77 (1H, m);

4.89 (1H, doublet of doublets, J = 2.7 47.6 Hz);

5.02 to 5.20 (6H, m);

5.30 (1H, t, J = 3.7 Hz);

5.53 (1H, doublet of doublets, J = 9.2 11.0 Hz);

6.92 (1H, doublet of doublets, J = 2.9 7.7 Hz);

7.12 to 7.74 (20H, m);

IR absorption spectrum (CHCI ₃ ) υ _max cm ^-1 :

3420, 1750, 1690, 1590, 1530, 1490, 960.

Elemental Analysis: C ₇₆ H ₁₁₁ NO ₁₇ FP:

Calculated: C, 67.09%; H, 8.22%; N, 1.03%; F, 1.40%; P, 2.28%

Found: C, 67.20%; H, 8. 29%; N, 0.97%; F, 1.28%; P, 2.21%

[9 (f) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3- ( Tetradecanoyloxy) tetradecanoyl] -4-0-diphenylphosphoryl-D-glucopyranose]

11.6 g of the compound obtained as described in Example 9 (e) is treated in the same manner as described in Example 5 (f) to give 8.14 g (yield 87.4%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85 to 0.90 (9H, m);

1.19-1.63 (62H, m);

2.15 to 2.20 (2H, m);

2.37 (1H, doublet of doublets, J = 8.4 17.2 Hz);

2.68 (1H, doublet, J = 8.8 Hz);

3.38 (1 H, m);

3.59 to 3.62 (2H, m);

4.02 to 4.05 (3H, m);

4.33 to 4.40 (1H, m);

4.74 (1H, doublet of doublets, J = 1.1 48.0 Hz);

4.77 (1H, doublet of doublets, J = 9.5 19.1 Hz);

5.11 to 5.15 (1 H, m);

5.30 (1H, t, J = 3.7 Hz);

5.54 (1H, doublet of doublets, J = 9.5 10.3 Hz);

6.83 (1H, doublet of doublets, J = 3.3 9.2 Hz);

7.15 to 7.39 (10 H, m).

IR absorption spectrum (KBr) υ _max cm ^-1 :

1736, 1661, 1585, 1560, 1492.

[9 (g) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-hydroxytetradecanoylamino] -3-0-[(3R) -3- ( Tetradecanoyloxy) tetradecanoyl] -D-glucopyranosyl-4-phosphate]

7.72 g of the compound obtained as described in Example 9 (f) are treated in the same manner as described in Example 5 (g) to give 6.7 g of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85 to 0.91 (9H, m);

1.25 to 2.01 (62H, m);

2.38 to 2.44 (2H, m);

3.19 (2H, doublet, J = 5.86 Hz);

4.11 to 4.18 (1H, m);

4.43-4.59 (3H, m);

4.99 to 5.07 (1H, m);

5.15 to 5.33 {(2H, m) [including 5.24 (1H, doublet of doublets, J = 2.0 48.8 Hz)]};

5.74 to 5.81 (2H, m);

6.28 (1H, t, J = 9.8 Hz):

8.02 (1H, doublet of doublets, J = 2.7 9.8 Hz);

8.61 (5H, broad singlet).

IR absorption spectrum (KBr) υ _max cm ^-1 :

1753, 1716, 1657, 1184, 1138, 1117, 1068.

Elemental analysis: C ₄₈ H ₉₁ FNO ₁₃ P:

Calculated: C, 61.32%; H, 9.76%; N, 1.49%; F, 2.02%; P, 3.29%

Found: C, 61.04%; H, 9.92%; N, 1.60%; F, 1.92%; P, 3.27%

Example 10

[2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R) -3-hydroxytetra Decanoyl] -D-glucopyranosyl-4-phosphate]

10 (a) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R) -3 -Benzyloxytetradecanoyl] -4,6-0-isopropylidene-β-D-glucopyranoside]

3.2 g of allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3 '-(tetradecanoyloxy) tetradecanoylamino] -4,6-0-isopropylidene -β-D-glucopyranoside [prepared as described in Example 6 (a)] was treated in the same manner as described in Example 2 (b) to give 4.12 g (89.2% yield) of the title compound To obtain.

[10 (b) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R)- 3-benzyloxytetradecanoyl] -β-D-glucopyranoside]

4 g of the compound obtained as described in Example 10 (a) was treated by the method as described in Example 4 (b) to yield 2.94 g (yield 75.4%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.5 to 2.0 (71 H, m);

2.1 to 2.8 (4H, m);

3.0 to 5.9 (18H, m);

6.3 to 6.6 (2H, m);

7.1 to 7.3 (5H, m).

[10 (c) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'- tetradecanoyloxytetedecanoylamino] -3-0-[(3R)- 3-benzyloxytetradecanoyl] -6-0-benzyloxymethyl-β-D-glucopyranoside]

2.73 g of the compound obtained as described in Example 10 (b) are treated by the method described in Example 7 (c) to give 1.7 g (yield 55.5%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.7 to 2.0 (71 H, m);

2.1 to 2.7 (4H, m);

2.90 (1 H, broad singlet);

3.4 to 5.5 (20H, m);

6.2 to 6.6 (2H, m);

7.1 to 7.4 (10 H, m).

[10 (d) Allyl 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R)- 3-benzyloxytetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxymethyl-β-D-glucopyranoside]

1.65 g of the compound obtained as described in Example 10 (c) are treated in the same manner as described in Example 4 (d) to yield 2.0 g of the title compound quantitatively.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.5 to 2.0 (71 H, m);

2.1 to 2.7 (4H, m);

3.5 to 5.6 (20H, m);

6.2 to 6.7 (2H, m);

7.1 to 7.5 (20 H, m).

[10 (e) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R) -3 -Benzyloxytetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxymethyl-D-β-glucopyranose]

1.9 g of the compound obtained as described in Example 10 (d) were treated by the method as described in Example 1 (g) to yield 0.88 g (yield 47.5%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (9H, t, J = 6.2 to 7.0 Hz);

1.15-1.70 (62H, m);

2.20 to 2.45 (4H, m);

3.07 (1 H, m);

3.60 to 3.82 (3H, m);

4.20 to 4.90 (10H, m);

5.17 (1 H, m);

5.30 (1H, t, J = 3.3 to 3.7 Hz);

5.57 (1H, doublet of doublets, J = 9.4 10.8 Hz);

6.68 (1H, doublet of doublets, J = 3.5 8.6 Hz);

7.1 to 7.35 (20 H, m).

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3450-3300, 2920, 2860, 1740, 1680.

[10 (f) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R) -3 -Hydroxytetradecanoyl] -4-0-diphenylphosphoryl-D-glucopyranose]

0.78 g of the compound obtained as described in Example 10 (e) was treated by the method as described in Example 7 (f) to yield 0.37 g (yield 51.4%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (9H, t, J = 6.2 to 7.0 Hz);

1.10 to 1.30 (58H, m);

1.40-1.75 (4H, m):

2.10 to 2.33 (4H, m);

3.50 to 4.10 (7H, m);

4.70 to 4.98 (3H, m);

5.13 to 5.50 (2H, m);

5.56 (1H, t, J = 9.5-10.3 Hz);

6.77 (1H, doublet of doublets, J = 3.7 9.2 Hz);

7.15-7.38 (10 H, m).

[10 (g) 2-deoxy-2-[(2'S, 3'R) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R) -3 Hydroxytetradecanoyl] -D-glucopyranosyl-4-phosphate]

0.29 g of the compound obtained as described in Example 10 (f) is treated in the same manner as described in Example 5 (g) to yield quantitatively 0.25 g of the title compound.

NMR Spectrum (CF ₃ COOD, 270MHz) δppm:

0.87-0.98 (9H, m);

1.20 to 1.55 (58H, m);

1.55 to 2.00 (4H, m);

2.43 to 2.64 (2H, m);

2.73 to 2.94 (2H, m);

4.14 to 4.65 (5H, m);

4.79 (1H, doublet of doublets, J = 9.3 18.5 Hz);

5.15 (1H, doublet of doublets, J = 1.0 46.9 Hz);

5.40 to 5.78 (3H, m).

FAB mass spectrum m / z: 938 [M ⁻ H] ⁻

Example 11

[2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R) -3-hydroxytetra Decanoyl] -D-glucopyranosyl-4-phosphate]

11 (a) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R) -3 -Benzyloxytetradecanoyl] -4,6-0-isopropylidene-β-D-glucopyranoside]

3.4 g of allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -4,6-0-isopropylidene-β -D-glucopyranoside [prepared by the method as described in Example 6 (a)] was treated by the method as described in Example 2 (b) to give 3.8 g (yield 77.4%) of the title compound. To obtain.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.5 to 2.0 (77 H, m);

2.0 to 2.8 (4H, m);

3.2 to 5.6 (16H, m);

6.1 to 6.4 (2H, m);

7.1 to 7.4 (5H, m).

[11 (b) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R)- 3-benzyloxytetradecanoyl] -β-D-glucopyranoside]

3.68 g of the compound obtained as described in Example 11 (a) are treated in the same manner as described in Example 4 (b) to give 2.97 g (84% yield) of the title compound.

[11 (c) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R)- 3-benzyloxytetradecanoyl] -6-0-benzyloxymethyl-β-D-glucopyranoside]

2.77 g of the compound obtained as described in Example 11 (b) are treated in the same manner as described in Example 7 (c) to give 2.36 g (76% yield) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.6 to 2.0 (71 H, m);

2.0 to 2.7 (4H, m);

3.4 to 6.2 (21H, m);

6.2 to 6.6 (2H, m);

7.1 to 7.5 (10 H, m).

[11 (d) Allyl 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R)- 3-benzyloxytetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxymethyl-β-D-glucopyranoside]

2.25 g of the compound obtained as described in Example 11 (c) were treated in the same manner as described in Example 4 (d) to yield 2.36 g (yield 86.4%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.6 to 2.0 (71 H, m);

2.1 to 2.4 (4H, m);

3.5 to 6.1 (20H, m);

6.1 to 6.6 (2H, m);

7.1 to 7.5 (20 H, m).

[11 (e) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R) -3 -Benzyloxytetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzyloxymethyl-D-glucopyranose]

2.2 g of the compound obtained as described in Example 11 (d) were treated by the method as described in Example 1 (g) to yield 1.83 g (yield 85.7%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

0.5 to 2.0 (71 H, m);

2.1 to 2.6 (4H, m);

3.6 to 5.9 (17H, m);

6.75 (1 H, broad singlet);

7.1-7.4 (20H, m).

[11 (f) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R) -3 Hydroxytetradecanoyl] -4-0-diphenylphosphoryl-β-D-glucopyranose]

1.7 g of the compound obtained as described in Example 11 (e) were treated by the method as described in Example 7 (f) to yield 0.6 g (yield 42.1%) of the title compound.

[11 (g) 2-deoxy-2-[(2'R, 3'S) -2'-fluoro-3'-tetradecanoyloxytetradecanoylamino] -3-0-[(3R) -3 Hydroxytetradecanoyl] -D-glucopyranosyl-4-phosphate]

0.54 g of the compound obtained as described in Example 11 (f) is treated by the method as described in Example 5 (g) to yield 0.45 g (yield 96.8%) of the title compound.

NMR Spectrum (CF ₃ COOD, 270MHz) δppm:

0.87-0.98 (9H, m);

1.27 to 1.60 (58H, m);

1.65-1.93 (4H, m);

2.50 to 2.60 (2H, m);

2.80 to 2.90 (2H, m);

4.12 to 4.62 (5H, m);

4.80 (1H, doublet of doublets, J = 9.5 18.3 Hz);

5.18 (1H, doublet of doublets, J = 2.7 48.6 Hz);

5.40 to 5.53 (3H, m).

FAB mass spectrum, m / z: 938 [M ⁻ H] ⁻

Example 12

[2-deoxy-2-[(R and S) -2 ', 2'-difluoro-3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyl Oxytetradecanoyl] -D-glucopyranosyl-4-phosphate

12 (a) allyl 2-deoxy-2-[(RS) -2 ', 2'-difluoro-3'-(benzyloxycarbonyloxy) tetradecanoylamino] -4,6-0-iso Propylidene-β-D-glucopyranoside]

2.2 g of (R, S) -3-benzyloxycarbonyloxy-2,2-difluorotetradecanoic acid are dissolved in 20 ml of anhydrous methylene chloride and 2 ml of oxalic acid chloride is added to the resulting solution. Then 1 drop of dimethylformamide is added and the mixture is stirred at room temperature for 1 hour. Thereafter, methylene chloride is removed by evaporation under reduced pressure to give an acid chloride.

On the other hand, 1.5 ml of allyl 2-deoxy-2-amino-4,6-0-isopropylidene-β-D-glucopyranoside [prepared as described in Example 1 (d)] of 20 ml of methylene anhydride To chloride and 700 mg of triethylamine was added to the resulting solution; The total amount of acid chloride prepared as described above is added under ice cooling. The mixture is then stirred at room temperature for 1 hour, after which methylene chloride is evaporated under reduced pressure. The residue is diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The ethyl acetate is then removed by evaporation under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: 2: 1 volume ratio mixture of ethyl acetate) to afford 2.64 g (yield 75.8%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (3H, t, J = 6.2 to 7.0 Hz);

1.25 to 1.61 {24H, m [including 1.45 (3H, s), 1.52 (3H, s)]};

1.72-1.79 (2H, m);

2.95 (0.5H, d, J = 3.3 Hz);

3.11 (0.5H, doublet, J = 3.3 Hz);

3.21 to 3.60 (3H, m);

3.76 to 4.13 (4H, m);

4.23 to 4.33 (1H, m);

4.70 (0.5H, doublet, J = 8.4 Hz);

4.81 (0.5H, d, J = 8.4 Hz);

5.14 to 5.31 (5H, m);

5.75 to 5.91 (1H, m);

6.47∼6.54 (1H, m):

7.30-7.40 (5H, m).

IR absorption spectrum (CHCI ₃ ) υ _max cm- ¹ :

3430, 2925, 2850, 1755, 1705, 1535, 1380, 1263.

Mass spectrum m / z:

655 (M ⁺ ), 640, 597, 532, 468, 385, 360, 242, 227, 184, 143, 108, 101, 91, 69, 43.

Elemental Analysis: C ₃₄ H ₅₁ F ₂ NO ₉ :

Calculated: C, 62.27%; H, 7.84%; N, 2.14%; F, 5.79%

Found: C, 62.20%; H, 7.76%; N, 2.06%; F, 5.74%

[12 (b) Allyl 2-deoxy-2-[(RS) -2 ', 2'-difluoro-3'-(benzyloxycarbonyloxy) tetradecanoylamino] -4,6-0- Isopropylidene-3-0-[(R) -3-tetradecanoyloxytetedecanoyl] -β-D-glucopyranoside]

230 mg (0.5 mmol) of (R) -3-tetradecanoyloxytetradecanoic acid were dissolved in 4 ml of methylene chloride and the resulting solution was treated with 0.5 ml of oxalyl chloride for 2 hours to produce the corresponding acid chloride. do. Excess oxalyl chloride and solvent are then removed by evaporation under reduced pressure and the residue is dried over anhydrous magnesium sulfate.

Meanwhile, 262 mg (0.4 mmol) of the compound obtained as described in Example 12 (a) and 50 mg of triethylamine are dissolved in 5 ml of methylene chloride, and the solution is thoroughly cooled with ice. The total amount of acid chloride prepared as described above was dissolved in methylene chloride to give 5 ml of the solution; This solution is added to the ice-cold solution. After 3 hours the starting material is consumed and the solvent is removed by evaporation under reduced pressure. The residue is diluted with ethyl acetate and the mixture is then treated with a 5% w / v aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The resulting mixture is then purified by silica gel column chromatography (20 g of silica gel, eluent: 5: 1 volume ratio mixture of cyclohexane and ethyl acetate) to give 325.8 mg (yield 74.3%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85-0.90 (9H, m):

1.20-1.80 (68H, m):

2.20-2.31 (2H, m):

2.43 to 2.66 (2H, m);

3.35 (1H, m):

3.68 to 4.07 (5H, m):

4.26 (1 H, m):

4.58 (1 H, m):

5.11 to 5.41 (7H, m):

5.74 (1H, m):

6.58 (1 H, m):

7.29 to 7.38 (5H, m).

IR absorption spectrum (liquid film) υ _max cm _-1 :

3350, 2925, 2850, 1780, 1710.

[12 (c) Allyl 2-deoxy-2-[(RS) -2 ', 2'-difluoro-3'-(benzyloxycarbonyloxy) tetradecanoylamino] -3-0-[( R) -3-tetradecanoyloxytetradecanoyl] -β-D-glucopyranoside]

50 ml of 85% acetic acid is added to 0.2 g of the compound obtained as described in Example 12 (b) and the mixture is stirred at 60 ° C. for 50 minutes. Subsequently, acetic acid was removed by evaporation under reduced pressure, and the residue was dried using a vacuum pump, and then the mixture was purified by column chromatography (15 g of silica gel, eluent: a 2: 1 volume ratio mixture of cyclohexane and ethyl acetate) to obtain 0.11 g ( Yield 57.9%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85 to 0.90 (9H, t, J = 6.4 to 6.8 Hz);

1.18-1.42 (47H, m);

1.43-1.80 (14H, m);

1.90-2.00 (1H, m):

2.09 (1H, t, J = 5.9 to 6.4 Hz);

2.25 to 2.32 (2H, m):

2.41 to 2.50 (2H, m):

3.37 to 3.53 (1H, m):

3.63 to 3.70 (2H, m):

3.78 to 4.08 (4H, m):

4.21 to 4.34 (1H, m):

4.53 (0.4H, d, J = 8.3 Hz);

4.59 (0.6H, d, J = 8.3 Hz);

4.92-5.36 (7H, m):

5.74-5.88 (1H, m):

6.59 (0.6H, doublet, J = 8.8 Hz);

6.69 (0.4H, d, J = 8.8 Hz);

7.35-7.39 (5H, m).

IR absorption spectrum (Nujol-trade name) υ _max cm ^-1 :

3350, 3450, 3300, 2950, 1760, 1690, 1620, 1550.

Elemental Analysis: C ₅₉ H ₉₉ F ₂ NO ₁₂ :

Calculated: C, 67.33%; H, 9.48%; N, 1.33%; F, 3.61%

Found: C, 67.24%; H, 9.04%; N, 1.68%; F, 3.41%

[12 (d) Allyl 6-0-benzyloxycarbonyl-2-deoxy-2-[(RS) -2 ', 2'-difluoro-3'-(benzyloxycarbonyloxy) tetradecanoyl Amino] -3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -β-D-glucopyranoside]

120 mg (0.11 mmol) and 25.4 mg (1.3 equivalents) of benzyloxycarbonyl chloride obtained as described in Example 12 (c) are dissolved in 20 ml of methylene chloride and the mixture is ice cooled. Then 17.2 mg (1.5 equivalents) of 4-dimethylaminopyridine is added to this solution and the mixture is stirred for 30 minutes. After 30 minutes, the temperature of the mixture is reduced to room temperature and then the mixture is stirred for 2 hours. Then purified by silica gel column chromatography (100 g of silica gel, eluent: 2: 1 volume ratio mixture of cyclohexane and ethyl acetate) to 80 mg (yield 59.2%) of the title compound and 36 mg of the material protected in both 4- and 6-positions (yield) 26.7%).

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (9H, t, J = 6.35 to 6.63 Hz);

1.25-1.73 (62H, m):

2.24 to 2.31 (2H, m):

2.41 to 2.48 (2H, m):

3.52 to 3.69 (4H, m):

3.90-4.02 (3H, m):

4.18-4.30 (1H, m):

4.42-4.57 (3H, m):

5.02 to 5.25 (7H, m):

5.68-5.85 (1H, m):

6.48 to 6.65 (1H, d):

7.32-7.40 (10H, m).

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3500, 3300, 2900, 2850, 1720, 1690, 1540.

Elemental analysis: C ₆₇ H ₁₀₅ F ₂ NO ₁₄ :

Calculated value: C, 67.82%; H, 8.92%; N, 1.18%; F, 3.20%

Found: C, 67.19%; H, 8.75%; N, 0.89%; F, 2.99%

[12 (e) Allyl 6-0-benzyloxycarbonyl-2-[(RS) -2 ', 2'-difluoro-3'-(benzyloxycarbonyloxy) tetradecanoylamino] -4- 0-diphenylphosphoryl-2-deoxy-3-0-[(R) -3-tetradecanoyloxytetedecanoyl] -β-D-glucopyranoside]

0.5 g of the compound obtained as described in Example 12 (d) was dissolved in 50 ml of tetrahydrofuran solvent, and 1 g of diphenylphosphoryl chloride and 4-dimethylaminopyridine (each in excess) were added to the resulting solution. Add. The mixture is then heated at reflux for 3 hours. Thereafter, the solvent is removed by evaporation under reduced pressure, and the residue is diluted with diethyl acetate. The mixture is then treated sequentially with a 5% aqueous solution of sodium hydrogen carbonate and a saturated aqueous sodium chloride solution. The resulting mixture was purified by silica gel column chromatography (30 g of silica gel, eluent: 3: 1 volume ratio mixture of cyclohexane and ethyl acetate) to give 0.62 g (yield 97.5%) of the title compound.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.90 (9H, t, J = 6.8 Hz);

1.14-1.75 (62H, m):

2.12-2.41 (3H, m):

3.61 to 3.83 (3H, m):

3.91 to 4.04 (1H, m):

4.13-4.23 (2H, m):

4.30-4.38 (1H, m):

4.69 (1H, doublet of doublets, J = 9.0, 0.0 18.0 Hz);

4.85 (1H, doublet, J = 7.0 Hz);

4.99-5.39 (7H, m):

5.47 to 5.63 (2H, m):

5.67-5.85 (1H, m):

6.80 (0.5H, d, J = 7.0 Hz);

6.95 (0.5H, d, J = 7.0 Hz);

7.10-7.36 (20 H, m).

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3300, 2900, 2850, 1750, 1700, 1590, 1540.

Elemental analysis: C ₇₉ H ₁₁₄ F ₂ NO ₁₇ P:

Calculated: C, 66.88%; H, 8. 10%; N, 0.99%; F, 2.68%; P, 2.15%

Found: C, 66.15%; H, 7.92%; N, 1.03%; F, 2.45%; P, 2.13%.

[12 (f) 6-0-Benzyloxycarbonyl-4-0-diphenylphosphoryl-2-deoxy-2-[(RS) -2 ', 2'-difluoro-3'-(benzyl Oxycarbonyloxy) tetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranoside]

50 mg and 30 mg (5 mol%) of 1,5-cyclooctadienebis [methyldiphenylphosphine] iridium hexafluorophosphate obtained as described in Example 12 (e) are dissolved in 5 ml of tetrahydrofuran. . The reaction vessel is first purged with nitrogen and then with hydrogen. The color of the solution changes and replaces the atmosphere in the reaction vessel with nitrogen. The mixture is then stirred at room temperature for 3 hours and then 1 ml of concentrated aqueous hydrochloric acid solution is added. The mixture is then stirred at 50 ° C. for 2 hours. After 2 hours, the mixture was purified by preparative thin membrane chromatography (1 mm, developing solvent: a 3: 1 volume ratio mixture of ethyl acetate) to obtain 40 mg (yield 82.1%) of the title compound (mixture of R and S isomers). do.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.83 to 0.90 (9H, t, J = 6.5 to 6.8 Hz);

1.16 to 1.74 (62H, m)

2.09 to 2.18 (2H, m):

2.32-2.49 (2H, m):

2.73 to 2.74 (0.5H, d, J = 3.9 Hz);

3.28 to 3.29 (0.5H, d, J = 3.9 Hz);

4.01 to 4.38 (4H, m):

4.63∼4.74 (1H, m):

4.89-5.23 (7H, m):

5.33 to 5.37 (1H, m);

6.72-6.73 (1H, m):

7.12-7.37 (20H, m).

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3350, 2925, 2850, 1750, 1710, 1590, 1540, 1490, 1460.

Elemental analysis: C ₇₆ H ₁₁₀ F ₂ NO ₁₇ P:

Calculated: C, 66.21%; H, 8.04%; N, 1.01%; F, 2.75%; P, 2.24%

Found: C, 66.73%; H, 7.37%; N, 0.71%; F, 2.43%; P, 2.05%

[12 (g) 4-0-diphenylphosphoryl-2-deoxy-2-[(RS) -2 ', 2'-difluoro-3'-hydroxytetradecanoylamino] -3-0 -[(R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranoside]

30 mg of the compound obtained as described in Example 12 (f) is dissolved in 2 ml of tetrahydrofuran and 20 mg of 10% w / w palladium on carbon is added. An aspirator is used to replace the atmosphere in the reaction vessel with hydrogen. The reaction mixture is stirred for 6 hours at room temperature and then left overnight. The mixture is then purified by preparative thin membrane chromatography (1 mm, developing solvent: 1: 1 volume ratio mixture of cyclohexane and ethyl acetate) to give the two title compounds (compounds having a substituent at 2-position in the R or S configuration). 10 mg (41.2% yield) of each were obtained.

2R compounds (compounds with low Rf values):

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85-0.90 (9H, t, J = 6.34-6.36 Hz);

1.20 to 1.68 (62H, m);

2.17 to 2.23 (2H, m);

2.34 to 2.47 (2H, m);

3.10 (1H, doublet, J = 4.5 Hz);

3.18 to 3.27 (2H, m);

3.54 to 3.61 (1H, m);

3.92 to 4.03 (3H, m);

4.27 to 4.36 (1H, m);

4.78 (1H, quartet J = 9.2 Hz);

5.02 to 5.11 (1H, m);

5.36 (1H, t, J = 3.4 Hz);

5.53 (1H, t, J = 9.3 Hz);

6.87 to 6.61 (1H, m);

7.14 to 7.39 (10 H, m).

IR absorption spectrum (Nujoul) υ _max cm- ¹ :

3500, 3450, 3375, 2900, 2850, 1730, 1680, 1600.

2S compound (compound with high Rf value):

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.85 to 0.90 (9H, t, J = 6.3 to 6.61 Hz);

1.21 to 1.68 (62H, m);

2.17 to 2.23 (2H, m);

2.34 to 2.50 (2H, m):

3.08 (1H, doublet, J = 4.4 Hz);

3.18 to 3.29 (2H, m);

3.54 to 3.61 (1H, m);

3.94 to 4.00 (3H, m);

4.27 to 4.36 (1H, m);

4.79 (1H, quartet J = 9.4 Hz);

5.02 to 5.12 (1H, m);

5.36 (1H, t, J = 3.4 Hz);

5.53 (1H, t, J = 9.7 Hz);

6.92 to 7.01 (1H, m);

7.14 to 7.39 (10 H, m).

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3500, 3450, 3375, 2900, 2850, 1730, 1680, 1600.

[12 (h) 2-deoxy-2-[(R or S) -2 ', 2'-difluoro-3'-hydroxytetradecanoylamino] -3-0-[(R) -3 Tetradecanoyloxytetradecanoyl] -D-glucopyranosyl-4-phosphate]

60 mg of each compound obtained in Example 12 (g) is separately dissolved in 2 ml of tetrahydrofuran and 5 mg of platinum oxide is added. Subsequently, the aspirator is used to replace the atmosphere in the reaction vessel with hydrogen, and then the mixture is stirred at room temperature for 3 hours. After 3 hours platinum oxide is removed by filtration and tetrahydrofuran is removed by evaporation under reduced pressure to give the title compound which is substituted for the 2-position of either the R or S configuration. 50 mg (95% yield) of a compound having a high Rf value are obtained from a starting compound having a high Rf value, and 52 mg (97% yield) of a compound having a low Rf value are obtained from a starting compound having a low Rf value. The developing solvent used is an 8: 5: 1: 1 volume ratio mixture of chloroform, ethanol, acetic acid and water.

2R compounds (compounds with low Rf values):

NMR spectrum (Deuterium pyridine + D ₂ O, 270 MHz) δ ppm:

0.85 to 0.90 (9H, m);

1.14 to 2.04 (62H, m);

2.39 to 2.48 (2H, m);

3.05 to 3.14 (1H, m);

3.28 to 3.37 (1H, m);

4.07 to 4.11 (1H, m);

4.49-4.66 (3H, m);

4.88 to 4.98 (1 H, m);

5.18-5.29 (1H, m);

5.71 to 5.81 (2H, m);

6.17-6.32 (1 H, m).

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3500, 3350, 2900, 2850, 1720, 1680, 1590, 1540, 1490, 1460.

2S compound (compound with high Rf value):

NMR spectrum (Deuterium pyridine + D ₂ O, 270 MHz) δ ppm:

0.88-0.97 (9H, m);

1.24 to 2.02 (62H, m);

2.33 to 2.48 (2H, m);

2.92 to 3.01 (1H, m);

3.36 to 3.59 (1H, m);

4.11 to 4.22 (1H, m);

4.53 to 4.69 (3H, m);

4.93 to 5.04 (1H, m);

5.49 to 5.56 (1H, m);

5.68 to 5.74 (1H, m);

5.82 to 5.83 (1H, m);

6.26-6.38 (1 H, m).

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3500, 3350, 2900, 2850, 1720, 1680, 1590, 1540, 1490, 1460.

Example 13

[1,2-dideoxy-1-fluoro-2-[(R) -3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranosyl-4-phosphate

13 (a) allyl 2-deoxy-2-amino-4,6-0-isopropylidene-α-D-glucopyranoside]

200 g of 10 g allyl 2-deoxy-2-trifluoroacetylamino-4,6-0-isopropylidene-α-D-glucopyranoside [prepared as described in Example 1 (c)] Dissolved in ethanol (99.5%), and 100 ml of 1N aqueous sodium hydroxide solution was added to the resulting solution; The mixture is heated at reflux for 4 h. After 4 hours the mixture is concentrated by evaporation under reduced pressure and the residue is diluted with ethyl acetate. The ethyl acetate layer was washed sequentially with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. It is then filtered and the ethyl acetate is removed from the filtrate by evaporation under reduced pressure. The resulting oily residue was purified by silica gel column chromatography (eluent: ethyl acetate) to yield 6.6 g (yield 90.5%) of the title compound.

NMR Spectrum (CDCI ₃ , 60MHz) δppm:

1.42 (3 H, s);

1.50 (3H, s);

2.98 (2H, broad singlet);

3.5 to 4.4 (5H, m);

4.6-6.3 (7H, m).

Elemental analysis: C ₁₂ H ₂₁ NO ₅ (molecular weight, 259.3)

Calculated: C, 55.58%; H, 8. 16%; N, 5.40%

Found: C, 55.37%; H, 8.05%; N, 5.40%

[13 (b) Allyl 2-deoxy-2-[(3'R) -3'-benzyloxytetradecanoylamino] -4,6-0-isopropylidene-α-D-glucopyranoside and Allyl 2-deoxy-2-[(3'S) -3'-benzyloxytetradecanoylamino] -4,6-0-isopropylidene-α-D-glucopyranoside]

5 g (19.3 mmol) of the compound obtained as described in Example 13 (a) are dissolved in 100 ml of methylene chloride. To the resulting solution was added 6.8 g of (+)-3-benzyloxytetradecanoic acid and 4.78 g of N, N'-dicyclohexylcarbodiimide in turn, and then the mixture was stirred at room temperature for 1 hour. The mixture is then filtered, the filtrate is concentrated by evaporation under reduced pressure and the residue is diluted with ethyl acetate. The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the ethyl acetate was evaporated to remove from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 9: 11 volume ratio mixture of cyclohexane and ethyl acetate) to give 4.2 g of 3'-R isomer (Rf = 0.289) of the title compound and 3'-S isomer of the title compound ( Rf = 0.196) to 4.2 g, respectively.

3'R compound:

IR absorption spectrum (KBr) υ _max cm ^-1 :

3510, 3280, 1643.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (3H, t, J = 6.9 Hz);

1.20 to 1.41 (18H, m);

1.45 (3 H, s);

1.52 (3H, s);

1.56 to 1.70 (2H, m);

2.43 (1H, doublet of doublets, J = 6.9 15.4 Hz);

2.56 (1H, doublet of doublets, J = 3.7 15.0 Hz);

3.19 to 3.29 (1H, m);

3.46 to 3.63 (2H, m);

3.75 to 3.94 (5H, m);

4.18 to 4.24 (1H, m);

4.36 (1H, doublet, J = 2.6 Hz);

4.45 to 4.62 (3H, m);

5.12-5.26 (2H, m);

5.70 to 5.88 (1H, m);

6.72 (1H, doublet, J = 5.9 Hz);

7.30-7.37 (5H, m).

3'S Compound:

IR absorption spectrum (KBr) υ _max cm ^-1 :

3510, 3280, 1643.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (3H, t J = 6.6 Hz);

1.15-1.73 (20H, m);

1.45 (3 H, s);

1.53 (3 H, s);

2.35 to 2.62 (2H, m);

3.02 (1H, doublet, J = 2.6 Hz);

3.55 to 4.25 (9H, m);

4.54, 4.59 (2H, AB quarter, J = 11.4 Hz);

4.78 (1H, doublet, J = 3.7 Hz);

5.10 to 5.28 (2H, m);

5.66 to 5.44 (1H, m);

6.77 (1H, doublet, J = 8.8 Hz);

7.25 to 7.37 (5H, m);

[13 (c) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -4 , 6-0-isopropylidene-α-D-glucopyranoside and allyl 2-[(S) -3'-benzyloxytetradecanoylamino] -2-deoxy-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -4,6-0-isopropylidene-α-D-glucopyranoside]

1 g of a compound (either 3'R compound or 3'S compound) obtained as described in Example 13 (b) is dissolved in 20 ml of tetrahydrofuran, and 0.869 g of 3 (R) -tetradecanoyloxytetra is dissolved in this solution. Add decanoic acid. 0.466 g of N, N'-dimethylcyclohexylcarbodiimide and 0.233 g of 4-dimethylaminopyridine are then added to the mixture, and the mixture is stirred at room temperature for 4 hours. The mixture was then filtered and the filtrate was concentrated by evaporation under reduced pressure, the residue was diluted with ethyl acetate, and then the mixture was washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution; Dry over anhydrous magnesium sulfate. The solution is then filtered and ethyl acetate is evaporated under reduced pressure to remove from the filtrate. The residue was purified by silica gel column chromatography (eluent: 85:15 volume ratio mixture of cyclohexane and ethyl acetate) to give 1.23 g of the 3'R isomer (70% yield) and 1.27 g of the 3'S isomer of the title compound (yield 73). %) Are obtained respectively.

3'R compound:

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3350, 1730, 1650, 1530, 1470, 1370.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.80 to 1.00 (9H, m);

1.00-1.80 (68H, m);

2.10-2.70 (6H, m);

3.60 to 4.40 (8H, m);

4.49, 4.54 (2H, doublet, J = 11.7 Hz);

4.65 to 4.90 (1H, m);

5.03 to 5.35 (4H, m);

5.60 to 5.95 (1 H, m);

6.25 (1H, doublet, J = 9.5 Hz);

7.25-7.75 (5H, m).

3'S Compound:

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3400, 1730, 1670, 1650.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.80 to 0.97 (9H, m);

1.10-1.70 (68H, m);

2.12 to 2.64 (6H, m);

3.63 to 3.90 (6H, m);

3.95 to 4.05 (1H, m);

4.22 to 4.34 (1H, m);

4.49, 4.60 (2H, doublet, J = 11.4 Hz);

4.78 (1H, doublet, J = 3.7 Hz);

5.05 to 5.23 (4H, m);

5.60 to 5.77 (1H, m);

6.85 (1H, doublet, J = 9.2 Hz);

7.25 to 7.40 (5H, m).

[13 (d) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -α -D-glucopyranoside and allyl 2-[(S) -3'-benzyloxytetradecanoylamino] -2-deoxy-3-0-[(S) -3-benzyloxytetradecanoylamino] -2-deoxy-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside]

1 g of each of the 3'R and 3'S isomers of the compound obtained as described in Example 13 (c) is separately dissolved in 20 ml of 90% acetic acid and the solution is stirred at 55-60 ° C for 1 hour. The acetic acid is then removed by evaporation under reduced pressure and the residue is diluted with ethyl acetate. The diluted mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then purified by silica gel column chromatography (eluent: 3: 2 volume ratio mixture of cyclohexane and ethyl acetate) to give 0.6 g of 3'R isomer of the title compound. (Yield 57%) O 0.66 g (yield 69%) of 3'S isomer of the title compound were obtained, respectively.

3'R compound:

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3480, 3400, 3300, 1735, 1720, 1700, 1650, 1550, 1465, 1380, 1310.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.82-0.95 (9H, m);

1.15-1.70 (64H, m);

2.24 to 2.58 (6H, m);

3.62 to 3.92 (6H, m);

4.00 to 4.10 (1H, m);

4.20 to 4.30 (1H, m);

4.50, 4.55 (2H, doublet, J = 11.5 Hz);

4.79 (1H, doublet, J = 3.3 Hz);

5.03 to 5.24 (4H, m);

5.65 to 5.82 (1H, m);

6.33 (1H, doublet, J = 9.5 Hz);

7.22 to 7.36 (5H, m).

3'S Compound:

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3280, 1737, 1722, 1643, 1550, 1466, 1177, 1103, 1053.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.80 to 0.95 (9H, m);

1.15 to 1.72 (62H, m);

2.24 to 2.50 (6H, m);

3.62 to 3.92 (6H, m);

4.00 to 4.10 (1H, m);

4.18 to 4.30 (1H, m);

4.50, 4.57 (2H, doublet, J = 11.4 Hz);

4.86 (1H, doublet, J = 3.3 Hz);

5.02 to 5.27 (4H, m);

5.64 to 5.81 (1H, m);

6.80 (1H, doublet, J = 8.8 Hz);

7.25 to 7.40 (5H, m).

[13 (e) Allyl 6-0-benzyloxycarbonyl-2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-3-0-[(R) -3-tetra Decanoyloxytetradecanoyl] -α-D-glucopyranoside and allyl 6-0-benzyloxycarbonyl-2-[(S) -3'-benzyloxytetradecanoylamino] -2-deoxy- 3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside]

0.645 g of each of the 3'R and 3'S isomers obtained as described in Example 13 (d) are separately dissolved in 10 ml of methylene chloride. 0.136 g of benzyloxycarbonylchloride and 0.122 g of 4-dimethylaminopyridine are then added to the solution under ice-cooling, and the mixture is stirred at room temperature for 2 hours. After completion of stirring, methylene chloride is removed by evaporation under reduced pressure, and the residue is diluted with ethyl acetate. The diluted mixture was washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. It is then filtered and the ethyl acetate is removed from the filtrate by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 4: 1 volume ratio mixture of cyclohexane and ethyl acetate) to give 0.46 g (yield 63%) of the 3'R isomer of the title compound and the 3'S isomer of the title compound, respectively.

3'R compound:

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3500, 3310, 1730, 1650, 1545, 1465, 1380, 1305, 1280.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.80 to 0.96 (9H, m);

1.10-1.70 (62H, m);

2.22 to 2.60 (6H, m);

3.34 (1H, doublet, J = 4.0 Hz);

3.53 to 3.66 (1H, m);

3.72 to 3.90 (3H, m);

3.95 to 4.05 (1H, m);

4.20 to 4.32 (1H, m);

4.35 to 4.52 (2H, m);

4.49, 4.56 (2H, doublet, J = 11.7 Hz);

4.77 (1H, doublet, J = 3.7 Hz);

5.00 to 5.25 (6H, m);

5.62 to 5.78 (1H, m);

6.29 (1 H, m);

7.22 to 7.43 (10H, m);

3'S compound

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3500, 3290, 1737, 1720, 1647, 1546, 1466, 1282.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.82 to 0.93 (9H, m);

1.15-1.65 (62H, m);

2.22 to 2.50 (6H, m);

3.33 (1H, doublet, J = 4.0 Hz);

3.55 to 3.67 (1H, m);

3.67 to 3.90 (3H, m);

3.96 to 4.05 (1H, m);

4.18 to 4.30 (1H, m);

4.18 to 4.30 (1H, m);

4.37 to 4.52 (2H, m);

4.49, 4.57 (2H, doublet, J = 11.4 Hz);

4.83 (1H, doublet, J = 3.3 Hz);

5.00 to 5.22 (6H, m);

5.60 to 5.77 (1H, m);

6.76 (1H, doublet, J = 8.8 Hz);

7.25 to 7.42 (10 H, m).

[13 (f) Allyl 2-deoxy-6-0-benzyloxycarbonyl-2-[(R) -3'-benzyloxytetradecanoylamino] -4-0-diphenylphosphoryl-3-0 -[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside and allyl 2-deoxy-6-0-benzyloxycarbonyl-2-[(S) -3 ' -Benzyloxytetradecanoylamino] -4-0-diphenylphosphoryl-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside]

11.3 g of each of the 3'R and 3'S isomers of the compound obtained as described in Example 13 (e) was separately dissolved in 230 ml of methylene chloride and 8.22 g of diphenylchlorophosphate and 7.48 g of 4-dimethyl in this solution Aminopyridine is added. The resulting mixture is then stirred at room temperature for 1 hour. After 1 hour, methylene chloride is removed by evaporation under reduced pressure and the residue is diluted with ethyl acetate. The diluted mixture is washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. It is then filtered and the ethyl acetate is removed from the filtrate by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 7: 3 volume ratio mixture of cyclohexane and ethyl acetate) to give 6.12 g (45% yield) of the 3'R isomer of the title compound and 11.34 g (Yield 83) of the 3'S isomer of the title compound. %) Are obtained respectively.

3'R compound:

IR absorption spectrum (Nujol) υ _max cm _-1 :

1735, 1720, 1665, 1590, 1485, 1255, 1066, 965.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.82 to 0.94 (9H, m);

1.10 to 1.60 (62H, m);

2.10 to 2.20 (2H, m);

2.30 to 2.46 (4H, m);

3.67 to 3.78 (1H, m);

3.78 to 3.90 (1H, m);

3.90 to 4.03 (1H, m);

4.15 to 4.37 (3H, m);

4.48 to 4.54 (2H, AB quartet, J = 11.4 Hz);

4.72 (1H, doublet of doublets, J = 9.2 19.1 Hz);

4.80 (1H, doublet, J = 3.3 Hz);

5.00 to 5.20 (5H, m);

5.40 (1H, doublet of doublets, J = 9.2 10.6 Hz);

5.62 to 5.77 (1H, m);

6.22 (1H, doublet, J = 8.8 Hz);

7.10-7.38 (20H, m).

3'S Compound:

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3350, 1745, 1650, 1590, 140, 960.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.80 to 0.93 (9H, m);

1.10 to 1.65 (62H, m);

2.08 to 2.20 (2H, m);

2.30 to 2.52 (4H, m);

3.65 to 3.87 (2H, m);

3.93 to 4.05 (2H, m);

4.16 to 4.35 (3H, m);

4.49, 4.60 (2H, doublet, J = 11.4 Hz);

4.72 (1H, doublet of doublets, J = 9.2 4.7 Hz);

4.85 (1H, doublet, J = 3.3 Hz);

5.01 to 5.20 (5H, m);

5.39 (1H, doublet of doublets, J = 9.2 10.6 Hz);

5.59 to 5.74 (1H, m);

6.86 (1H, doublet, J = 8.8 Hz);

7.10-7.20 (20 H, m).

[13 (g) 2-deoxy-6-0-benzyloxycarbonyl-2-[(R) -3'-benzyloxytetradecanoylamino] -4-0-diphenylphosphoryl-3-0- [(R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranoside and 2-deoxy-6-0-benzyloxycarbonyl-2-[(S) -3'-benzyloxytetra Decanoylamino] -4-0-diphenylphosphoryl-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranoside]

0.28 g of each of the 3'R isomer 3'S isomer of a compound obtained as described in Example 13 (f) was separately dissolved in 5 ml of tetrahydrofuran, and 8.9 mg of 1,5-cyclooctadiene bis (methyl) was added to the resulting solution. Diphenylphosphine) iridium hexafluorophosphate is added. The reaction vessel is then purged with nitrogen and then with hydrogen to activate the iridium complex and then the atmosphere in the reaction vessel is replaced with nitrogen. The mixture is stirred at room temperature for 3 hours, after which 0.5 ml of water, 0.1 g of iodine and 0.066 g of pyridine are added. The mixture is then stirred for an additional 30 minutes at room temperature. After 30 minutes, tetrahydrofuran is removed by evaporation under reduced pressure and the residue is diluted with ethyl acetate. The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then ethyl acetate was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 7: 3 volume ratio mixture of cyclohexane and ethyl acetate) to give 0.23 g of the 3'R isomer of the title compound (yield 84%) and 0.24 g of the 3'S isomer of the title compound (yield 88). %) Are obtained respectively.

3'R compound:

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3320, 1735, 1650, 1590, 1535, 1490, 1455.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.82 to 0.93 (9H, m);

1.08-1.70 (62H, m);

2.10 to 2.22 (2H, m);

2.27 to 2.25 (2H, m);

2.38 to 2.44 (2H, m);

2.50 (1H, doublet of doublets, J = 1.1 4.4 Hz);

3.82 to 3.93 (1H, m);

4.10 to 4.39 (4H, m);

4.39, 4.60 (2H, AB quartet, J = 11.0 Hz);

4.68 (1H, doublet of doublets, J = 9.2 18.3 Hz);

5.00 to 5.13 (4H, m);

5,39 (1H, doublet of doublets, J = 9.2 11.6 Hz);

6.22 (1H, doublet, J = 8.8 Hz);

7.09 to 7.39 (20 H, m).

3'S Compound:

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3600-3200, 1748, 1640, 1540, 1490, 961.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.82-0.96 (9H, m);

1.07 to 1.65 (62H, m);

2.12 to 2.22 (2H, m);

2.32 to 2.46 (4H, m);

2.99 (1H, doublet of doublets, J = 1.5, 4.0 Hz);

3.70 to 3.82 (1H, m);

4.13 to 4.38 (4H, m);

4.52 to 4.57 (2H, d, J = 11.0 Hz);

4.71 (1H, doublet of doublets, J = 9.2 18.7 Hz);

4.97 to 5.25 (4H, m);

5.46 (1H, doublet of doublets, J = 9.2 10.6 Hz);

6.86 (1H, doublet, J = 8.4 Hz);

7.08 to 7.40 (20 H, m).

[13 (h) 6-0-benzyloxycarbonyl-2-[(R) -3'-benzyloxytetradecanoylamino] -1,2-dideoxy-4-0-diphenylphosphoryl-1- Fluoro-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside]

1.36 g (8.44 mmol) of diethylaminosulfur trifluoride (DAST) was dissolved in 30 ml of anhydrous methylene chloride and 2.74 g (2.11 mmol) of 2-deoxy-6 dissolved in anhydrous methylene chloride in this solution. -0-benzyloxycarbonyl-2-[(R) -3'-benzyloxytetradecanoylamino] -4-0-diphenylphosphoryl-3-0-[(R) -3-tetradecanoyloxy 25 ml of a solution of tetradecanoyl] -D-glucopyranoside [obtained as described in Example 13 (g)] is slowly added. The mixture is then stirred under ice cooling for 1 hour. After 1 hour, the reaction mixture is poured into 130 ml of ice water to collect the methylene chloride layer. The aqueous layer is extracted with methylene chloride and washed with saturated aqueous sodium chloride solution; It is then dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 8: 2 volume ratio mixture of cyclohexane and ethyl acetate) to obtain 1.10 g (40% yield) of the α-fluoro isomer of the title compound and 1.14 of the β-fluoro isomer of the title compound. g (yield 42%) is obtained as a white solid, respectively.

α-fluoro compounds:

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3380, 1740, 1660, 1590.

Elemental analysis: C ₇₅ H ₁₁₁ NO ₁₄ FP:

Calculated: C, 69.26%; H, 8. 60%; N, 1.08%; F, 1.46%; P, 2.38%.

Found: C, 69.11%; H, 8.62%; N, 1.02%; F, 1.42%; P, 2.35%

β-fluoro compounds:

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3320, 1745, 1725, 1662, 1590.

Elemental Analysis: C7 ₅ H ₁₁₁ NO ₁₄ FP:

Calculated: C, 69.26%; H, 8. 60%; N, 1.08%; F, 1.46%; P, 2.38%

Found: C, 69.25%; H, 8.53%; N, 1.07%; F, 1.44%; P, 2.51%

[13 (i) 1,2-dideoxy-4-0-diphenylphosphoryl-1-fluoro-2-[(R) -3'-hydroxytetradecanoylamino] -3-0-[( R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside]

0.4 g of the obtained glycofyranosyl fluoride as described in Example 13 (h) is dissolved in 6 ml of tetrahydrofuran and 0.4 g of 10% w / w palladium-on-carbon is added to the resulting solution. Then, 24 ml of methanol and 50 mg of formic acid are added to the mixture, and the mixture is stirred at room temperature under hydrogen stream for 4 hours. After 4 hours, the palladium-on-carbon is filtered off using a Celite Filter aid to remove from the reaction mixture and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by silica gel flash chromatography (eluent: mixture of cyclohexane and ethyl acetate 6: 4 volume ratio) to give 0.1 g (yield 30%) of the title compound as a powder.

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3550, 3420, 1732, 1646, 1590.

[13 (j) 1,2-dideoxy-1-fluoro-2-[(R) -3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxy Tetradecanoyl] -α-D-glucopyranosyl-4-phosphate]

85 mg of the compound obtained as described in 13 (i) was dissolved in 5 ml of anhydrous tetrahydrofuran, 17 mg of platinum oxide was added to the resulting solution, and the mixture was stirred at room temperature under air for 4 hours. The reaction mixture is then heated to 45 ° C. to dissolve the insolubles and then filtered using Celite filter aid. The solvent is then evaporated off under reduced pressure to give 72 mg (yield 97%) of the title compound as a powder.

NMR spectrum (Duteropyridine, 270MHz) δ ppm:

0.82-0.95 (9H, m);

1.15 to 1.90 (62H, m);

2.48 (2H, t, J = 7.3 Hz);

2.80 to 2.90 (2H, m);

3.06 to 3.30 (2H, m);

4.01 to 4.60 (7H, m);

5.00 to 5.50 (2H, m);

5.71 (1H, t, J = 5.9 Hz);

5.97 (1H, doublet of doublets, J = 2.4 52.5 Hz);

6.06 (1H, t, J = 10.3 Hz);

9.56 (1H, doublet, J = 9.3 Hz).

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3250, 1722, 1645, 1550.

Example 14

[1,2-dideoxy-1-fluoro-2-[(S) -3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranosyl-4-phosphate]

14 (a) 6-0-benzyloxycarbonyl-2-[(S) -3'-benzyloxytetradecanoylamino] -1,2-dideoxy-4-0-diphenylphosphoryl-1-fluor Rho-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside

1.49 g of diethylaminosulfur trifluoride was dissolved in 30 ml of anhydrous ethylene chloride, and 3.0 g (2.31 mmol) of 2-deoxy-6-0-benzyloxycarb dissolved in anhydrous methylene chloride in the resulting solution. Bonyl-2-[(S) -3'-benzyloxytetradecanoylamino] -4-0-diphenylphosphoryl-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -D -30 ml of a solution of glucopyranoside [prepared as described in Example 13 (g)] is slowly added under ice-cooling. After the addition is completed, the mixture is stirred for an additional 30 minutes at room temperature under ice cooling. After completion of stirring, the reaction mixture is poured into 150 ml of ice water and the methylene chloride layer is collected. The aqueous layer was extracted with methylene chloride and washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the mixture was evaporated under reduced pressure and concentrated to a residue, 5 g of silica gel (No. 9385, commercially available from Merck) and 100 ml of methylene Chloride is added and the mixture is stirred overnight to convert the α, β-fluoro compounds to α-fluoro compounds. The silica gel is then removed by filtration and the methylene chloride is removed from the filtrate by evaporation under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 85:15 volume ratio mixture of cyclohexane and ethyl acetate) to give 2.4 g (yield 80% of the title compound).

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3390, 1740, 1650, 1590.

[14 (b) 1,2-dideoxy-4-0-diphenylphosphoryl-1-fluoro-2-[(S) -3'-hydroxytetradecanoylamino] -3-0-[( R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside]

1.82 g of the compound obtained as described in Example 14 (a) is dissolved in 12 ml of tetrahydrofuran and 1.8 g of 10% w / w palladium-silver-carbon is added to the resulting solution. 45 ml of methanol and 70 mg of formic acid are then added to the mixture, and the mixture is stirred at room temperature under hydrogen stream for 5 hours. Palladium-silver-carbon is filtered off using a celite filter aid to remove it from the reaction mixture, and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by silica gel flash chromatography (eluent: 6: 4 volume ratio mixture of cyclohexane and ethyl acetate) to give 0.38 g (25% yield) of the title compound as a solid.

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3600-3100, 1740, 1720, 1645, 1590.

Elemental Analysis: C ₆₀ H ₉₉ NO ₁₂ FP:

Calculated: C, 66.95%; H, 9. 27%; N, 1.30%; F, 1.76%; P, 2.88%

Found: C, 67.04%; H, 8.98%; N, 1.37%; F, 1.59%; P, 3.06%

[14 (c) 1,2-dideoxy-1-fluoro-2-[(S) -3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxy Tetradecanoyl] -α-D-glucopyranosyl-4-phosphate]

80 mg of the compound obtained as described in Example 14 (b) is dissolved in 3 ml of anhydrous tetrahydrofuran, 16 ml of platinum oxide is added to the resulting solution, and the mixture is stirred at room temperature under hydrogen stream for 4 hours. The reaction mixture is then heated to 45 ° C. to dissolve the insolubles and then filtered using Celite filter aid. The solvent is then evaporated under reduced pressure to remove from the filtrate to give 60 mg (87% yield) of the title compound as a solid.

NMR Spectrum (Duteropyridin, 270MHz) δppm:

0.80 to 0.97 (9H, m);

1.10 to 1.90 (62H, m);

2.46 (2H, t, J = 7.3 Hz);

2.82 (2H, doublet, J = 5.9 Hz);

3.04 to 3.25 (2H, m);

3.60 to 3.70 (1H, m);

3.80 to 4.55 (6H, m);

5.65 to 7.77 (1H, m);

6.00 to 6.10 (1H, m);

6.10 (1H, doublet of doublets, J = 2.9 53.7 Hz);

9.47 (1H, doublet, J = 9.3 Hz).

IR absorption spectrum (Nujol) υ _max cm _-1 :

3550, 3300, 1730, 1650.

Example 15

[2,6-dideoxy-6-fluoro-2-[(R) -3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranosyl-4-phosphate

15 (a) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-6-0-t-butyldimethylsilyl-3-0-[(R) -3-tetra Decanoyloxytetradecanoyl] -α-D-glucopyranoside]

0.49 g (0.5 mmol) of allyl 2-[(R) -2'-benzyloxytetradecanoylamino] -2-deoxy-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside [prepared as described in Example 13 (d)] was dissolved in 10 ml of anhydrous methylene chloride and 0.15 g (1.25 mmol) of 4-dimethylaminopyridine and 0.11 g in the resulting solution. (0.75 mmol) t-butyldimethylsilyl chloride is added. The mixture is then stirred at rt for 4 h and then methylene chloride is removed by evaporation under reduced pressure. The residue is diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium chloride. The mixture is then concentrated by evaporation under reduced pressure. The residue is purified by silica gel flash chromatography (eluent: 85:15 volume ratio mixture of cyclohexane and ethyl acetate) to afford 0.53 g (97% yield) of the title compound as a colorless oil.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.08 (6H, s);

0.82 to 0.94 (18H, m);

1.16-1.67 (62H, m);

2.28 (2H, t, J = 7.6 Hz);

2.35 (2H, doublet, J = 5.9 Hz);

2.42 to 2.63 (2H, m);

3.30 (1 H, broad singlet);

3.60 to 4.10 (7H, m);

4.18 to 4.30 (1H, m);

4.49, 4.54 (2H, AB quartet, J = 12.0 Hz);

4.77 (1H, doublet, J = 3.9 Hz);

5.04-5.22 (4H, m);

5.65 to 5.82 (1H, m);

6.27 (1H, doublet, J = 9.3 Hz);

7.22 to 7.35 (5H, m).

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3550-3150, 1730, 1650.

[15 (b) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-4-0-diphenylphosphoryl-6-0-t-butyldimethylsilyl-3- 0-[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside]

100 mg (0.09 mmol) of the compound obtained as described in Example 15 (a) and 34 mg (0.27 mmol) of 4-dimethylaminopyridine were dissolved in 2 ml of anhydrous methylene chloride, and the resulting solution was dissolved in anhydrous methylene chloride. 1 ml of a solution of 70 mg (0.27 mmol) of diphenylchlorophosphate is slowly added. The mixture was then stirred at room temperature for 1 hour, and the methylene chloride was then removed by evaporation under reduced pressure; The residue is diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then the mixture is dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue is purified by silica gel flash chromatography (eluent: 9: 1 volume ratio mixture of cyclohexane and ethyl acetate) to give 110 mg (94% yield) of the title compound as a colorless oil.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.013 (6H, s);

0.82-0.95 (18H, m);

1.10 to 2.66 (62.H, m);

2.14 (2H, t, J = 6.3-8.3 Hz);

2.35 (2H, doublet, J = 5.9 Hz);

2.44 (2H, doublet, J = 6.8 Hz);

3.65 to 4.12 (7H, m);

4.23 to 4.35 (1H, m);

4.53, 4.57 (2H, AB quarter, J = 11.5 Hz);

4.67 (1H, doublet of doublets, J = 9.3 18.6 Hz);

4.80 (1H, doublet, J = 3.4 Hz);

5.05 to 5.25 (3H, m);

5.43 (1H, doublet of doublets, J = 9.3 10.7 Hz);

5.67-5.85 (1H, m);

6.23 (1H, doublet, J = 9.3 Hz);

7.12-7.40 (15H, m).

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3350, 1740, 1675, 1590.

[15 (c) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2-deoxy-4-0-diphenylphosphoryl-3-0-[(R) -3-tetra Decanoyloxytetradecanoyl] -α-D-glucopyranoside]

100 mg of the compound obtained as described in Example 15 (b) is dissolved in 2 ml of tetrahydropfuran, 0.4 ml of 3N hydrochloric acid is added to the resulting solution, and the mixture is stirred at room temperature for 3 hours. Tetrahydrofuran is then removed by evaporation under reduced pressure. The residue is dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 7: 3 volume mixture of cyclohexane and ethyl acetate) to give 90 mg of the sieve compound (yield 95%) as a solid.

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3470, 3330, 1735, 1720, 1650, 1590.

Elemental analysis: C ₇₀ H ₁₁₀ O ₁₃ NP:

Calculated: C, 69.80%; H, 9.20%; N, 1.16%; P, 2.57%

Found: C, 70.07%; H, 9.20%; N, 1.21%; P, 2.30%

[15 (d) Allyl 2-[(R) -3'-benzyloxytetradecanoylamino] -2,6-dideoxy-4-0-diphenylphosphoryl-6-fluoro-3-0- [ (R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside]

0.7 ml of a solution of 70 mg (0.06 mmol) of the compound according to Example 15 (c) dissolved in anhydrous methylene chloride was ice-cooled in 0.8 ml of a solution of 40 mg (0.23 mmol) of diethylaminosulfur trifluoride dissolved in anhydrous methylene chloride. Is added and the mixture is stirred for 3 hours under ice-cooling. After stirring is complete, the mixture is stirred for an additional 30 minutes at room temperature. The reaction mixture was then poured into 40 ml of ice water and the methylene chloride layer was collected. The aqueous layer is extracted with methylene chloride, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the mixture is concentrated by evaporation under reduced pressure. The residue is purified by silica gel flash chromatography (eluent; 8: 2 volume ratio mixture of cyclohexane and ethyl acetate) to give 60 mg (87% yield) of the title compound as a solid.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

0.88 (9H, t, J = 7.3-7.8 Hz);

1.10 to 1.65 (62H, m);

2.15 (2H, t, J = 7.6 Hz);

2.34 (2H, doublet, J = 5.9 Hz);

2.42 (2H, doublet, J = 6.3 Hz);

3.07 to 4.07 (4H, m);

4.27 to 4.55 (3H, m);

4.49, 4.55 (2H, AB quarter, J = 11.5 Hz);

4.69 (1H, doublet of doublets, J = 9.3 19.OHz);

4.84 (1H, doublet, J = 3.9 Hz);

5.03 to 5.24 (3H, m);

5.43 (1H, doublet of doublets, J = 9.3 10.7 Hz);

5.63 to 5.80 (1H, m);

6.25 (1H, doublet, J = 8.8 Hz);

7.12-7.38 (15 H, m).

1R Absorption Spectrum (Nujol) ν _max cm ^-1 :

3330, 1740, 1730, 1660, 1600.

[15 (e) 2-[(R) -3'-benzyloxytetradecanoylamino] -2,6-dideoxy-4-0-diphenylphosphoryl-6-fluoro-3-0-[( R) -3-tetradecanoyloxydecanoyloxytetradecanoyl] -D-glucopyranose]

16 mg (0.019 mmol) of bis (methyldiphenylphosphine) cyclooctadiene iridium (I) hexafluorophosphate in Example 15 (d) based on anhydrous tetrahydrofuran 460 mg (0.37 mmol) of compound based To the ml, the iridium complex is activated with hydrogen and then the mixture is stirred for 3 hours under a stream of nitrogen. After completion of stirring, 0.19 g (0.74 mmol) iodine, 1 ml of water and 0.12 g (1.48 mmol) pyridine were added to the reaction mixture, the resulting mixture was stirred at room temperature for 30 minutes, and the mixture was evaporated under reduced pressure. Concentrate. The residue is dissolved in 80 ml of ethyl acetate and washed sequentially with 5% w / v aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then the mixture is dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was purified by silica gel flash chromatography (75:25 volume ratio mixture of eluent: cyclohexene | ethyl acetate) to give 370 mg (85% yield) of the title compound as a pale yellow solid. To obtain.

NMR Spectrum (CDCI ₃ , 270MHz) δppm:

1.07 to 1.72 (62H, m);

2.15 (2H, t, J = 7.6 Hz);

2.25 to 2.45 (5H, m);

3.82 to 4.25 (3H, m);

4.39, 4.62 (2H, AB quarter, J = 11.2 Hz):

4.42 (2H, doublet of doublets, J = 2.4 46.9 Hz);

4.67 (1H, doublet of doublets, J = 9.3 19.1 Hz);

5.04 (1H, doublet, J = 3.4 Hz);

5.04-5.15 (1H, m);

5.41 (1H, doublet of doublets, J = 9.3 10.7 Hz);

6.22 (1H, doublet, J = 8.8 Hz);

7.12-7.40 (15H, m).

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3400, 1740, 1720, 1665, 1590.

[15 (f) 2,6-dideoxy-4-0-diphenylphosphoryl-6-fluoro-2-[(R) -3'-hydroxytetradecanoylamino] -3-0-[( R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranose]

370 mg of the compound obtained as described in Example 15 (e) is dissolved in 4 ml of tetrahydrofuran and 0.37 g of 10% w / w palladium-on-carbon is added to the resulting solution. 24 ml of methanol and 2 drops of formic acid are then added, followed by stirring for 3 hours under a stream of hydrogen while heating to 35 ° C. The reaction mixture is then diluted with tetrahydrofuran and the palladium-on-carbon is filtered off using a celite filter aid to remove from the reaction mixture. The filtrate is then evaporated to dryness under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 65:35 volume ratio mixture of cyclohexane and ethyl acetate) to give 220 mg (yield 65%) of the title compound as a solid.

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3450-3200, 1740, 1642, 1595.

Elemental Analysis: C ₆₀ H ₉₉ NO ₁₂ FP:

Calculated: C, 66.95%; H, 9. 27%; N, 1.30%; F, 1.76%; P, 2.88%

Found: C, 67.00%; H, 9.0 1%; N, 1.39%; F, 1.73%; P, 2.88%

[15 (g) 2,6-dideoxy-6-fluoro-2-[(R) -3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxy Tetradecanoyl] -D-glucopyranosyl-4-phosphate]

0.135 g of the compound obtained as described in Example 15 (f) is dissolved in 8 ml of anhydrous tetrahydrofuran, 27 mg of platinum oxide is added to the resulting solution, and the mixture is stirred at room temperature under hydrogen stream for 1 hour. The reaction mixture is then diluted with tetrahydrofuran to dissolve the insolubles and the platinum is filtered off. The filtrate was evaporated to dryness under reduced pressure to give 107 mg (92% yield) of the title compound as a powder.

NMR spectrum (deuterium pyridine, 270MHz) δ ppm:

0.80 to 0.98 (9H, m);

1.12-1.95 (62H, m);

2.47 (2H, t, J = 7.3 Hz);

2.77 to 2.92 (2H, m);

2.97 to 3.36 (2H, m);

3.62 to 3.70 (1H, m);

4.45 to 5.80 (7H, m);

6.24 (1H, doublet of doublets, J = 8.8 10.7 Hz);

8.88 (1H, doublet, J = 9.8 Hz).

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3600-3200, 1730, 1640, 1380.

Elemental analysis: C ₄₈ H ₉₁ NO ₁₂ FP:

Calculated: C, 62.38%; H, 9.92%; N, 1.52%; F, 2.06%; P, 3.35%.

Found: C, 61.56%; H, 9.75%; N, 1.50%; F, 1.91%; P, 3.09%.

Example 16

[2,6-dideoxy-6-fluoro-2-[(S) -3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranosyl-4-phosphate

16 (a) allyl 2-[(S) -3'benzyloxytetradecanoylamino] -2-deoxy-6-0-t-butyldimethylsilyl-3-0-[(R) -3-tetradeca Noyloxytetradecanoyl] -α-D-glucopyranoside]

0.5 g (0.51 mmol) alkyl 2-[(S) -3'-benzyloxytetradecanoylamino] -2-deoxy-3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -aD-glucopyranoside [prepared as described in Example 13 (d)] was dissolved in 10 ml of anhydrous methylene chloride, and 0.16 g (1.29 mmol) of 4-dimethylaminopyridine (DMAP) and 0.12 were dissolved in the resulting solution. After g (0.78 mmol) of t-butyldimethylsilyl chloride is added, the mixture is stirred at room temperature for 4 hours. After stirring is complete, the methylene chloride is removed by evaporation under reduced pressure, and the residue is diluted with ethyl acetate. The mixture is then washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution. It is then dried over anhydrous magnesium sulfate and the solvent is removed by evaporation under reduced pressure. The residue is purified by silica gel flash chromatography (eluent: 9: 1 volume ratio mixture of cyclohexane and ethyl acetate) to give 0.56 g (yield 99%) of the title compound as a colorless oil.

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3600-3150, 1730, 1650.

Elemental analysis: C ₆₄ H ₁₁₅ NO ₁₀ Si

Calc .: C, 70.74%; H, 10.67%; N, 1.29%

Found: C, 70.93%; H, 10.40%; N, 1.24%

[16 (b) allyl2-[(S) -3'benzyloxytetradecanoylamino] -2-deoxy-4-0-diphenylphosphoryl-6-0-t-butyldimethylsilyl-3-0 -[(R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside]

0.56 g (0.51 mmol) of the compound obtained as described in Example 16 (a) and 0.19 g (1.54 mmol) of 4-dimethylaminopyridine were dissolved in 12 ml of anhydrous methylene chloride, and this solution was dissolved in anhydrous methylene chloride. After slowly adding 4 ml of a solution of phenyl chlorophosphate, the mixture is stirred at room temperature for 4 hours. After stirring is complete, the methylene chloride is removed by evaporation under reduced pressure, and the residue is diluted with ethyl acetate. The mixture is then washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was purified by silica gel flash chromatography (eluent: 9: 1 volume ratio mixture of cyclohexane and ethyl acetate) to give 0.63 g (93% yield) of the title compound as a colorless oil. To obtain.

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3350, 1735, 1670, 1590.

Elemental Analysis: C ₇₆ H ₁₂₄ NO ₁₃ PSi

Calculated: C, 69.21%; H, 9.48%; N, 1.06%; P, 2.35%

Found: C, 69.37%; H, 9. 22%; N, 1.05%; P, 2.29%

[16 (c) allyl2-[(S) -3'benzyloxytetradecanoylamino] -2-deoxy-4-0-diphenylphosphoryl-3-0-[(R) -3-tetradeca Noyloxytetradecanoyl] -α-D-glucopyranoside]

0.56 g (0.42 mmol) of the compound obtained as described in Example 16 (b) is dissolved in 10 ml of tetrahydrofuran, 2 ml of 3N hydrochloric acid is added to the resulting solution, and the mixture is stirred at room temperature for 4 hours. . After stirring is complete, tetrahydrofuran is removed by evaporation under reduced pressure and the residue is dissolved in ethyl acetate. The mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure, and the residue is purified by silica gel flash chromatography (eluent: 7: 3 volume mixture of cyclohexane and ethyl acetate) to give 0.45 g (89% yield) of the title compound as a powder.

IR absorption spectrum (Nujol) υ _max cm ^-1 :

3450, 3320, 1730, 1650, 1585.

Elemental analysis: C ₇₀ H ₁₁₀ NO ₁₃ P

Calculated: C, 69.80%; H, 9.20%; N, 1.16%; P, 2.57%

Found: C, 70.07%; H, 9. 13%; N, 1.16%; P, 2.53%

[16 (d) allyl2-[(S) -3'benzyloxytetradecanoylamino] -2,6-dideoxy-4-0-diphenylphosphoryl-6-fluoro-3-0-[( R) -3-tetradecanoyloxytetradecanoyl] -α-D-glucopyranoside]

A solution of 0.21 g (1.3 mmol) of diethylaminosulfurtrifluorolide in which 4 ml of a solution of 0.39 g (0.32 mmol) of a compound dissolved in anhydrous methylene chloride was dissolved in anhydrous methylene chloride under ice cooling. To 4 ml, the mixture is stirred for 3 hours under ice cooling, and then the mixture is stirred for an additional 30 minutes at room temperature. After stirring was complete, the reaction mixture was poured into 40 ml of ice water and the methylene chloride layer was collected.

The aqueous layer is extracted with methylene chloride, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the mixture is concentrated by evaporation under reduced pressure. The residue is purified by silica gel flash chromatography (eluent: 8: 2 volume ratio mixture of cyclohexane and ethyl acetate) to give 0.36 g (91% yield) of the title compound as a powder.

IR absorption spectrum (liquid film) υ _max cm ^-1 :

3350, 1740, 1675, 1590.

Elemental analysis: C ₇₀ H ₁₀₉ O ₁₂ NPF

Calculated: C, 69.68%; H, 9.11%; N, 1.16%; P, 1.57%; F, 2.57%

Found: C, 69.88%; H, 9.09%; N, 1.19%; P, 1.60%; F, 2.58%

[16 (e) 2-[(S) -3'-benzyloxytetradecanoylamino] -2,6-dideoxy-4-0-diphenylphosphoryl-6-flfuuro-3-0-[( R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranose]

A solution of 100 mg (0.08 mmol) of the compound of Example 16 (d), wherein 3.6 mg (0.004 mmol) of bis (methyldiphenylphosphine) cyclooctadieneiridium (1) hexaplefuorophosphate was dissolved in anhydrous tetrahydrofuran. To 2 ml, the iridium complex is activated with hydrogen, and the mixture is stirred at room temperature under nitrogen stream for 3 hours. 40 mg (0.17 mmol) of iodine, 0.2 ml of water and 30 mg (0.33) of pyridine are then added to the reaction mixture, and the resulting mixture is stirred at room temperature for 30 minutes, after which the mixture is concentrated by evaporation under reduced pressure. The residue is dissolved in 20 ml of ethyl acetate, and the resulting solution is washed sequentially with 5% aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent is then removed by evaporation under reduced pressure and the resulting residue is terminated by silica gel flash chromatography (eluent: 3: 1 volume ratio mixture of cyclohexane and ethyl acetate) to yield 90 mg (90% yield) of the title compound as a pale yellow powder. do.

IR absorption spectrum (Nujol) ν _max cm ^-1 :

3400, 1735, 1720, 1665, 1590.

Elemental Analysis: C6 ₇ H ₁₀₅ NO ₁₂ PF

Calculated: C, 68, 98%; H, 9.07%; N, 1.20%; F, 1.63%; P, 2.66%

Found: C, 69.04%; H, 9.16%; N, 1.12%; F, 1.60%; P, 2.53%,

[16 (f) 2,6-dideoxy-4-0-diphenylphosphoryl-6-fluoro-2-[(S) -3'-hydroxytetradecanoylamino] -3-0-[( R) -3-tetradecanoyloxytetradecanoyl] -D-glucopyranose]

0.20 g DFM 2 ml of the compound obtained as described in Example 16 (e) was dissolved in tetrahydrofuran, and 0.2 g of 10% w / w palladium on carbon was added to the resulting solution. 12 ml of methanol and 1 drop of formic acid are then added to the mixture, and the mixture is stirred for 5 hours under a stream of hydrogen while heating to 35 ° C. After stirring is complete, the reaction mixture is diluted with tetrahydrofuran and the palladium on carbon is filtered off using a celite filter aid. The filtrate is evaporated to dryness and dried, and the residue is purified by silica gel flash chromatography (eluent: cyclohexane and ethyl acetate 7: 3 vol. Mixture) to give 0.15 g (yield 81%) dfm of the title compound.

IR absorption spectrum (Nujol) ν _max cm ⁻¹ ;

3600-3100, 1730, 1660, 1590.

Elemental Analysis: C ₆₀ H ₉₉ NO ₁₂ PF

Calculated: C, 66.95%; H, 9.27%: N, 1.30%; F, 1.76%; P, 2.88%

Found: C, 67.03%; h, 9.22%; n, 1.38%; F, 1.71%; P, 2.70%

[16 (g) 2,6-dideoxy-6-fluoro-2-[(S) -3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxy Tetradecanoyl] -D-glucopyranosyl-4-phosphate]

72 mg of the compound obtained as described in Example 16 (f) is dissolved in 4 ml of anhydrous tetrahydrofuran, 15 mg of platinum oxide is added to the resulting solution, and the mixture is stirred at room temperature under hydrogen stream for 30 minutes. The reaction mixture is then diluted with tetrahydrofuran and the mixture is heated to 45 ° C. to dissolve the agar analog. The platinum is then filtered off and the filtrate is evaporated to dryness under reduced pressure to yield 62 mg of the title compound quantitatively.

NMR spectrum (Duteropyridine, 270MHz) δ ppm:

0.80 to 0.97 (9H, m);

1.10-1.90 (62H, m);

2.45 (2H, t, J = 7.3 Hz);

2.84 (2H, doublet, J = 5.9 Hz);

3.11 (1H, doublet of doublets, J = 6.4 16.3 Hz);

3.27 (1H, doublet of doublets, J = 6.4 16.3 Hz);

3.62 to 3.70 (1 H, m);

4.38-5.50 (7H, m);

6.25 (1H, doublet of doublets, J = 9.3 10.9 Hz).

IR absorption spectrum (Nujol) ν _max cm ^-1 :

3600-3200, 1730, 1700, 1650.

Example 17

[2-deoxy-2-[(3'R) -3'-hydroxytetradecanoylamino] -3-0-[(3R) -3- (2,2-difluorotetradecanoyloxy) Tetradecanoyl] -D-glucopyranosyl-4-phosphate

17 (a) allyl2-deoxy-2-[(3'R) -3'-benzyloxytetradecanoylamino] -3-0-[(3R) -3- (2,2-difluorotetra Decanoyloxy) tetradecanoyl] -4,6-0-isopropylidene-β-D-glucopyranoside]

Allyl2-deoxy-2-[(3'R) -3'-benzyloxytetradecanoylamino] -4,6-0-isopropylidene-β-D-glucopyranoside [Example 1 (e Prepared as described above) 4.1 g (7.12 mmol) is dissolved in 100 ml of diethyl ether. In the resulting solution, 4.54 g (9.26 mmol) of (3R) -3- (2 ', 2'-difluorotetradecanoyloxy) tetradecanoic acid, 1.9 g (9.26 mmol) of N, N'-dish Clohexylcarbodiimide and 0.087 g (0.712 mmol) of 4-dimethylaminopyridine are then added sequentially. The resulting mixture is then stirred at room temperature for 1 hour, after which the solvent is removed by evaporation under reduced pressure and ethyl acetate is added to the mixture. The resulting precipitate is filtered off and the ethyl acetate layer is washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Ethyl acetate is then removed by evaporation under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: 5: 1 volume ratio mixture of ethyl acetate) to give 5.5 g (74% yield) of the title compound. .

NMR spectrum (CDCI ₃ , 270 MHz) δ ppm:

0.88 (9H, t, J = 6.6 Hz);

1.16 to 1.72 {66H, m [including 1.36 (3H, s), 1.45 (3H, s)]};

1.93 to 2.08 (2H, m);

2.32 to 2.45 (2H, m);

2.55 (1H, doublet of doublets, J = 5.9 16.1 Hz);

2.69 (1H, doublet of doublets = 7.3 16.1 Hz);

3.18 to 3.28 (1H, m);

3.64 to 3.82 (4H, m);

3.85 to 3.99 (3H, m);

4.18 to 4.17 (1H, m);

4.34 (1H, doublet, J = 8.1 Hz);

4.47 (1H, doublet, J = 11.7 Hz);

4.59 (1H, doublet, J = 11.7 Hz);

5.05 to 5.36 (3H, m);

5.71 to 5.83 (1H, m);

6.33 (1H, doublet, J = 9.5 Hz);

7.23 to 7.41 (5H, m).

1R Absorption Spectrum (CDCl ₃ ) υ _max cm ^-1 :

1765, 1675.

Mass spectrum (m / z):

1048 (M + + 1), 1032, 1006, 941, 822, 806, 780, 742, 715, 677, 657, 634, 596, 558,

516, 502, 472, 388, 361, 334, 318, 276, 250, 209, 151, 101, 91, 55, 41.

Elemental analysis: C ₆₁ H ₁₀₃ F ₂ NO ₁₀ (Molecular Weight, 1048.5)

Calculated: C, 69.88%; H, 9.90%; N, 1.34%; F, 3.62%.

Found: C, 70.04%; H, 9.74%; N, 1.45%; F, 3.55%

[17 (b) allyl2-deoxy-2-[(3'R) -3'-benzyloxytetradecanoylamino) -3-0-[(3R) -3- (2,2-difluoro Tetradecanoyloxy) tetradecanoyl-β-D-glucopyranoside]

4.8 g (4.58 mmol) of the compound obtained as described in Example 17 (a) above are suspended in 200 ml of an aqueous 90% acetic acid solution. The resulting suspension is then stirred at 50 ° C. for 2 hours. After completion of stirring, acetic acid was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: mixture of cyclohexane and ethyl acetate 1: 1 volume ratio) to give 3.1 g (yield 67%) of the title compound.

NMR Spectrum (CDCl ₃ , 270 MHz) ppm:

0.82-0.95 (9H, m);

1.15 to 1.77 (60H, m);

1.91 to 2.12 (3H, m);

2.31 to 2.48 (2H, m);

2.55 (1H, doublet of doublets, J = 4.4 16.1 Hz);

2.68 (1H, doublet of doublets, J = 8.3 16.1 Hz);

2.73 (1H, doublet, J = 4.4 Hz);

3.29 to 3.38 (1H, m);

3.66 (1H, doublet of doublets, J = 4.4, 9.3 9.3 Hz);

3.70 to 4.00 (5H, m);

4.18 to 4.28 (1H, m);

4.35 (1H, doublet, J = 8.3 Hz);

4.47 (1H, doublet, J = 11.7 Hz);

4.60 (1H, doublet, J = 11.7 Hz);

4.97-5.33 (4H, m);

5.71 to 5.88 (1H, m);

6.34 (1H, doublet, J = 8.8 Hz);

7.28 to 7.41 (5H, m).

1R Absorption Spec + Trum (CHCl ₃ ) υ _max cm ^-1 :

1760, 1673.

Elemental analysis: C ₅₈ H ₉₉ F ₂ NO ₁₀ (molecular weight, 1008.4)

Calculated: C, 69.08%; H, 9.90%; N, 1.39%; F, 3.77%.

Found: C, 69.17%; H, 9.85%; N, 1.38%; F, 3.62%.

[17 (c) allyl2-deoxy-2-[(3'R) -3'-benzyloxytetradecanoylamino] -3-0-[(3R) -3- (2,2-difluoro Tetradecanoyloxy) tetradecanoyl] -6-0-benzyloxymethyl-β-D-glucopyranoside]

2.5 g (2.48 mmol) of the compound obtained as described in Example 17 (b) above are dissolved in 50 ml of methylene chloride. 500 mg (3.22 mmol) of benzylchloromethyl ether is added to the solution, followed by 374 mg (3.22 mmol) of tetramethylurea. The mixture is stirred overnight at room temperature. The solvent is removed by evaporation under reduced pressure and the resulting residue is dissolved in ethyl acetate. The ethyl acetate layer was washed sequentially with saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution; Dry over anhydrous magnesium sulfate. The ethyl acetate was then removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 3: 1 volume mixture of cyclohexane and ethyl acetate) to give 1.65 g (59% yield) of the title compound and 0.95 g of starting material. To obtain.

NMR spectrum (CDCl ₃ , 270 MHz) δ ppm:

0.84 to 0.94 (9H, m);

1.16 to 1.75 (60H, m);

1.91 to 2.11 (2H, m);

2.32 to 2.46 (2H, m);

2.51 to 2.63 (3H, m);

3.35 to 3.46 (1H, m);

3.60-3.99 (6H, m); 4.18-4.30 (1H, m);

4.34 (1H, doublet, J = 8.3 Hz);

4.44 to 4.66 (4H, m);

4.79 (2H, s);

4.98-5.38 (4H, m);

5.69-5.87 (1H, m);

6.89 (1H, doublet, J = 8.8 Hz);

7.23-7.43 (10 H, m).

1R Absorption Spectrum (CHCI ₃ ) ν _max cm- ¹ :

1760, 1675.

Elemental analysis: C ₆₆ H ₁₀₇ F ₂ NO ₁₁ (molecular weight, 1128.6)

Calculated: C, 70.24%; H, 9.56%; N, 1.24%; F, 3.37%.

Found: C, 70.03%; H, 9.49%; N, 1.29%; F, 3.38%

[17 (d) allyl2-deoxy-2-[(3'R) -3'-benzeloxytetradecanoylamino] -3-0-[(3R) -3- (2,2-dioluoro Tetracarnoyloxy) tetradecanoyl] -4-0-diphenylphosphoryl-6-0-benzeloxymethyl-β-D-glucopyranoside]

610 mg (0.54 mmol) of the compound obtained as described in Example 17 (c) are dissolved in 20 ml of methylene chloride. To this solution are then added 100 mg (0.59 mmol) diphenyl chlorophosphate, 33 mg (0.27 mmol) 4-dimethylaminopyridine in that order. The mixture is then stirred for 3 hours at room temperature. While checking the progress of the reaction, a total of 640 mg (2.38 mmol) of diphenyl chlorophosphate and 198 mg (1.62 mmol) of 4-dimethylaminopyridine were added to the reaction mixture in four portions. The reaction mixture was then washed sequentially with IN aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The methylene chloride is then removed by evaporation under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: p: 1 mixture of p cyclohexane and ethyl acetate) to give 530 mg (72% yield) of the title compound.

NMR spectrum (CDCl ₃ , 270 MHz) δ ppm:

0.83 to 0.94 (9H, m);

1.08-1.75 (60H, m);

1.87 to 2.09 (2H, m);

2.29 to 2.55 (4H, m);

3.56 to 3.87 (4H, m);

3.94 (1H, doublet of doublets, J = 6.4 12.7 Hz);

4.24 (1H, doublet of doublets, J = 5.4 12.7 Hz);

4.43-4.81 (8H, m);

5.03 to 5.29 (4H, m);

5.50-(1H, doublet of doublets, J = 9.3 9.8 Hz);

5.69-5.87 (1H, m);

6.34 (1H, doublet, J = 8.8 Hz);

7.18-7.39 (20 H, m).

1 R Absorption Spectrum (CHCl ₃ ) υ _max cm ^-1 :

1760, 1678, 1597, 1496, 960.

Elemental analysis: C ₇₈ H ₁₁₆ NO ₁₄ F ₂ P (Molecular Weight, 1360.7)

Calculated: C, 68.85%; H, 8.59%; N, 1.03%; F, 2.79%; P, 2.28%.

Found: C, 68.15%; H, 8.32%; N, 0.92%; F, 2.60%; P, 2.72%.

[17 (e) 2-deoxy-2-[(3'R) -3'-benzyloxytetradetracanoylamino] -3-0-[((3R) -3- (2,2-di Fluorotetradecanoyloxy) tetradecanoyl] -4-diphenylphosphyl-D-glucopyranose]

530 mg (0.39 mmol) of the compound obtained as described in Example 17 (d) are dissolved in 5 ml of tetrahydrofuran. To this solution is then added 33 mg (10 mmol%) of 1,5-cyclooctadienebis (methyldiphenylphosphine) iridium hexafluorophosphate and the atmosphere in the reactor is first replaced by nitrogen and then by hydrogen. . After the catalyst is activated and the color of the catalyst is reduced from red to colorless, the atmosphere in the vessel is replaced with nitrogen again. The reaction mixture is stirred at room temperature for 3 hours and then 2 ml of concentrated hydrochloric acid is added. The mixture is stirred at rt overnight, then the solvent is removed by evaporation under reduced pressure. Ethyl acetate is added to the residue, and the mixture is washed sequentially with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 1: 2 volume ratio mixture of cycloacetic acid and ethyl acetate) to give 258 mg (yield 55%) of the title compound.

NMR spectrum (CDCl ₃ , 270 MHz) δ PPM:

0.82 to 0.98 (9H, m);

1.07-1.77 (60H, m);

1.84-2.09 (2H, m);

2.21-2.50 (5H, m);

3.26 (1H, t, J = 7.3 Hz);

3.52 to 3.62 (2H, m);

3.81 to 3.91 (2H, m);

4.19-4.30 (1H, m);

4.39 (1H, doublet, J = 11.2 Hz);

4.61 (1H, doublet, J = 11.2 Hz);

4.67-4.78 (1H, m);

4.98 (1H, t, J = 3.9 Hz);

5.19-5.29 (1H, m);

5.41 (1H, doublet of doublets, J = 9.3 10.7 Hz);

6,23 (1H, doublet, J = 9.3 Hz);

7.13-7.38 (15 H, m).

1R Absorption Spectrum (CHCl3) ν _max cm ^-1:

1750,1660.

Elemental analysis: C ₆₇ H ₁₀₄ NO ₁₃ FP (Molecular Weight 1200.5)

Calculated: C, 67.03%; H, 8.73%; N, 1.17%; F, 3.16%: P, 2.58%.

Found: C, 66.91%; H, 8.61%; N, 1.13%; F, 3.04%; P, 2.46%.

[1 (f) 2-deoxy-2- (3'R) -3'-hydroxytetradecanoylamino] -3-0-[(3R) -3- (2,2-difluorotetradera Canoyloxy) tetradecanoyloxy) tetradecanoyl] -4-diphenylphosphoryl-D-glucopyranose]

250 mg (0.21 mmol) of the compound obtained as described in Example 17 (e) are dissolved in 10 ml of methanol. 100 mg 10% w / w palladium on carbon is then added to the resulting solution. The reaction mixture is then subjected to catalytic reduction for 3 hours at room temperature under a hydrogen atmosphere. After 3 hours, methanol is removed by evaporation under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: ethyl acetate) to give 122 mg (53% yield) of the title compound.

IR absorption spectrum (CHCL ₃ ) ν _max cm ^-1 :

3425, 2925, 2855, 1760, 1660, 1590, 1490, 1180, 1157, 965.

NMR spectrum (CDCL ₃ , 270 MHZ) δ ppm:

0.82 to 0.95 (9H, m);

1.07-1.63 (60H, m);

1.80-2.11 (2H, m);

2.17 to 2.53 (4H, m);

3.20-3.39 (2H, m);

3.55 to 3.66 (2H, m);

3.70 (1H, doublet, J = 3.4 Hz);

3.38-4.04 (2H, m);

4.21-4.33 (1 H, m);

4.76 (1H, doublet of doublets, J = 9.3 9.8 Hz);

5.18 to 5.28 (1 H, m);

5.31 (1H, doublet of doublets, J = 3.4 3.9 Hz);

5.48 (1H, doublet of doublets, J = 9.8 10.3 Hz);

6.25 (1H, doublet, J = 8.8 Hz);

7.13 to 7.42 (10 H, m).

[17 (g) 2-deoxy-2-[(3'R) -3'-hydroxytetradecanoylamino] -3-0-[(3''R) -3- (2,2-di Fluorotetradecanoyloxy) tetradecanoyl] -D-glutopyranosyl-4-phosphate]

85 mg (0.08 mmol) of the compound obtained as described in Example 17 (f) are dissolved in 10 ml of tetrahydrofuran. 15 mg of platinum oxide is then added to the solution, and the reaction mixture is subjected to catalytic reduction for 5 hours at room temperature under a hydrogen atmosphere. After 5 hours, tetrahydrofuran was removed by evaporation under reduced pressure to give 72 mg (98% yield) of the title compound.

IR Absorption Spectrum (KBr) ν _max cm- ¹ :

2956, 2923, 2853, 1761, 1644, 1549, 1467, 1188, 1128, 1058, 972.

Example 18

[Triethylamine Salt of Phosphorylated Compound]

To water-soluble the triethylamine salt of the phosphorylated compound obtained in one of the above examples was treated as follows. 30 mg of the phosphorylated compound is suspended in 8 ml of 0.1 N hydrochloric acid, 30 ml of a 1: 2 volume ratio mixture of chloroform and methanol is added thereto, and the suspension is dissolved using ultrasonic waves. Then 10 ml of chloroform and 10 ml of 0.1 N hydrochloric acid are added to the solution, and the mixture is separated into two layers. The chloroform layer is collected and removed by evaporation under claws. The residue is dissolved in 0.1% aqueous triethylamine solution to obtain an aqueous solution which can be used as a sample for activity measurement.

The novel compounds of formula (1) according to the invention can more easily provide a method for treating, preventing, diagnosing and maintaining patients suffering from or resulting from diseases or disorders caused by a tumor or lack of an immune system.

Claims (32)

The following compounds of the general formula (1) and salts thereof, and esters thereof when the compound of the general formula (1) contains a carboxyl group

[Wherein R ¹ is a hydroxy group, a protected hydroxy group as defined below, a fluorine atom or a formula

Represents group; R ² and R ³ are the same or different and each represents an aliphatic carboxyl acyl group having 6 to 20 carbon atoms which is unsubstituted or substituted with one or more substituents selected from the group consisting of substituents (a) as defined below; R ⁴ is a hydroxy group, a protected hydroxy group as defined below, or a formula

Wherein at least one of R ¹ and R ⁴ is

Represents a group of; R ⁵ represents hydroxy, a protected hydroxy group as defined below, or a fluorine atom; Except where at least one of R ¹ and R ⁵ represents a fluorine atom, At least one of R ² and R ³ is (i) an aliphatic carboxyl acyl substituted with (i) one or more hilogen substituents and (ii) one or more halogen atoms, a hydroxy group or an aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms. Represents an oxy group, or At least one of R ² and R ^{3 represents} an aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms substituted with at least one halogen-substituted aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms; The protected hydroxy group is an aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms; Halogenated carboxyl acyloxy group having 6 to 20 carbon atoms; The alkoxy moiety has 1 to 6 carbon atoms and the acyl moiety has 2 to 6 alkoxy-substituted carboxyl acyloxy groups; The aromatic moiety is a carbocyclic aromatic carboxyl acyloxy group having 6 to 14 carbon atoms and unsubstituted or substituted with one or more substituents selected from the group consisting of substituents (b) as defined below; A group of the formula Het-0-, wherein Het represents a heterocyclic group which is a 5 or 6 membered ring which is a hetero atom selected from the group consisting of 1 to 3 atoms of nitrogen, oxygen and sulfur atoms, wherein the heterocyclic group is unsubstituted or Is substituted with one of the substituents (c) defined in the above); Groups of the formula R ^a R ^b R ^c Si-0- wherein R ^a , R ^b and R ^c are the same or different and represent an alkyl group having 1 to 6 carbon atoms or a carbocyclic aryl group having 6 to 10 carbon atoms, respectively, The group is unsubstituted or substituted with one or more of the substituents (b) defined below); An alkoxy alkoxy group having two alkoxy moieties which are the same or different and each having 1 to 6 carbon atoms; An alkyl group having 1 to 6 carbon atoms is substituted with 1 to 3 aryl groups, the aryl group being unsubstituted or substituted with one or more of the substituents (b) defined below; Alcohol-carbonyloxy group having 1 to 6 carbon atoms in the alkoxy moiety; A substituted alkoxycarbonyloxy group having 1 to 6 carbon atoms in the alkoxy moiety and the substituent being at least one of the substituents (d) defined below; Alkenyloxycarbonyloxy groups having 2 to 6 carbon atoms in the alkenyl moiety; Alkenyloxy groups having 2 to 6 carbon atoms; A carboxy-substituted aliphatic carboxyl acyloxy group having from 6 to 6 carbon atoms in the acyl moiety, wherein the acyl moiety is unsubstituted or has a hydroxy substituent; Acyloxy methoxycarbonyloxy group which is a carboxyl acyl group whose acyl group is C1-C6; An (aryl selenyl) ethoxy group having an aryl moiety having 6 to 14 carbon atoms and unsubstituted or substituted with one or more of the substituents (b) defined below; An alkoxyalkoxy methoxy group having 1 to 6 carbon atoms in each alkoxy moiety; A methoxy group substituted with one, two or three haloalkoxy substituents having 1 to 6 carbon atoms and substituted with one or more halogen atoms; Haloethoxy groups in which the ethyl moiety is substituted with one or more halogen atoms; And an alkyl group having 1 to 6 carbon atoms in which the aralkyl moiety is substituted with 1 to 3 aryl groups, wherein the aryl group is selected from an aralkyloxycarbonyloxy group unsubstituted or substituted with one or more of the substituents (b) defined below do ; Substituent (a); Halogen atom; An aryl group having 6 to 14 carbon atoms which is unsubstituted or substituted with one or more of the substituents (b) defined below; An alkyl group having 1 to 6 carbon atoms is substituted with 1 to 3 aryl groups, the aryl group being unsubstituted or substituted with one or more of the substituents (b) defined below; Hydroxyl group; Aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms; And a halogen-substituted aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms; Substituent (b): Halogen atom; An alkyl group having 1 to 6 carbon atoms; Halogen-substituted alkyl group having 1 to 6 carbon atoms; An alkoxy group having 1 to 6 carbon atoms; Nitro group; An alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy group portion; An aryl group having 6 to 14 carbon atoms and unsubstituted or substituted with one or more of the substituents (b) defined herein in addition to the aryl group; Cyano group; An alkylenedioxy group having 1 to 4 carbon atoms; An alkylenedioxy group having 1 to 4 carbon atoms; A divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms; A group of formula -NR ^d R ^e wherein R ^d and R ^e are the same or different and each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; Haloalkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy moiety; An aralkyloxycarbonyl group in which the aralkyl moiety contains an alkyl group having 1 to 6 carbon atoms substituted with 1 to 3 aryl groups, and the aryl group is unsubstituted or substituted with one or more of the substituents (b) defined below; A group of the formula -CO-NR ^d R ^e wherein R ^d and R ^e are as defined above; And aliphatic acyl groups having 1 to 20 carbon atoms; Substituent (c): halogen atom; An alkyl group having 1 to 6 carbon atoms; Halogen-substituted alkylkeys having 1 to 6 carbon atoms; An alkoxy group having 1 to 6 carbon atoms; Aryl groups, unsubstituted or substituted with one or more of the substituents (b), in addition to an aryl group, an aryl group having 6 to 14 rings: and an oxygen atom: Substituent (b): halogen atom; A group of the formula R ^a R ^b R ^c Si -0-, wherein R ^a , R ^b , and R ^c are as defined above; And alkinoyloxy groups having 1 to 6 carbon atoms in the alkanoyl group. The compound of claim 1, wherein one of R ¹ and R ⁴ is a hydroxy group, a protected hydroxy group as defined in claim 1, or a formula

Group, the other

Represents a group of; One of R ² and R ³ is substituted with 0 or one or more halogen substituents and 0 or 1 hydroxy, an aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms or a halogen-substituted aliphatic carboxyl alkoxy group having 6 to 20 carbon atoms An acyl group having 6 to 20 tin atoms, and the other of R ² and R ³ is (i) substituted with one or more halogen substituents and one hydroxy group or an aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms or (ii) 6 carbon atoms Aliphatic carboxyl groups having 6 to 20 carbon atoms substituted with one or more halogen-substituted aliphatic carboxyl alkoxy groups which are from 20 to 20 and further substituted with 0 or 1 halogen atom, a hydroxy group or an aliphatic carboxyl alkoxy group having 6 to 20 carbon atoms; R ⁵ represents a hydroxy group or a protected hydroxy group as defined in claim 1 The compound of claim 1, wherein one of R ¹ and R ⁵ represents a hydroxy group or a protected hydroxy group as defined in claim ^1, and the other represents a fluorine atom; R ² and R ³ are the same or different and each acyl group represents an aliphatic carboxyacyl group having 6 to 20 carbon atoms which is unsubstituted or substituted with one or more of the substituents (a) as defined in claim 1; R ⁴ is an expression

Compound which shows group of. The compound of claim 2, wherein one of R ¹ and R ⁴ is a formula

Group, the other being a hydroxy group or

Compound which shows group of. The aliphatic acyl group of claim 2, wherein one of R ² and R ³ represents one or more halogen atoms and a 0 or 1 hydroxy group or an aliphatic acyl group substituted with an aliphatic carboxyl alkoxy group having 10 to 16 carbon atoms and the other one. Is an aliphatic carboxyl acyl group having 10 to 16 carbon atoms substituted with at least one halogen atom, a hydroxy group or an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms. The compound of claim 5, wherein R ² represents an aliphatic acyl group having 10 to 16 carbon atoms substituted with one or more halogen atoms and a 0 or 1 position hydroxy group or an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms. The compound according to claim 2, wherein R ⁵ represents a hydrogen atom or an acyl moiety having 1 to 6 carbon atoms, and a carboxyl substituent represents a carboxy-substituted aliphatic carboxyl acyloxy group located at a terminal far from an oxy group of acyloxy. The compound of claim 3, wherein R 1 represents a hydroxy group or a protected hydroxy group as defined in claim 3. 4. The compound of claim 3, wherein one of R ² and R ³ is an aliphatic carboxyacyl group having 12 to 16 carbon atoms or at least one halogen atom, a hydroxy group, an aliphatic carboxyl acyloxy group having 12 to 16 carbon atoms or a halogen having 12 to 16 carbon atoms. A substituted aliphatic carboxyl acyl group having 12 to 16 carbon atoms substituted with a substituted aliphatic carboxyl acyloxy group, provided that only one hydroxy group and one acyloxy group are substituted, and the other of R ² and R ³ is one or more A compound representing a substituted aliphatic carboxylacyl group having 12 to 16 carbon atoms substituted with a halogen atom and a 0 or 1 hydroxy group or an aliphatic carboxyl acyloxy group having 12 to 16 carbon atoms. The compound of claim 3, wherein R ⁵ represents a fluorine atom. The compound of claim 3, wherein R ¹ represents a hydroxy group or a protected hydroxy group as defined in claim 3: one of R ² and R ³ is an aliphatic carboxyl group having from 12 to 16 carbon atoms or at least one halogen atom, hydroxy group or carbon number A substituted aliphatic carboxyl acyl group having 12 to 16 carbon atoms substituted with an aliphatic carboxyl acyloxy group having 12 to 16, provided that only one hydroxy group and one acyloxy group are substituted, and the other of R ² and R ³ is one or more halogen atoms, and 0 or 1 hydroxy group or a carbon number of 12 to 16 aliphatic carboxylic acyloxy group represents a substituted carbon atoms from 12 to 16, a substituted aliphatic carboxylic acyl Kyrgyz: R ⁴ is formula

A group of: and R5 represents a fluorine winza. The compound of claim 3, wherein R ¹ represents a hydroxy group. 4. The substituted aliphatic acyl group of claim 3, wherein one of R ² and R ³ represents one or more halogen atoms and 0 or 1 hydroxy group substituted with an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms. And the other of ² and R ³ represents a substituted aliphatic carboxyl acyl group having 10 to 16 carbon atoms substituted with one or more halogen atoms, a hydroxy group or an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms. The compound of claim 3, wherein R ¹ represents a hydroxy group; One of R ² and R ³ represents a substituted aliphatic acyl group having 10 to 16 carbon atoms substituted with one or more halogen atoms or aliphatic carboxyl acyloxy groups having 10 to 16 carbon atoms, and the other of R ² and R ³ is one or more halogen A substituted carboxyl acyl group having 10 to 16 carbon atoms substituted with an atom, a hydroxy group or an aliphatic carboxyl acyloxy group having 10 to 16 carbon atoms; R ⁴ is an expression

Represents a group of; And R 5 represents a fluorine atom. The compound of claim 1, wherein R ¹ is a hydroxy group, a fluorine atom, or a formula

Represents a group of; R ² and R ³ are the same or different and each represent an aliphatic carboxyl acyl group which is 6 to 20 carbon atoms, unsubstituted or substituted with one or more of the substituents (a ') defined below; R ⁴ is a hydroxy group or

Represents a group of at least one of R ¹ and R ⁴

Represents a group of; R ⁵ represents a hydroxy group or a fluorine atom; When at least one of R ¹ and R ⁵ represents a fluorine atom, at least one of R ² and R ³ is (i) at least one halogen atom and (ii) at least one halogen atom, hydroxy group or 6 to 20 carbon atoms. A substituted aliphatic carboxyl acyl group having 6 to 20 carbon atoms substituted with a phosphorus aliphatic carboxyl acyloxy group, or at least one of R ² and R ³ is at least one halogen-substituted aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms A substituted aliphatic acyl group having 6 to 20 substituted carbon atoms; Substituent (a '): halogen atom; Hydroxyl group; Aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms; And halogen-substituted aliphatic carboxyl acyloxy groups having 6 to 20 carbon atoms. The compound of claim 15, wherein one of R ¹ and R ⁴ is a hydroxy group or

Represents the group of

Represents a group of; One of R ² and R ³ is substituted with 0 or 1 or more halogen atoms and 0 or 1 hydroxy group, an aliphatic carbosyl acyloxy group having 6 to 20 carbon atoms or a halogen- molten aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms A substituted aliphatic carboxyl acyl group having 6 to 20 carbon atoms, or The other of R ² and R ³ is (iv) substituted with one or more halo substituents and one hydroxy substituent and an aliphatic carbosyl acyloxy group having 6 to 20 carbon atoms, or (ii) one or more halogen having 6 to 20 carbon atoms- A substituted aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms substituted with a substituted aliphatic carboxyl acyloxy group and 0 or 1 halogen atom, a hydroxy group or an aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms; R ⁵ represents a hydroxy group The compound of claim 15, wherein R^OneAnd R5 One represents a hydroxy group and the other represents a fluorine atom; R²And R³Represents the same or different aliphatic acyl groups each having 6 to 20 carbon atoms and unsubstituted or substituted with at least one of the substituents (a ') defined below; R⁴Is

Compound which represents group of Substituent (a '): Halogen atom; Hydroxyl group; Aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms; And a halogen-substituted aliphatic carboxyl acyloxy group having 6 to 20 carbon atoms. 18. The compound of any one of claims 1-17, wherein the glucopyran moiety is a D − configuration. 2-deoxy-2-(2'- fluoro-3'- hydroxytetradecanoylamino)-3-0-[3 ''-(tetradecanoyloxy) tetradecanoyl] glucopyranosyl-4-phosphate . 2-deoxy-2-(3'- hydroxytetradecanoylamino)-3-0 [3 "-(2,2-difluorotetradecanoyloxy) tetradecanoyl] glucopyranosyl-4-phosphate . 2-deoxy-2-[(3′R) -3′-hydroxytetradecanoylamino] -3-0-[(3 ″ R) -3 ″-(2,2-difluorotetradecanoyl Oxy) tetradecanoyl] -D-glucopyranosyl-4-phosphate. 2-deoxy-2- (3′-hydroxytetradecanoylamino) -3-0- [2 ″, 2 ″ -difluoro-3 ″-(tetradecanoyloxy) tetradecanoyl] glucopyranosyl -4-phosphate 2-deoxy-2- (2 ', 2-difluoro-3'-hydroxytetradecanoylamino) -3-0 (3-tetradecanoyloxytetradecanoyl) glucopyranosyl-4-phosphate. 2-deoxy-2-[(R) -2 ', 2'-difluoro-3'-hydroxytetradecanoylamino) -3-0-[(R) -3-tetradecanoyloxytetedeca Noyl] -D-glucopyranosyl-4-phosphate. 2-deoxy-2-[(S) -2 ', 2'-difluoro-3'-hydroxytetradecanoylamino) -3-0-[(R) -3-tetradecanoyloxytetedeca Noyl] -D-glucopyranosyl-4-phosphate. 2-deoxy-2- (2 ', 2'-difluoro-3'-hydroxytetradecanoylamino) -3-0- (3-dodecanoyloxytetradecanoyl) glucopyranosyl-4- Phosphate. 2-deoxy-2- (2 ', 2'-difluoro-3'-hydroxytetradecanoylamino) -3-0- (2,2-difuluro-3-tetradecanoyloxytetedeca Noyl) -glucopyranosyl-4-phosphate. 2-deoxy-2- (2 ', 2'-difluoro-3'-hydroxytetradecanoylamino) -3-0- (2,2-difluoro- 3-dodecanoyloxytetedeca Noyl) glucopyranosyl-4-phosphate. 2, 6-dideoxy-6-fluoro-2- (3'-hydroxytetradecanoylamino) -3-0- (3-tetradecanoyloxytetradecanoyl) glucopyranosyl-4-phosphate. 2,6-dideoxy-6-fluoro-2- (R) -3'-hydroxytetradecanoylamino] -3-0-[(R) -3-tetradecanoyloxytetradecanoyl] -D Glucopyranosyl-4-phosphate. 2,6-dideoxy-6-fluoro-2- (3'-hydroxytetradecanoylamino) -3-0- (2,2-difluoro-3-tetradecanoyloxytedecanoyl) gluco Pyranosyl-4-phosphate 2.6-dideoxy-6-fluoro-2- (2,2-difluoro-3'-hydroxytetradecanoylamino) -3-0- (3-tetradecanoyloxytetradecanoyl) glucopyranosyl 4-post.