CA2087805C - Immuno-suppressing agent - Google Patents
Immuno-suppressing agentInfo
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- CA2087805C CA2087805C CA 2087805 CA2087805A CA2087805C CA 2087805 C CA2087805 C CA 2087805C CA 2087805 CA2087805 CA 2087805 CA 2087805 A CA2087805 A CA 2087805A CA 2087805 C CA2087805 C CA 2087805C
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Abstract
An immuno-suppressive agent containing, as an effective component, an enopyranose derivative of the following formula (I) or its salt:
Description
. 2Q~~8~~
Our Ref.: IH-94 IMMUNO-SUPPRESSIVE AGENT
The present invention relates to an immuno-suppressive agent containing an enopyranose derivative of the formula (I) as an effective component.
An immuno-suppressive agent is usually used for treating a disease caused_by:abnormal sthenia of an immunological function. for example, a so-called autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, chronic nephritis, chronic thyroiditis or autoimmune hemolytic anemia or for supgressing a rejection at the time of transplantation of an organ. Heretofore,. steroid hormone, azathioprine and cyclophosphamide have been used as immuno-suppressive agents.
However, conventional immuno-suppressive agents are active not only against lymphocytes but also against a Wide range of cells non-selectively to give influences over their functions and proliferation. Thus, serious 2U~'~~0~
...,. - 2 _ side effects such as agranulocytosis and renal injury have been problematic.
Thus, it has been desired to develop a drug which has a strong activity to control an immunological function and which has no substantial side effect.
The present inventors have found that an enopyranose derivative having a chemical structure totally different from conventional immuno-suppressive agents, has immuno-suppressive activities. The present invention has been accomplished on the basis of this discovery.
Thus, the present invention provides an immuno-suppressive agent or an anti-inflammatory agent containing, as an effective component, an enopyranose derivative of the following=formula (I) or its salt:
0-R4 ° -R3 R6 (I) R ~y vY
2p wherein R1 is a hydrogen atom; alkyl which may be substituted, alkenyl, alkynyl, -OSOZR~, a halogen atom, -OCOR~, -NHCOR8, alkoxy, phenyl which may be substituted or a saccharose residue, R2 is a hydrogen atom or alkyl, R3 is a hydrogen atom or a halogen atom, R4 is a hydrogen atom, -COR9. silyl which may be substituted or alkyl which may be substituted, one of R5 and R6 is hydroxyl, alkoxy which may be substituted, a saccharose residue, 20-~~~~~ -"''- _ cycloalkyloxy which may be substituted or -OCOR1~ and the other is a hydrogen atom or alkyl which may be substituted, or R4 and R5 together form a single bond, while R6 is a hydrogen atom or alkyl which may be substituted, each of R~, R9 and R1~ is alkyl or phenyl which may be substituted, R8 is alkyl, phenyl which may be substituted or benzyloxy, X is a hydrogen atom, alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, phenyl which may be substituted, pyridyl which may be substituted, furanyl which may be substituted, thienyl which may be substituted, formyl, -COR11, -C(W1)WZR11 or -SOzRll, R11 is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group_which may be substituted, a polycyclic hydrocarbon group which may be substituted, monocyclic heterocycle group which may be substituted, or a polycyclic heterocycle group which may be substituted, W1 is an oxygen atom or a sulfur atom, W2 is an oxygen atom, a sulfur atom or -NH-, Y is a hydrogen atom, alkyl which may be substituted, alkenyl which may be substituted or alkynyl which may be substituted.
Now, the present invention will be described in detail with reference to the preferred embodiments.
In the accompanying drawing, Figure 1 is a graph showing the inhibiting effects of the compounds of the formula (I) on collagen-induced arthritis model.
2Q8'~8~5 -The alkyl group represented by or the alkyl moiety of a functional group represented by each of R1, R2. R4, R5, R6, R~. R8, R9, R1~. X and Y in the formula (I), may be C1-C2o alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, hepthyl, octyl, nonyl, decyl, tetradecyl, pentadecyl, octadecyl or nonadecyl, and they include linear or branched aliphatic structural isomers. The alkenyl group represented by each of R1, X and Y, may be CZ-Czo alkenyl such as ethenyl, propenyl or butenyl, and they include linear or branched aliphatic structural isomers. The alkynyl group represented by each of R1, X
and Y, may be C2-C2o alkynyl such as ethynyl, propynyl or butynyl, and they also include linear or branched aliphatic structural isomers:
The halogen atom repres~~ted by each of R1 and R3 in the formula (I) may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The saccharose residue represented by each of R1. R5 and R6 in the formula (I) may, for example, be:
H3 Cp OCH3 The cycloalkyl group represented by or the cycloalkyl moiety of a cycloalkyloxy group represented by each of R5, R6 and X in the formula (I), may be C3-Ce cycloalkyl 248'~8~~
such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The substituent for the phenyl which may be substituted, represented by each of R1, R~, R8, R9 and Rlo in the formula (I), may be a halogen atom such as fluorine, chlorine, bromine or iodine, alkyl such as methyl or ethyl, or nitro.
The substituent for the silyl which may be substituted, represented by R4 in the formula (I), may be alkyl such as methyl, ethyl, propyl or butyl, or phenyl.
The substituent for the alkyl which may be substituted, the alkoxy which may be substituted, or the cycloalkyloxy which may be substituted, represented by each of R1, R4, R5 and R6 in~-the formula (I), may be alkoxy such as methoxy or_ethoxy, phenyl or hydroxyl.
The number of such substituents may be one or more.'-If the number is two or more, such a plurality of substituents may be the same or different.
Further, in the definitions of X and Y in the formula (I). the substituent for the alkyl which may be substituted, the alkenyl which may be substituted or the alkynyl which may be substituted, may be a halogen atom such as fluorine, chlorine, bromine or iodine. hydroxyl, phenyl, alkyl-substituted phenyl such as tolyl or xylyl, pyridyl, furanyl, thienyl, acyloxy such as acetoxy or vareloxy, azide, or amino. Further, in the definition of X, the substituent for the cycloalkyl which may be 20~780~
substituted, the phenyl which may be substituted, the pyridyl which may be substituted, the furanyl which may be substituted or the thienyl which may be substituted, may be a halogen atom such as a fluorine, chlorine, bromine or iodine, hydroxyl, alkyl such as methyl or ethyl, acyloxy such as acetoxy or vareloxy, nitro, or amino. The number of such substituents may be one or more. When the number is two or more, such a plurality of substituents may be the same or different.
In the formula (I), the chain hydrocarbon group for R11 may be alkyl, alkenyl or alkynyl. The monocyclic hydrocarbon group may be cycloalkyl, cycloalkenyl or phenyl. The polycyclic hydrocarbon group may be a condensed polycyclic hydrocarbon group such as naphthyl, tetrahydronaphthyl or indanyl, or a bridged polycyclic hydrocarbon group such as adamantyl, noradamantyl, norbornanyl or norbornanonyl. The monocyclic heterocycle group may be pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl-, thiadiazolyl, pyrrolinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrazolinyl, hydantoinyl, oxazolinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thioazolidinyl, dioxolanyl, dithiolanyl, pyridyl, pYridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydrooxopyridazinyl, tetrahydrooxapyridazinyl, dihydrooxopyrimidinyl, r 2Q~'~~~~
tetrahydrooxopyrimidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dihydrodithinyl, dithianyl or morphorinyl. The polycyclic heterocycle group may be a condensed polycyclic heterocycle group such as thienothienyl, dihydrocyclopentathienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, tetrahydrobenzothienyl, dihydrobenzofuranyl, tetrahydrobenzisoxazolyl, benzodioxolyl, quinolinyl, isoquinolinyl, benzodioxanyl or quinoxalinyl, or a bridged polycyclic heterocycle group such as quinuclidinyl..
The substituent for the chain hydrocarbon group which may be substituted for R11, may be a halogen atom, alkoxy, haloalkoxy, alkylthio, cycloalkyl, cycloalkoxy, cycloalkenyl, _cycloalkenyloxy, alkoxycarbonyl, carboxyl, alkylcarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthib, amino, alkyl-substituted amino. The number of such substitutents or substituents on such substitutents may be one or more. When the number is two or more, such a plurality of substituents may be the same or different.
Further, the substituent for the mo.nocyclic hydrocarbon group which may be substituted, the polycyclic hydrocarbon group which may be substituted, the monocyclic heterocycle group which may be substituted, or the polycyclic heterocycle group which may be substituted for R11, may be a halogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy. alkylthio, cycloalkyl, ~o~7~Q
-cycloalkoxy, cycloalkenyl, cycloalkenyloxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, alkyl-substituted amino, cyano, nitro or hydroxyl. The number of such substituents or substituents on such substituents may be one or more.
When the number is two or more, such a plurality of substituents may be the same or different.
In the formula (I), the alkyl group or the alkyl moiety contained in R11, may be C1-C18 alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl or nonadecyl, and they include linear or branched aliphatic structural isomers. The alkenyl contained in R11, may be CZ-C18 alkenyl such as vinyl, propenyl, butenyl. pentenyl;-hexenyl, decenyl or nonadecenyl, and they include linear or branched aliphatic structural isomers. The alkynyl group contained in R11, may be C2-C1a alkynyl such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, decynyl or nonadecynyl, and they include linear or branched aliphatic structural isomers. The cycloalkyl group or the cycloalkyl moiety contained in R11, may be C3-C8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloctyl. The cycloalkenyl or the cycloalkenyl moiety contained in Rll, may be C5-C8 cycloalkenyl such as cyclopentenyl, cyclohexenyl or cycloctenyl. Further, the halogen atom contained in R11, may be a fluorine atom, a chlorine atom, a bromine atom ~~~'~~05 _ g _ or an iodine atom. The aryl group or the aryl moiety contained in R11, may be phenyl, thienyl, furanyl, pyridyl, naphthyl, benzothienyl, benzofuranyl or quinolinyl.
The enopyranose derivatives of the formula (I) have stereoisomers, since the carbon atoms at the 1-, 2- and 5-positions of the pyranose ring are asymmetric carbon atoms, and such stereoisomers are also useful for the present invention.
Further, the salt of an enopyranose derivative of the formula (I) may be an acid addition salt with a mineral acid such as hydrochloric acid or sulfuric acid.
The enopyranose derivative of the formula (I) is preferably the following: i' (1) the enopyranose derivative is a stereoisomer of the following formula (I-1) or (I-2):
(I-1) Rs v R s R2 ~~ ~
Y
R' (I-2) Rs ~ Rs R w Y
Rt 2~~'~~Q~
wherein Rl to R6, X and Y are as defined above.
(2) an enopyranose derivative of the formula (I-1) or (I-2) wherein R1 is a hydrogen atom, alkyl which may be substituted, alkenyl or alkynyl, R2 is a hydrogen atom or alkyl, each of R3 and R6 is a hydrogen atom, RQ and R5 together form a single bond, and X and Y are as defined above. The formula (I-1) is more preferable.
Enopyranose derivatives of the formula (I) include novel compounds. The present invention provides the following compounds as such novel compounds.
Namely, the present invention provides a compound of the following formula (I-1) or (I-2):
0_R4 0 R~ _ _ (I 1) R 3 R ss ..
R2 1v Y
R~
0_R4 Rs ~ R s 0-X (I_2) RZ
Y
R~
wherein R1 is a hydrogen atom, alkyl which may be substituted, alkenyl, alkynyl, -OS02R~, a halogen atom, -OCOR~, -NHCOR8. alkoxy, phenyl which may be substituted or a saccharose residue, R2 is a hydrogen atom or alkyl, R3 is a hydrogen atom or a halogen atom, R4 and R5 together form a single bond, R6 is a hydrogen atom or alkyl which may be substituted. R~ is alkyl or phenyl which may be substituted, R8 is alkyl, phenyl which may be substituted or benzyloxy, X is a hydrogen atom, alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, phenyl which may be substituted, pyridyl which may be substituted, furanyl which may be substituted, thienyl which may be substituted, formyl, -COR11, -C(W1)W2R11 or -SOZR11, R11 is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group-which may be substituted, a polycyclic hydrocarbon group_which may be substituted, a monocyclic heterocycle group which may be substituted oz a polycyclic heterocycle group which may be substituted, W1 is an oxygen atom or a sulfur atom, W2 is an oxygen atom, a sulfur atom or -NH-, Y is a hydrogen atom, alkyl which may be substituted, alkenyl which may be substituted or alkynyl which may be substituted, provided that the following cases are excluded:
l~ a case where in the formula (I-1), each of R1, Rz, R3, R6 and X is a hydrogen atom, and Y is a hydrogen atom or alkyl which may be substituted, ~2 a case where in the formula (I-1), each of R1, R2, R3, R6 and Y is a hydrogen atom, X is acetyl, 3,5-2~8'~8~
~" - 12 -dinitrobenzoyl or p-toluenesulfonyl, 3~ a case where in the formula (I-1), each of Rl, R2, R3 and Y is a hydrogen atom, R6 is alkyl which may be substituted, and X is a hydrogen atom or acetyl, and ~ a case where in the formula (I-2), each of R1, R2, R3, R6 and X is a hydrogen atom, and Y is methyl, ~5 a case where in the formula (I-2), each of Rl, R2, R3, R6 and Y is a hydrogen atom, and X is a hydrogen atom, methyl, benzyl, formyl, acetyl, benzoyl, 4-chlorobenzoyl, 3,5-dichlorobenzoyl, 4-nitrobenzoyl, 3,5-dinitrobenzoyl, 4-methoxybenzoyl, 3,5-dimethoxybenzoyl, methylsulfonyl or p-toluenesulfonyl, and ~ a case where in the formula (I-2), Rl is p-toluenesulfonyloxy, each of-R2, R3, R6 and Y is a hydrogen atom, and X is a,hydrogen atom, acetyl or p-toluenesulfonyl.
The following compounds are preferred as the compounds of the present invention.
(1) a compound of the formula (I-1) wherein R1 is a hydrogen atom, alkyl which may be substituted, alkenyl or alkynyl, R2 is a hydrogen atom or alkyl, each of R3 and R6 is a hydrogen atom, and R4 and R5 together form a single bond.
(2) a compound of the formula (I-1) wherein X is alkyl which may be substituted or -COR11 (Rii is as defined above), more preferably furfuryl or -COR11 (Rii is furanyl which may be substituted), R1. R2. R3. R4~ R5 2~~'~~~~
"""..' - 13 -and R6 are as defined in the (1).
(3) a compound of the formula (I-1) wherein X is furancarbonyl or furfulyl.
Our Ref.: IH-94 IMMUNO-SUPPRESSIVE AGENT
The present invention relates to an immuno-suppressive agent containing an enopyranose derivative of the formula (I) as an effective component.
An immuno-suppressive agent is usually used for treating a disease caused_by:abnormal sthenia of an immunological function. for example, a so-called autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, chronic nephritis, chronic thyroiditis or autoimmune hemolytic anemia or for supgressing a rejection at the time of transplantation of an organ. Heretofore,. steroid hormone, azathioprine and cyclophosphamide have been used as immuno-suppressive agents.
However, conventional immuno-suppressive agents are active not only against lymphocytes but also against a Wide range of cells non-selectively to give influences over their functions and proliferation. Thus, serious 2U~'~~0~
...,. - 2 _ side effects such as agranulocytosis and renal injury have been problematic.
Thus, it has been desired to develop a drug which has a strong activity to control an immunological function and which has no substantial side effect.
The present inventors have found that an enopyranose derivative having a chemical structure totally different from conventional immuno-suppressive agents, has immuno-suppressive activities. The present invention has been accomplished on the basis of this discovery.
Thus, the present invention provides an immuno-suppressive agent or an anti-inflammatory agent containing, as an effective component, an enopyranose derivative of the following=formula (I) or its salt:
0-R4 ° -R3 R6 (I) R ~y vY
2p wherein R1 is a hydrogen atom; alkyl which may be substituted, alkenyl, alkynyl, -OSOZR~, a halogen atom, -OCOR~, -NHCOR8, alkoxy, phenyl which may be substituted or a saccharose residue, R2 is a hydrogen atom or alkyl, R3 is a hydrogen atom or a halogen atom, R4 is a hydrogen atom, -COR9. silyl which may be substituted or alkyl which may be substituted, one of R5 and R6 is hydroxyl, alkoxy which may be substituted, a saccharose residue, 20-~~~~~ -"''- _ cycloalkyloxy which may be substituted or -OCOR1~ and the other is a hydrogen atom or alkyl which may be substituted, or R4 and R5 together form a single bond, while R6 is a hydrogen atom or alkyl which may be substituted, each of R~, R9 and R1~ is alkyl or phenyl which may be substituted, R8 is alkyl, phenyl which may be substituted or benzyloxy, X is a hydrogen atom, alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, phenyl which may be substituted, pyridyl which may be substituted, furanyl which may be substituted, thienyl which may be substituted, formyl, -COR11, -C(W1)WZR11 or -SOzRll, R11 is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group_which may be substituted, a polycyclic hydrocarbon group which may be substituted, monocyclic heterocycle group which may be substituted, or a polycyclic heterocycle group which may be substituted, W1 is an oxygen atom or a sulfur atom, W2 is an oxygen atom, a sulfur atom or -NH-, Y is a hydrogen atom, alkyl which may be substituted, alkenyl which may be substituted or alkynyl which may be substituted.
Now, the present invention will be described in detail with reference to the preferred embodiments.
In the accompanying drawing, Figure 1 is a graph showing the inhibiting effects of the compounds of the formula (I) on collagen-induced arthritis model.
2Q8'~8~5 -The alkyl group represented by or the alkyl moiety of a functional group represented by each of R1, R2. R4, R5, R6, R~. R8, R9, R1~. X and Y in the formula (I), may be C1-C2o alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, hepthyl, octyl, nonyl, decyl, tetradecyl, pentadecyl, octadecyl or nonadecyl, and they include linear or branched aliphatic structural isomers. The alkenyl group represented by each of R1, X and Y, may be CZ-Czo alkenyl such as ethenyl, propenyl or butenyl, and they include linear or branched aliphatic structural isomers. The alkynyl group represented by each of R1, X
and Y, may be C2-C2o alkynyl such as ethynyl, propynyl or butynyl, and they also include linear or branched aliphatic structural isomers:
The halogen atom repres~~ted by each of R1 and R3 in the formula (I) may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The saccharose residue represented by each of R1. R5 and R6 in the formula (I) may, for example, be:
H3 Cp OCH3 The cycloalkyl group represented by or the cycloalkyl moiety of a cycloalkyloxy group represented by each of R5, R6 and X in the formula (I), may be C3-Ce cycloalkyl 248'~8~~
such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The substituent for the phenyl which may be substituted, represented by each of R1, R~, R8, R9 and Rlo in the formula (I), may be a halogen atom such as fluorine, chlorine, bromine or iodine, alkyl such as methyl or ethyl, or nitro.
The substituent for the silyl which may be substituted, represented by R4 in the formula (I), may be alkyl such as methyl, ethyl, propyl or butyl, or phenyl.
The substituent for the alkyl which may be substituted, the alkoxy which may be substituted, or the cycloalkyloxy which may be substituted, represented by each of R1, R4, R5 and R6 in~-the formula (I), may be alkoxy such as methoxy or_ethoxy, phenyl or hydroxyl.
The number of such substituents may be one or more.'-If the number is two or more, such a plurality of substituents may be the same or different.
Further, in the definitions of X and Y in the formula (I). the substituent for the alkyl which may be substituted, the alkenyl which may be substituted or the alkynyl which may be substituted, may be a halogen atom such as fluorine, chlorine, bromine or iodine. hydroxyl, phenyl, alkyl-substituted phenyl such as tolyl or xylyl, pyridyl, furanyl, thienyl, acyloxy such as acetoxy or vareloxy, azide, or amino. Further, in the definition of X, the substituent for the cycloalkyl which may be 20~780~
substituted, the phenyl which may be substituted, the pyridyl which may be substituted, the furanyl which may be substituted or the thienyl which may be substituted, may be a halogen atom such as a fluorine, chlorine, bromine or iodine, hydroxyl, alkyl such as methyl or ethyl, acyloxy such as acetoxy or vareloxy, nitro, or amino. The number of such substituents may be one or more. When the number is two or more, such a plurality of substituents may be the same or different.
In the formula (I), the chain hydrocarbon group for R11 may be alkyl, alkenyl or alkynyl. The monocyclic hydrocarbon group may be cycloalkyl, cycloalkenyl or phenyl. The polycyclic hydrocarbon group may be a condensed polycyclic hydrocarbon group such as naphthyl, tetrahydronaphthyl or indanyl, or a bridged polycyclic hydrocarbon group such as adamantyl, noradamantyl, norbornanyl or norbornanonyl. The monocyclic heterocycle group may be pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl-, thiadiazolyl, pyrrolinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrazolinyl, hydantoinyl, oxazolinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thioazolidinyl, dioxolanyl, dithiolanyl, pyridyl, pYridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydrooxopyridazinyl, tetrahydrooxapyridazinyl, dihydrooxopyrimidinyl, r 2Q~'~~~~
tetrahydrooxopyrimidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dihydrodithinyl, dithianyl or morphorinyl. The polycyclic heterocycle group may be a condensed polycyclic heterocycle group such as thienothienyl, dihydrocyclopentathienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, tetrahydrobenzothienyl, dihydrobenzofuranyl, tetrahydrobenzisoxazolyl, benzodioxolyl, quinolinyl, isoquinolinyl, benzodioxanyl or quinoxalinyl, or a bridged polycyclic heterocycle group such as quinuclidinyl..
The substituent for the chain hydrocarbon group which may be substituted for R11, may be a halogen atom, alkoxy, haloalkoxy, alkylthio, cycloalkyl, cycloalkoxy, cycloalkenyl, _cycloalkenyloxy, alkoxycarbonyl, carboxyl, alkylcarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthib, amino, alkyl-substituted amino. The number of such substitutents or substituents on such substitutents may be one or more. When the number is two or more, such a plurality of substituents may be the same or different.
Further, the substituent for the mo.nocyclic hydrocarbon group which may be substituted, the polycyclic hydrocarbon group which may be substituted, the monocyclic heterocycle group which may be substituted, or the polycyclic heterocycle group which may be substituted for R11, may be a halogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy. alkylthio, cycloalkyl, ~o~7~Q
-cycloalkoxy, cycloalkenyl, cycloalkenyloxy, alkoxycarbonyl, alkylcarbonyl, alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, alkyl-substituted amino, cyano, nitro or hydroxyl. The number of such substituents or substituents on such substituents may be one or more.
When the number is two or more, such a plurality of substituents may be the same or different.
In the formula (I), the alkyl group or the alkyl moiety contained in R11, may be C1-C18 alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl or nonadecyl, and they include linear or branched aliphatic structural isomers. The alkenyl contained in R11, may be CZ-C18 alkenyl such as vinyl, propenyl, butenyl. pentenyl;-hexenyl, decenyl or nonadecenyl, and they include linear or branched aliphatic structural isomers. The alkynyl group contained in R11, may be C2-C1a alkynyl such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, decynyl or nonadecynyl, and they include linear or branched aliphatic structural isomers. The cycloalkyl group or the cycloalkyl moiety contained in R11, may be C3-C8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloctyl. The cycloalkenyl or the cycloalkenyl moiety contained in Rll, may be C5-C8 cycloalkenyl such as cyclopentenyl, cyclohexenyl or cycloctenyl. Further, the halogen atom contained in R11, may be a fluorine atom, a chlorine atom, a bromine atom ~~~'~~05 _ g _ or an iodine atom. The aryl group or the aryl moiety contained in R11, may be phenyl, thienyl, furanyl, pyridyl, naphthyl, benzothienyl, benzofuranyl or quinolinyl.
The enopyranose derivatives of the formula (I) have stereoisomers, since the carbon atoms at the 1-, 2- and 5-positions of the pyranose ring are asymmetric carbon atoms, and such stereoisomers are also useful for the present invention.
Further, the salt of an enopyranose derivative of the formula (I) may be an acid addition salt with a mineral acid such as hydrochloric acid or sulfuric acid.
The enopyranose derivative of the formula (I) is preferably the following: i' (1) the enopyranose derivative is a stereoisomer of the following formula (I-1) or (I-2):
(I-1) Rs v R s R2 ~~ ~
Y
R' (I-2) Rs ~ Rs R w Y
Rt 2~~'~~Q~
wherein Rl to R6, X and Y are as defined above.
(2) an enopyranose derivative of the formula (I-1) or (I-2) wherein R1 is a hydrogen atom, alkyl which may be substituted, alkenyl or alkynyl, R2 is a hydrogen atom or alkyl, each of R3 and R6 is a hydrogen atom, RQ and R5 together form a single bond, and X and Y are as defined above. The formula (I-1) is more preferable.
Enopyranose derivatives of the formula (I) include novel compounds. The present invention provides the following compounds as such novel compounds.
Namely, the present invention provides a compound of the following formula (I-1) or (I-2):
0_R4 0 R~ _ _ (I 1) R 3 R ss ..
R2 1v Y
R~
0_R4 Rs ~ R s 0-X (I_2) RZ
Y
R~
wherein R1 is a hydrogen atom, alkyl which may be substituted, alkenyl, alkynyl, -OS02R~, a halogen atom, -OCOR~, -NHCOR8. alkoxy, phenyl which may be substituted or a saccharose residue, R2 is a hydrogen atom or alkyl, R3 is a hydrogen atom or a halogen atom, R4 and R5 together form a single bond, R6 is a hydrogen atom or alkyl which may be substituted. R~ is alkyl or phenyl which may be substituted, R8 is alkyl, phenyl which may be substituted or benzyloxy, X is a hydrogen atom, alkyl which may be substituted, alkenyl which may be substituted, alkynyl which may be substituted, cycloalkyl which may be substituted, phenyl which may be substituted, pyridyl which may be substituted, furanyl which may be substituted, thienyl which may be substituted, formyl, -COR11, -C(W1)W2R11 or -SOZR11, R11 is a chain hydrocarbon group which may be substituted, a monocyclic hydrocarbon group-which may be substituted, a polycyclic hydrocarbon group_which may be substituted, a monocyclic heterocycle group which may be substituted oz a polycyclic heterocycle group which may be substituted, W1 is an oxygen atom or a sulfur atom, W2 is an oxygen atom, a sulfur atom or -NH-, Y is a hydrogen atom, alkyl which may be substituted, alkenyl which may be substituted or alkynyl which may be substituted, provided that the following cases are excluded:
l~ a case where in the formula (I-1), each of R1, Rz, R3, R6 and X is a hydrogen atom, and Y is a hydrogen atom or alkyl which may be substituted, ~2 a case where in the formula (I-1), each of R1, R2, R3, R6 and Y is a hydrogen atom, X is acetyl, 3,5-2~8'~8~
~" - 12 -dinitrobenzoyl or p-toluenesulfonyl, 3~ a case where in the formula (I-1), each of Rl, R2, R3 and Y is a hydrogen atom, R6 is alkyl which may be substituted, and X is a hydrogen atom or acetyl, and ~ a case where in the formula (I-2), each of R1, R2, R3, R6 and X is a hydrogen atom, and Y is methyl, ~5 a case where in the formula (I-2), each of Rl, R2, R3, R6 and Y is a hydrogen atom, and X is a hydrogen atom, methyl, benzyl, formyl, acetyl, benzoyl, 4-chlorobenzoyl, 3,5-dichlorobenzoyl, 4-nitrobenzoyl, 3,5-dinitrobenzoyl, 4-methoxybenzoyl, 3,5-dimethoxybenzoyl, methylsulfonyl or p-toluenesulfonyl, and ~ a case where in the formula (I-2), Rl is p-toluenesulfonyloxy, each of-R2, R3, R6 and Y is a hydrogen atom, and X is a,hydrogen atom, acetyl or p-toluenesulfonyl.
The following compounds are preferred as the compounds of the present invention.
(1) a compound of the formula (I-1) wherein R1 is a hydrogen atom, alkyl which may be substituted, alkenyl or alkynyl, R2 is a hydrogen atom or alkyl, each of R3 and R6 is a hydrogen atom, and R4 and R5 together form a single bond.
(2) a compound of the formula (I-1) wherein X is alkyl which may be substituted or -COR11 (Rii is as defined above), more preferably furfuryl or -COR11 (Rii is furanyl which may be substituted), R1. R2. R3. R4~ R5 2~~'~~~~
"""..' - 13 -and R6 are as defined in the (1).
(3) a compound of the formula (I-1) wherein X is furancarbonyl or furfulyl.
(4) a compound of the formula (I-1) wherein Y is alkynyl which may be substituted. Among them, the following compounds or salts thereof are most preferable;
1,6-anhydro-3,4-dideoxy-2-0-(2-furancarbonyl)-(~-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O-(2-furancarbonyl)-3-methyl-(~-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-C-ethynyl-2-O-(2-furancarbonyl)-(3-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-0-(2-furfuryl)-(3-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O-(2-furfuryl)-3-methyl-/3-D-threo-hex-3-enopyranose or 1,6-anhydro-3;4-dideoxy-2-C-ethynyl-2-O-(2-furfuryl)-(3-D-threo-hex-3-enopyranose.
The enopyranose derivative of the formula (I) or it's salt can be prepared by various methods. For example, 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose is reduced to obtain 1,6-anhydro-3,4-dideoxy-(~-D-threo-hex-3-enopyranose, which is then acylated, carbonated, carbamated, etherified or sulfonylated by a conventional method to obtain a desired compound.
Otherwise, the 2-position of 1,6-anhydro-3,4-dideoxy-/3-D-glycero-hex-3-enopyranos-2-ulose is alkylated, alkenylated or alkynylated by a conventional method to obtain a desired compound. Further, this 2-position reaction product may be acylated, carbonated, carbamated, ~~~~~0 ".".~, - 14 -etherified or sulfonylated as mentioned above to obtain a desired compound. On the other hand, 1,6-anhydro-3,4-dideoxy-(3-D-erythro-hex-3-enopyranose can be obtained also by the above-mentioned reduction reaction. However, it can be prepared also by isomerization of the above-mentioned threo-isomer. Further, the product may be acylated, carbonated, carbamated, etherified or sulfonylated by a conventional method to obtain a desired compound.
Further, a compound of the following formula (II) may be used instead of 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose.
~R4 RS:.
(II) ..
wherein R1, R2, R3, R4, R5 and R6 are as defined above.
The compound of the formula (II) is reduced, or alkylated, alkenylated or alkynylated by a conventional method and acylated, carbonated, carbamated, etherified or sulfonylated by a conventional method to obtain a desired compound. Otherwise, the compound of the formula (II) may be reduced and then isomerized, and acylated, carbonated, carbamated, etherified or sulfonylated by a conventional method to obtain a desired compound.
The compound of the formula (II) has an enantiomer 20~'~SJ~
""" - 15 -(L-isomer), and the same reaction as mentioned above can be conducted by using this enantiomer.
These reactions may be carried out usually under an inert atmosphere such as nitrogen gas, helium gas or argon gas, whereby a side reaction and a decrease in the yield can be prevented. Now, common methods for production using these reactions will be described.
A. Reduction A dry ether solution containing 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose, or water or a solution of an alcohol such as methanol, ethanol or isopropanol containing it, is gradually added to at least 0.3 equivalent, preferably from 0.4 to 0.5 equivalent, of lithium aluminum hydride or sodium borohydride, respectively. The reaction-:mixture is stirred and reacted at a temperature of not higher than room temperature, preferably from -10 to 0°C, for from 0.5 to 2 hours. After adding a small amount of water, the reaction product is post-treated by a conventional method for purification and separation.
B. Acylation A suitable acyl halide is gradually added in an amount of at least 1 equivalent, preferably from 1.5 to 2 equivalent, to a dry pyridine solution containing a reduced product of 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose or its 2-position reaction product. The reaction mixture is stirred and reacted at 2~~'~~a~
..."~ - 16 -a temperature of not higher than room temperature, preferably from -10 to 0°C, for from 0.5 to 2 hours.
After adding a small amount of water, the reaction product is concentrated under reduced pressure to obtain a crude product, which is then purified and separated by a conventional method.
When acylation is directly conducted by means of a carboxylic acid instead of an acyl halide, from 1.5 to 2 equivalent of dicyclohexylcarbodiimide or diethylcarbodiimide, from 1.5 to 2 equivalent of a suitable carboxylic acid and from 0.1 to 0.2 equivalent of N,N-dimethylaminopyridine or diisopropylethylamine as a catalyst are added to a dry methylene chloride solution containing 1,6-anhydro-3,4-dideoxy-~-D-threo-hex-3-_ -enopyranose, and the reaction is conducted under stirring at a temperature of from 0 to 30°C, preferably from 10'~to 20°C, for from 6 to 12 hours. The reaction product is post-treated by a conventional method for purification and separation.
C. Carbonation At least 2 equivalent, preferably from 2 to 3 equivalent, of a suitable chlorocarbonate is gradually added to a dry pyridine solution containing the reduced product of 1,6-anhydro-3,4-dideoxy-(~-D-glycero-hex-3-enopyranos-2-ulose or its 2-position reaction product, and the reaction mixture is stirred and reacted at a temperature of from 0 to 30°C, preferably from 10 to 2Q~'~~~-20°C, for from 6 to 12 hours. After adding a small amount of water, the reaction product is post-treated by a conventional method for purification and separation.
D. Carbamation At least 1.3 equivalent, preferably from 1.5 to 2 equivalent, of a suitable isocyanate or isothiocyanate is gradually added to a dry toluene solution containing the reduced product of 1,6-anhydro-3,4-dideoxy-f3-D-glycero-hex-3-enopyranos-2-ulose or its 2-position reaction product, and the mixture is stirred for from 10 to 15 minutes. Then, from 0.1 to 0.2 equivalent of the diisopropylethylamine, triethylamine or the like, or from 0.8 to 1.2 equivalent of sodium hydride, potassium hydride or the like is added-thereto, and the mixture is further stirred and reacted.: In the case of a reaction where triethylamine or the like is added, refluxing under heating is required.
In a case where phenyl isocyanate is used, diisopropylethylamine, triethylamine or the like is preferred, and in other cases, potassium hydride, sodium hydride or the like is preferred. After completion of the reaction, the reaction product is post-treated by a conventional method for purification and separation.
E. Etherification The reduced product of 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose or its 2-position reaction product is gradually added to a dry 2~~~~
tetrahydrofuran suspension containing from 1.0 to 1.5 equivalent, preferably 1.3 equivalent, of a base such as sodium hydride or potassium hydride. The reaction mixture is stirred at a temperature of from 0 to 20°C, preferably from 0 to 10°C, for from 10 to 15 minutes, and then at least 1 equivalent, preferably from 1.3 to 1.5 equivalent, of a suitable organic halide is added thereto. The mixture is stirred and reacted at a temperature of from 10 to 30°C, preferably from 20 to 30°C for from 6 to 12 hours. The above-mentioned organic halide may be selected depending upon the desired object, and it may, for example, be methyl iodide, butyl iodide or benzyl bromide. After adding a small amount of water, the reaction product is concentrated under reduced pressure to obtain a crudQ product, which is then subjected to purification and separation by a conventional method.
F. Sulfonylation At least, l equivalent, preferably from 1.5 to 2 equivalent, of a suitable sulfonyl halide is gradually added to a dry pyridine solution containing the reduced product of 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose or its 2-position reaction product, and the reaction mixture is stirred and reacted at a temperature of from 10 to 30°C, preferably from 20 to 30°C, for from 6 to 12 hours. The above-mentioned sulfonyl halide is selected depending upon the desired 2~~'~~
object, and it may, for example. be p-toluenesulfonyl chloride, methanesulfonyl chloride. After adding a small amount of water, the reaction product was extracted with a solvent such as toluene. Then, the solvent is distilled off under reduced pressure to obtain a crude product, which is then subjected to purification and separation by a conventional method.
G. Alkylation, alkenylation or alkynylation From 1.2 to 1.5 equivalent of an alkylation, alkenylation or alkynylation organic metal reagent, such as a suitable alkyl, alkenyl or alkynyl lithium or an alkyl, alkenyl or alkynyl magnesium bromide. is gradually added to a dry tetrahydrofuran solution containing 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose.
The reaction mixture is stirxed and reacted at a temperature of from -78 to 0°C, preferably from -10 to' 0°C, for from 0.5 to 1 hour. After adding a small amount of water, the reaction mixture is concentrated under reduced pressure to obtain a crude product, which is subjected to purification and separation by a conventional method.
H. Isomerization From 1 to 2 equivalent, preferably 2 equivalent, of a metal salt of a carboxylic acid such as sodium benzoate, is added to a dry N,N-dimethylformamide solution of a p-toluenesulfonyl ester of the reduced product of 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose ~0~~~0~
or its 2-position reaction product, and the mixture is stirred and reacted at a temperature of from 100 to 150°C, preferably at a refluxing temperature, for 30 minutes. The reaction mixture is post-treated by a conventional method to remove the solvent and then dissolved in dry methanol. Then, from 1 to 2 equivalent, preferably 1.5 equivalent, of a base is added thereto, and the mixture is stirred and reacted at a temperature of from 0 to 30°C, preferably from 20 to 30°C, for 30 minutes. The above-mentioned base may, for example, be sodium hydroxide, potassium hydroxide or sodium methoxide. After completion of the reaction, the reaction product is post-treated by a conventional method for purification and separat-ion.
The compound of the abo-v_e-mentioned formula (II) can be produced by various methods. For example, the 3- '-position of 1,6-anhydro-3,4-dideoxy-(~-D-glycero-hex-3-enopyranos-2-ulose is halogenated to obtain a desired compound, and this 3-position reaction product is alkylated. alkenylated, alkynylated or aryl-modified by a coupling reaction to obtain a desired compound. Further, 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose or its 3-position, 4-position or 5-position substituted derivative is treated under an acidic condition to conduct ring opening of acetal and etherification at the 1-position simultaneously, or acylated at the 1-position and 6-position, to obtain a 2~8'~8 desired compound. Furthermore, the 6-position of the compound having the 1-position etherified, is etherified, acylated or silylated to obtain a desired compound. The obtained compound may be hydrolyzed for deacylation at the 1-position or at the 1- and 6-positions. On the other hand, using a natural saccharose such as glucose, galactose or mannose as the starting material, its 2-keto derivative is prepared by an oxidation reaction to obtain a desired enone derivative having an oxygen or nitrogen functional group at the 3-position.
In practical operation of these reactions, a side-reaction and a decrease in the yield can usually be prevented by conducting the reactions under an inert atmosphere such as nitrogen~gas, helium gas or argon gas.
Now, common methods for production using these reactions will be described.
A. Halogenation reaction (A-1) Bromination At least 0.9 equivalent, preferably from 1.5 to 2 equivalent, of bromine is slowly added at a temperature of not higher than 0°C, preferably from -10 to -15°C to a carbon halide solution such as dry carbon tetrachloride or chloroform containing 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose. The reaction mixture is stirred and reacted at a temperature of not higher than 0°C, preferably from -10 to -15°C, for from 10 to 30 minutes. Then, at least 5 equivalent, preferably from 8 v to 10 equivalent, of a base such as pyridine, triethylamine or diisopropylethylamine is added thereto, and the mixture is stirred and reacted for 12 hours.
After adding water, the reaction solution was post-treated by a conventional method for purification and separation.
(A-2) Iodination A dry pyridine-carbon tetrachloride solution containing at least 5 equivalent, preferably from 8 to 10 equivalent, of iodine, is gradually added at a temperature of not higher than 5°C. preferably from 0 to 5°C, to a dry pyridine-carbon tetrachloride solution containing 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose. The reaction mixture is stirred and reacted at room temperatu~e;_ preferably from 15 to 25°C, for two hours. After~adding ethyl acetate, the reaction mixture is post-treated by a conventional method for purification and separation. With respect to tnis method, the synthesis was conducted in accordance with ZO the method by Carl R. Johnson et at. (Tetrahedron Lett., 33, 917-918, (1992)). With respect to the synLnes~S
an a-iodine derivative directly from an enone, there are other methods by John M. McIntosh (Can. J. Chem., 49, 3045-3047, (1971)) and by T. H. Kim et al. CChem.
Express, 5, 221, (1990)).
B. Coupling reaction From 0.01 to 0.3 equivalent, preferably from 0.05 to 0.15 equivalent, of copper(I) iodide, from 0.01 to 0.3 equivalent, preferably from 0.05 to 0.15 equivalent, of triphenylarsine and from 0.01 to 0.1 equivalent, preferably from 0.03 to 0.07 equivalent, of a palladium catalyst such as dichlorobis(benzonitrile)palladium(II) were added to a dry 1-methyl-2-pyrrolidinone solution containing 1,6-anhydro-3,4-dideoxy-3-iodo-(3-D-glycero-hex-3-enopyranos-2-ulose, to conduct the reaction. To the reaction mixture, an organotin compound or an organozinc compound is added, and the reaction is conducted at a temperature of from 0 to 100°C, preferably from 25 to 80°C, for from 1 to 10 hours. preferably from 2 to 6 hours. After adding ethyl acetate, the reaction product was post-treated by~a conventional method for purification and separation: With respect to this method, the synthesis can be conducted in accordance with the method by C. R. Johnson et al. (Tetrahedron Lett., 33, 919-922 (1992)). Further, in a case where R1 in the formula (II) is alkyl which may be substituted, the following method may be employed. Namely, 1,6-anhydro-3-bromo-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose is reacted together with at least 1 equivalent of ethylene glycol and a catalytic amount of p-toluenesulfonic acid at a refluxing temperature of a solvent such as benzene or toluene to obtain 1,6-anhydro-3-bromo-3,4-dideoxy-(3-D-glycero-hexo-3-enopyranos-2-ulose ethylene acetal having the carbonyl group at the 2-position of the pyranose ring _2~~7~a~
protected. Then, this product is reacted in a solvent such as tetrahydrofuran together with at least one equivalent of n-butyl lithium and at least one equivalent of an alkyl iodide at a reaction temperature of from -60 to -80°C. After the reaction, the protecting group at the 2-position of the pyranose ring is removed by a catalytic amount of p-toluenesulfonic acid at a refluxing temperature of tetrahydrofuran and water. Instead of the above-mentioned alkyl iodide. various ketones or aldehydes may be employed. In such a case, a compound wherein R1 is an alkyl group substituted by a hydroxyl group, will be obtained. Further, if an alcohol such as methanol is used as a solvent in the reaction for removing the protecting group, the hydroxyl moiety of a hydroxyl-substituted alkyd group can be converted to an alkoxy group such as methoxy. Further, the hydroxy '-moiety of the hydroxyl-substituted alkyl group may be aminated by a conventional method.
C. Ring opening reaction of acetal From 0.05 to 0.5 equivalent, preferably from 0.08 to 0.15 equivalent, of a Lewis acid such as sulfuric acid or boron trifluoride etherate is gradually added at a temperature of from -20°C to 15°C, preferably from -10°C
to 0°C, to a suitable acid anhydride containing 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose or its 1-position, 3-position, 4-position or 5-position substituted derivative or to a dry chloroform solution of such an acid anhydride. The reaction mixture is stirred for 10 minutes to 2 hours, preferably from 15 to 30 minutes. Then, the reaction solution is added to an ice-cooled saturated sodium bicarbonate solution and then treated by a conventional method for purification and separation (Carbohydr. Res., 71, 169-191 (1979)).
On the other hand, to prepare a 1-alkoxy derivative, from 1 to 5%. preferably from 3 to 4%, of concentrated sulfuric acid is added to a solution of a corresponding alcohol such as methanol, ethanol or propanol, and the mixture is stirred at a temperature of from 10 to 30°C, preferably from 15 to 25°C, for from 5 to 48 hours, preferably from 12 to 36 hours. The reaction solution is neutralyzed with a base such-as sodium hydrogencarbonate and then treated by a conventional method for purification and separation. The alcohol at the 6-position formed, can be converted by a conventional method such as etherification or acylation to a corresponding derivative.
D. Hydrolysis From 0.05 to 0.3 equivalent, preferably from 0.1 to 0.15 equivalent, of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, is added to a solution of water or an alcohol such as methanol, ethanol or isopropanol, containing 1,6-di-O-acyl-3,4-dideoxy-a-D-glycero-hex-3-enopyranos-2-ulose or its 1-position, 3-position, 4-position or 5-position substituted 2~8'~80~
"~.' - 2 6 -derivative, and the mixture is stirred at a temperature of from 10 to 30°C, preferably from 15 to 25°C, for from to 45 minutes, preferably from 20 to 30 minutes.
Ethyl acetate is added to the reaction product, and then 5 the precipitate is removed by filtration. The filtrate is concentrated under reduced pressure to obtain a product, which is subjected to purification and separation by a conventional method.
E. Oxidation reaction 10 From 1 to 10 equivalent, preferably from 2 to 5 equivalent, of pyridinium chlorochromate is added to a dry methylene chloride solution containing 3,4-dideoxy-hex-3-enopyranose or its derivative, and the mixture is stirred and reacted at a temperature of from 0 to 40°C, preferably from 10 to 20°C,-for from 1 to 20 hours, preferably from 2 to 12 hours. Diethyl ether is added°to the reaction product, and the mixture is filtered through silica gel, and the filtrate is concentrated to obtain a crude product. The crude product is subjected to purification and separation by a conventional method.
The compounds of the formula (II) contain compounds which have not been disclosed in literatures. For example, a compound of the formula (II') 2~s?~~5 ~R6 (II' ) R 1, wherein R1~ is alkyl which may be substituted, alkenyl, alkynyl, -OSOZR~, a halogen atom, phenyl which may be substituted, or a saccharose residue, and R4. R5, R6 and R~ are as defined above, excluding a case wherein R1~ is a bromine atom, R4 and R5 together form a single bond, and R6 is a hydrogen atom, or its salt, is a novel compound.
Further, immuno-suppressive effects are observed also with the compounds of the formula (II).
The enone derivatives= o~ the formula (II) will be presented in Tables l and 2.
2Q~'~B~J-~..... _ 2 8 _ Table 1 R
ERs CII) RZ ~~0 R
nerme e R, Rz R3 RA R5 Rc ia o.
li H 11 Single [[
bond 1 C H 3 H H Single tl 2 bond H
3 -OSOz~O -CEI3H H Single H
bond H It Single H
bond I H H Single H
bond g -OCOC113 H tl Single H
bond H tl H _ -CHzOH
: Single.
bond tt Ii H Single CH3 bond 0 tl li Single H
bond n H n H/otl oH/H
to H tl fl H H -OCII
a 11 II FI ll -COCH, -OCIf, II
12 H H H Silauhlez -OCH3 14 II tl tl H -OCIl3 II
H II 11 -COC11, -OCOCH3 H
16 Dr II II -COCIIz -OCOCtI~
II II 11 -COCIIa OH 11 11 gr 11 Ii -COCII, 011/11 lg II/011 19 II 11 H -COCzlls -OCOCzIIs fl CII, II 11 11 II -OClla 21 11 II II CII, -OCII, II
II II II -CO- OO II
-OCII, II II 1'r II -UCII, 23 II 1 II -COC11, 11 2,t 11 -OC., II~, l 2J II II II II -OC.,IIo II
L
2G II ll il -COCII, II
-UC, II, i m.,r,i~
g 6 ntermedia R R' R R R
a R ' z 27 11 H H S i tBuMez H
OCzlls 2$ ~ H Il H S i tBuhlez 11 OC~Hs t 2g 11 H H -CO -~O - H
NO z OC113 H -CH(CHa)OCzlls 11 H H OCIl3 31 -NHCOCI13 H H -COCH3 OCtl3 II
4 -OCO-OQ H Br -CO-QO -OCO-QO I1 -OCO-QO II H -CO-QO -0 ll 35 .
36 -OCOC,Het H H -OC113 H
-COC~Hot 37 -NIICOOCHz-~H H H -OC113 11 0 Me -OCHz H
3g -OCH3 H II CH3 Me0 hle ht a 3g -OCOCHa H H -COCH3 -OCOCiIa II , H C113 H -CO-QO -OCzHs I1 40 H CH, H Tr -OCZHs H
42 - O~ C113 I! H Singly: bond 11 43 H CH3 I1 Single bond II
44 -CH=Cllz H fl Single bond 1 45 -C= CIl H H Single bond II
II
46 -CHzCHz H Il Single bond II
47 -(CHz)aCH3 II 11 Single bond II
II Single bond 4g -CIIzOC113 11 H/OH and OH/H
for RS
and R6 mean that either RS or is an OH group.
SitBuMe2 represents a tert-butyl dimethylsilyl group, C4H9t represents a tert-butyl group, and C3H~i represents 25 an iso-propyl group.
Tr represents a triphenylmethyl group, and -~H~
represents a cyclohexyl group.
Preparation of 1.6-anhydro-3.4-dideoxy-3-iodo-Q-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 5) 150 ml of a dry pyridine-carbon tetrachloride (1:1) solution containing 40 g of iodine, was gradually added at 0°C to 150 ml of a dry pyridine-carbon tetrachloride (1:1) solution containing 5 g of 1,6-anhydro-3,4-dideoxy-(~-D-glycero-hex-3-enopyranos-2-ulose (disclosed in US
Patent 3,926,947) under an inert atmosphere of nitrogen gas. The mixture was stirred at room temperature for two hours. Then, disappearance of the starting material was confirmed by thin layer chromatography, and 200 ml of ethyl acetate was added thereto. The mixture was washed twice with 200 ml of a saturated sodium chloride aqueous solution and once with 209 m~ of 20~ sodium thiosulfate.
The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:3) to obtain 6.1 g of the desired product (Intermediate No. 5) as slightly yellow crystals.
The NMR analytical data and physical data of this product are as follows.
1H NMR (CDC13, 400MHz): 3.81(lH,d,J=6.8Hz);
3.87(lH,dd,J=6.8,5.OHz; 4.93(lH,t,J=S.OHz); 5.57(lH,s);
7.96(lH,d,J=5.OHz) m.p. 66-67°C
20~~~~~
Preparation of 1,6-anhydro-3.4-dideoxy-3-methyl-Q-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 2) 5.3 g of tetramethyltin was added to 20 ml of a dry N-methylpyrrolidinone solution containing a mixture comprising 5 g of 1,6-anhydro-3,4-dideoxy-3-iodo-/3-D-glycero-hex-3-enopyranos-2-ulose, 0.4 g of copper(I) iodide, 0.6 g of triphenylarsine and 0.4 g of dichlorobis(benzonitrile)palladium(II) under an inert atmosphere of nitrogen gas. The mixture was stirred at 80°C for 4 hours. Then, 200 ml of ethyl acetate was added thereto, and the mixture was washed three times with 100 ml of a 10~ potassium fluoride aqueous solution.
The organic layer was dried:bver anhydrous sodium sulfate, and then the solver~t was distilled off under reduced pressure. The obtained syrup product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:3) and then distilled under reduced pressure to obtain 1.61 g of the desired product (Intermediate No. 2) as a colorless transparent liquid.
The NMR analytical data of this product are as follows.
1 H N M R (CDC13. 400MHz) : 1. 79 (3H, s) ; 3. 68 (llt, d. J=6. 8Hz) ; 3. 83 (1H, dd. J
=6. 8. 4. 8Hz) ; 4. 95 (1H, t. J=4. 8Hz) ; 5. 36 (1H, s) : 6. 96 (1H. dq. J=4.
8. 1. 6ftz) b. p. 150-170°C (40mmttg) The following compounds were prepared in the same manner as in the above Intermediate Preparation Example 2, and their physical properties will be given.
Intermediate No. 42 1 H N M R (CDC13. 400MHz) : 2. 36 (3H, s) ; 3. 85 (1H, d, J=6. 6Hz) ; 3. 95 (1H, dd, J
=6. 6, 4. 8Hz) ; 5. 15 (1H, t, J=4. 8Hz) : 5. 50 (1H, s) ; 7. 19 (2H, br, d.
J=8. 1Hz) ; 7. 23 (1H, d, J=4. 8Hz) ; 7. 32 (2H, br, d, J=8. 1Hz) m. p. 117-119°C
Intermediate No. 9 1 H N M R (CDC13, 400MHz) : 1. 82 (1H, dt. J=11. 5, 4. 8Hz) ; 1. 90 (1H, m) ;
1. 98 (1 H, dt, J=11. 5. 3. 3Hz) ; 2. 22 (1H, m) ; 2. 64 (1H, dddd, J=20. 0. 3. 5. 3.
5, 3. 5Hz) ; 3. 15 (1H, m) ; 3. 62(1H, d, J=6. 9Hz) ;3.68 (1H, d, J=7. 3Hz) ; 3. 79(1H, dd, J=7.
3. 4. 7flz) ;
3. 87 (1H, dd, J=6. 9, 4. 3Hz) ; 4. 40 (llf, d, J=4. 7Hz) ; 5. O1 (1H, t. J=4.
7Hz) ; 5. 17 (1 H, s) ; 5. 35(1H, s) ; 6. 80(llf, dd, J=4. 7,~1. 2fiz) ; 6. 93(1H, q, J=3.
5Hz) Preparation of methyl 3.4-dideoxy-3-methyl-a-D-glycero-hex 3 enopyranos-2-ulose (Intermediate No. 20) 0.1 ml of concentrated sulfuric acid was added to 30 ml of a dry methanol solution containing 500 mg of 1,6-anhydro-3,4-dideoxy-3-methyl-(3-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 2), and the mixture was stirred at room temperature for 48 hours. Then, 30 ml of a saturated sodium hydrogencarbonate aqueous solution was added thereto, and the mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. Then, 200 ml of ethyl acetate was added thereto, and the mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 2:3) to obtain 350 mg of the desired compound (Intermediate No. 20) as a colorless liquid.
The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 1. 86 (3H, m) ; 1. 95 (1H, t, J=6. OHz) ; 3. 54 (3H, s) ;
3. 76 (1H, ddd. J=11. Z, 6. 8, 6. OHz) : 3. 84 (1H, ddd; J=11. 2, 6. 0. 3.
6Hz) ; 4. 63 (1H. m, 4. 80 (1H, s) ; 6. 68 (1H, m) Preparation of 1,6-di-0-propionyl-3,4-dideoxy-a-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 19) 100 mg of 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose was dissolved in 3 ml of propionic anhydride, and the solution_was cooled to -20°C. Then, 0.06 ml of concentrated snl~~tric acid was added thereto, and the mixture was stirred for 30 minutes. Then, the~~
reaction mixture was added to 100 ml of an ice-cooled saturated sodium hydrogencarbonate aqueous solution. The mixture was stirred for 30 minutes and then extracted with 100 ml of ethyl acetate. The extract was washed three times with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:2) to obtain 100 mg of the desired product (Intermediate No. 19) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
Intermediate No. 19 1 H N M R (CDC13, 400h1Hz) : 1. 14 (3H, t, J=5. 2Hz) ; 1. 16 (3H, t. J=5. 2Hz) ; 2. 38 (4H, m) ; 4. 22 (1H, dd. J=11. 4. 4. 6Hz) ; 4. 41 (1H. dd, J=11. 4, 4. 7Hz) ;
4. 81 (1H, m, ) ;
1,6-anhydro-3,4-dideoxy-2-0-(2-furancarbonyl)-(~-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O-(2-furancarbonyl)-3-methyl-(~-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-C-ethynyl-2-O-(2-furancarbonyl)-(3-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-0-(2-furfuryl)-(3-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O-(2-furfuryl)-3-methyl-/3-D-threo-hex-3-enopyranose or 1,6-anhydro-3;4-dideoxy-2-C-ethynyl-2-O-(2-furfuryl)-(3-D-threo-hex-3-enopyranose.
The enopyranose derivative of the formula (I) or it's salt can be prepared by various methods. For example, 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose is reduced to obtain 1,6-anhydro-3,4-dideoxy-(~-D-threo-hex-3-enopyranose, which is then acylated, carbonated, carbamated, etherified or sulfonylated by a conventional method to obtain a desired compound.
Otherwise, the 2-position of 1,6-anhydro-3,4-dideoxy-/3-D-glycero-hex-3-enopyranos-2-ulose is alkylated, alkenylated or alkynylated by a conventional method to obtain a desired compound. Further, this 2-position reaction product may be acylated, carbonated, carbamated, ~~~~~0 ".".~, - 14 -etherified or sulfonylated as mentioned above to obtain a desired compound. On the other hand, 1,6-anhydro-3,4-dideoxy-(3-D-erythro-hex-3-enopyranose can be obtained also by the above-mentioned reduction reaction. However, it can be prepared also by isomerization of the above-mentioned threo-isomer. Further, the product may be acylated, carbonated, carbamated, etherified or sulfonylated by a conventional method to obtain a desired compound.
Further, a compound of the following formula (II) may be used instead of 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose.
~R4 RS:.
(II) ..
wherein R1, R2, R3, R4, R5 and R6 are as defined above.
The compound of the formula (II) is reduced, or alkylated, alkenylated or alkynylated by a conventional method and acylated, carbonated, carbamated, etherified or sulfonylated by a conventional method to obtain a desired compound. Otherwise, the compound of the formula (II) may be reduced and then isomerized, and acylated, carbonated, carbamated, etherified or sulfonylated by a conventional method to obtain a desired compound.
The compound of the formula (II) has an enantiomer 20~'~SJ~
""" - 15 -(L-isomer), and the same reaction as mentioned above can be conducted by using this enantiomer.
These reactions may be carried out usually under an inert atmosphere such as nitrogen gas, helium gas or argon gas, whereby a side reaction and a decrease in the yield can be prevented. Now, common methods for production using these reactions will be described.
A. Reduction A dry ether solution containing 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose, or water or a solution of an alcohol such as methanol, ethanol or isopropanol containing it, is gradually added to at least 0.3 equivalent, preferably from 0.4 to 0.5 equivalent, of lithium aluminum hydride or sodium borohydride, respectively. The reaction-:mixture is stirred and reacted at a temperature of not higher than room temperature, preferably from -10 to 0°C, for from 0.5 to 2 hours. After adding a small amount of water, the reaction product is post-treated by a conventional method for purification and separation.
B. Acylation A suitable acyl halide is gradually added in an amount of at least 1 equivalent, preferably from 1.5 to 2 equivalent, to a dry pyridine solution containing a reduced product of 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose or its 2-position reaction product. The reaction mixture is stirred and reacted at 2~~'~~a~
..."~ - 16 -a temperature of not higher than room temperature, preferably from -10 to 0°C, for from 0.5 to 2 hours.
After adding a small amount of water, the reaction product is concentrated under reduced pressure to obtain a crude product, which is then purified and separated by a conventional method.
When acylation is directly conducted by means of a carboxylic acid instead of an acyl halide, from 1.5 to 2 equivalent of dicyclohexylcarbodiimide or diethylcarbodiimide, from 1.5 to 2 equivalent of a suitable carboxylic acid and from 0.1 to 0.2 equivalent of N,N-dimethylaminopyridine or diisopropylethylamine as a catalyst are added to a dry methylene chloride solution containing 1,6-anhydro-3,4-dideoxy-~-D-threo-hex-3-_ -enopyranose, and the reaction is conducted under stirring at a temperature of from 0 to 30°C, preferably from 10'~to 20°C, for from 6 to 12 hours. The reaction product is post-treated by a conventional method for purification and separation.
C. Carbonation At least 2 equivalent, preferably from 2 to 3 equivalent, of a suitable chlorocarbonate is gradually added to a dry pyridine solution containing the reduced product of 1,6-anhydro-3,4-dideoxy-(~-D-glycero-hex-3-enopyranos-2-ulose or its 2-position reaction product, and the reaction mixture is stirred and reacted at a temperature of from 0 to 30°C, preferably from 10 to 2Q~'~~~-20°C, for from 6 to 12 hours. After adding a small amount of water, the reaction product is post-treated by a conventional method for purification and separation.
D. Carbamation At least 1.3 equivalent, preferably from 1.5 to 2 equivalent, of a suitable isocyanate or isothiocyanate is gradually added to a dry toluene solution containing the reduced product of 1,6-anhydro-3,4-dideoxy-f3-D-glycero-hex-3-enopyranos-2-ulose or its 2-position reaction product, and the mixture is stirred for from 10 to 15 minutes. Then, from 0.1 to 0.2 equivalent of the diisopropylethylamine, triethylamine or the like, or from 0.8 to 1.2 equivalent of sodium hydride, potassium hydride or the like is added-thereto, and the mixture is further stirred and reacted.: In the case of a reaction where triethylamine or the like is added, refluxing under heating is required.
In a case where phenyl isocyanate is used, diisopropylethylamine, triethylamine or the like is preferred, and in other cases, potassium hydride, sodium hydride or the like is preferred. After completion of the reaction, the reaction product is post-treated by a conventional method for purification and separation.
E. Etherification The reduced product of 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose or its 2-position reaction product is gradually added to a dry 2~~~~
tetrahydrofuran suspension containing from 1.0 to 1.5 equivalent, preferably 1.3 equivalent, of a base such as sodium hydride or potassium hydride. The reaction mixture is stirred at a temperature of from 0 to 20°C, preferably from 0 to 10°C, for from 10 to 15 minutes, and then at least 1 equivalent, preferably from 1.3 to 1.5 equivalent, of a suitable organic halide is added thereto. The mixture is stirred and reacted at a temperature of from 10 to 30°C, preferably from 20 to 30°C for from 6 to 12 hours. The above-mentioned organic halide may be selected depending upon the desired object, and it may, for example, be methyl iodide, butyl iodide or benzyl bromide. After adding a small amount of water, the reaction product is concentrated under reduced pressure to obtain a crudQ product, which is then subjected to purification and separation by a conventional method.
F. Sulfonylation At least, l equivalent, preferably from 1.5 to 2 equivalent, of a suitable sulfonyl halide is gradually added to a dry pyridine solution containing the reduced product of 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose or its 2-position reaction product, and the reaction mixture is stirred and reacted at a temperature of from 10 to 30°C, preferably from 20 to 30°C, for from 6 to 12 hours. The above-mentioned sulfonyl halide is selected depending upon the desired 2~~'~~
object, and it may, for example. be p-toluenesulfonyl chloride, methanesulfonyl chloride. After adding a small amount of water, the reaction product was extracted with a solvent such as toluene. Then, the solvent is distilled off under reduced pressure to obtain a crude product, which is then subjected to purification and separation by a conventional method.
G. Alkylation, alkenylation or alkynylation From 1.2 to 1.5 equivalent of an alkylation, alkenylation or alkynylation organic metal reagent, such as a suitable alkyl, alkenyl or alkynyl lithium or an alkyl, alkenyl or alkynyl magnesium bromide. is gradually added to a dry tetrahydrofuran solution containing 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose.
The reaction mixture is stirxed and reacted at a temperature of from -78 to 0°C, preferably from -10 to' 0°C, for from 0.5 to 1 hour. After adding a small amount of water, the reaction mixture is concentrated under reduced pressure to obtain a crude product, which is subjected to purification and separation by a conventional method.
H. Isomerization From 1 to 2 equivalent, preferably 2 equivalent, of a metal salt of a carboxylic acid such as sodium benzoate, is added to a dry N,N-dimethylformamide solution of a p-toluenesulfonyl ester of the reduced product of 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose ~0~~~0~
or its 2-position reaction product, and the mixture is stirred and reacted at a temperature of from 100 to 150°C, preferably at a refluxing temperature, for 30 minutes. The reaction mixture is post-treated by a conventional method to remove the solvent and then dissolved in dry methanol. Then, from 1 to 2 equivalent, preferably 1.5 equivalent, of a base is added thereto, and the mixture is stirred and reacted at a temperature of from 0 to 30°C, preferably from 20 to 30°C, for 30 minutes. The above-mentioned base may, for example, be sodium hydroxide, potassium hydroxide or sodium methoxide. After completion of the reaction, the reaction product is post-treated by a conventional method for purification and separat-ion.
The compound of the abo-v_e-mentioned formula (II) can be produced by various methods. For example, the 3- '-position of 1,6-anhydro-3,4-dideoxy-(~-D-glycero-hex-3-enopyranos-2-ulose is halogenated to obtain a desired compound, and this 3-position reaction product is alkylated. alkenylated, alkynylated or aryl-modified by a coupling reaction to obtain a desired compound. Further, 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose or its 3-position, 4-position or 5-position substituted derivative is treated under an acidic condition to conduct ring opening of acetal and etherification at the 1-position simultaneously, or acylated at the 1-position and 6-position, to obtain a 2~8'~8 desired compound. Furthermore, the 6-position of the compound having the 1-position etherified, is etherified, acylated or silylated to obtain a desired compound. The obtained compound may be hydrolyzed for deacylation at the 1-position or at the 1- and 6-positions. On the other hand, using a natural saccharose such as glucose, galactose or mannose as the starting material, its 2-keto derivative is prepared by an oxidation reaction to obtain a desired enone derivative having an oxygen or nitrogen functional group at the 3-position.
In practical operation of these reactions, a side-reaction and a decrease in the yield can usually be prevented by conducting the reactions under an inert atmosphere such as nitrogen~gas, helium gas or argon gas.
Now, common methods for production using these reactions will be described.
A. Halogenation reaction (A-1) Bromination At least 0.9 equivalent, preferably from 1.5 to 2 equivalent, of bromine is slowly added at a temperature of not higher than 0°C, preferably from -10 to -15°C to a carbon halide solution such as dry carbon tetrachloride or chloroform containing 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose. The reaction mixture is stirred and reacted at a temperature of not higher than 0°C, preferably from -10 to -15°C, for from 10 to 30 minutes. Then, at least 5 equivalent, preferably from 8 v to 10 equivalent, of a base such as pyridine, triethylamine or diisopropylethylamine is added thereto, and the mixture is stirred and reacted for 12 hours.
After adding water, the reaction solution was post-treated by a conventional method for purification and separation.
(A-2) Iodination A dry pyridine-carbon tetrachloride solution containing at least 5 equivalent, preferably from 8 to 10 equivalent, of iodine, is gradually added at a temperature of not higher than 5°C. preferably from 0 to 5°C, to a dry pyridine-carbon tetrachloride solution containing 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose. The reaction mixture is stirred and reacted at room temperatu~e;_ preferably from 15 to 25°C, for two hours. After~adding ethyl acetate, the reaction mixture is post-treated by a conventional method for purification and separation. With respect to tnis method, the synthesis was conducted in accordance with ZO the method by Carl R. Johnson et at. (Tetrahedron Lett., 33, 917-918, (1992)). With respect to the synLnes~S
an a-iodine derivative directly from an enone, there are other methods by John M. McIntosh (Can. J. Chem., 49, 3045-3047, (1971)) and by T. H. Kim et al. CChem.
Express, 5, 221, (1990)).
B. Coupling reaction From 0.01 to 0.3 equivalent, preferably from 0.05 to 0.15 equivalent, of copper(I) iodide, from 0.01 to 0.3 equivalent, preferably from 0.05 to 0.15 equivalent, of triphenylarsine and from 0.01 to 0.1 equivalent, preferably from 0.03 to 0.07 equivalent, of a palladium catalyst such as dichlorobis(benzonitrile)palladium(II) were added to a dry 1-methyl-2-pyrrolidinone solution containing 1,6-anhydro-3,4-dideoxy-3-iodo-(3-D-glycero-hex-3-enopyranos-2-ulose, to conduct the reaction. To the reaction mixture, an organotin compound or an organozinc compound is added, and the reaction is conducted at a temperature of from 0 to 100°C, preferably from 25 to 80°C, for from 1 to 10 hours. preferably from 2 to 6 hours. After adding ethyl acetate, the reaction product was post-treated by~a conventional method for purification and separation: With respect to this method, the synthesis can be conducted in accordance with the method by C. R. Johnson et al. (Tetrahedron Lett., 33, 919-922 (1992)). Further, in a case where R1 in the formula (II) is alkyl which may be substituted, the following method may be employed. Namely, 1,6-anhydro-3-bromo-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose is reacted together with at least 1 equivalent of ethylene glycol and a catalytic amount of p-toluenesulfonic acid at a refluxing temperature of a solvent such as benzene or toluene to obtain 1,6-anhydro-3-bromo-3,4-dideoxy-(3-D-glycero-hexo-3-enopyranos-2-ulose ethylene acetal having the carbonyl group at the 2-position of the pyranose ring _2~~7~a~
protected. Then, this product is reacted in a solvent such as tetrahydrofuran together with at least one equivalent of n-butyl lithium and at least one equivalent of an alkyl iodide at a reaction temperature of from -60 to -80°C. After the reaction, the protecting group at the 2-position of the pyranose ring is removed by a catalytic amount of p-toluenesulfonic acid at a refluxing temperature of tetrahydrofuran and water. Instead of the above-mentioned alkyl iodide. various ketones or aldehydes may be employed. In such a case, a compound wherein R1 is an alkyl group substituted by a hydroxyl group, will be obtained. Further, if an alcohol such as methanol is used as a solvent in the reaction for removing the protecting group, the hydroxyl moiety of a hydroxyl-substituted alkyd group can be converted to an alkoxy group such as methoxy. Further, the hydroxy '-moiety of the hydroxyl-substituted alkyl group may be aminated by a conventional method.
C. Ring opening reaction of acetal From 0.05 to 0.5 equivalent, preferably from 0.08 to 0.15 equivalent, of a Lewis acid such as sulfuric acid or boron trifluoride etherate is gradually added at a temperature of from -20°C to 15°C, preferably from -10°C
to 0°C, to a suitable acid anhydride containing 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose or its 1-position, 3-position, 4-position or 5-position substituted derivative or to a dry chloroform solution of such an acid anhydride. The reaction mixture is stirred for 10 minutes to 2 hours, preferably from 15 to 30 minutes. Then, the reaction solution is added to an ice-cooled saturated sodium bicarbonate solution and then treated by a conventional method for purification and separation (Carbohydr. Res., 71, 169-191 (1979)).
On the other hand, to prepare a 1-alkoxy derivative, from 1 to 5%. preferably from 3 to 4%, of concentrated sulfuric acid is added to a solution of a corresponding alcohol such as methanol, ethanol or propanol, and the mixture is stirred at a temperature of from 10 to 30°C, preferably from 15 to 25°C, for from 5 to 48 hours, preferably from 12 to 36 hours. The reaction solution is neutralyzed with a base such-as sodium hydrogencarbonate and then treated by a conventional method for purification and separation. The alcohol at the 6-position formed, can be converted by a conventional method such as etherification or acylation to a corresponding derivative.
D. Hydrolysis From 0.05 to 0.3 equivalent, preferably from 0.1 to 0.15 equivalent, of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, is added to a solution of water or an alcohol such as methanol, ethanol or isopropanol, containing 1,6-di-O-acyl-3,4-dideoxy-a-D-glycero-hex-3-enopyranos-2-ulose or its 1-position, 3-position, 4-position or 5-position substituted 2~8'~80~
"~.' - 2 6 -derivative, and the mixture is stirred at a temperature of from 10 to 30°C, preferably from 15 to 25°C, for from to 45 minutes, preferably from 20 to 30 minutes.
Ethyl acetate is added to the reaction product, and then 5 the precipitate is removed by filtration. The filtrate is concentrated under reduced pressure to obtain a product, which is subjected to purification and separation by a conventional method.
E. Oxidation reaction 10 From 1 to 10 equivalent, preferably from 2 to 5 equivalent, of pyridinium chlorochromate is added to a dry methylene chloride solution containing 3,4-dideoxy-hex-3-enopyranose or its derivative, and the mixture is stirred and reacted at a temperature of from 0 to 40°C, preferably from 10 to 20°C,-for from 1 to 20 hours, preferably from 2 to 12 hours. Diethyl ether is added°to the reaction product, and the mixture is filtered through silica gel, and the filtrate is concentrated to obtain a crude product. The crude product is subjected to purification and separation by a conventional method.
The compounds of the formula (II) contain compounds which have not been disclosed in literatures. For example, a compound of the formula (II') 2~s?~~5 ~R6 (II' ) R 1, wherein R1~ is alkyl which may be substituted, alkenyl, alkynyl, -OSOZR~, a halogen atom, phenyl which may be substituted, or a saccharose residue, and R4. R5, R6 and R~ are as defined above, excluding a case wherein R1~ is a bromine atom, R4 and R5 together form a single bond, and R6 is a hydrogen atom, or its salt, is a novel compound.
Further, immuno-suppressive effects are observed also with the compounds of the formula (II).
The enone derivatives= o~ the formula (II) will be presented in Tables l and 2.
2Q~'~B~J-~..... _ 2 8 _ Table 1 R
ERs CII) RZ ~~0 R
nerme e R, Rz R3 RA R5 Rc ia o.
li H 11 Single [[
bond 1 C H 3 H H Single tl 2 bond H
3 -OSOz~O -CEI3H H Single H
bond H It Single H
bond I H H Single H
bond g -OCOC113 H tl Single H
bond H tl H _ -CHzOH
: Single.
bond tt Ii H Single CH3 bond 0 tl li Single H
bond n H n H/otl oH/H
to H tl fl H H -OCII
a 11 II FI ll -COCH, -OCIf, II
12 H H H Silauhlez -OCH3 14 II tl tl H -OCIl3 II
H II 11 -COC11, -OCOCH3 H
16 Dr II II -COCIIz -OCOCtI~
II II 11 -COCIIa OH 11 11 gr 11 Ii -COCII, 011/11 lg II/011 19 II 11 H -COCzlls -OCOCzIIs fl CII, II 11 11 II -OClla 21 11 II II CII, -OCII, II
II II II -CO- OO II
-OCII, II II 1'r II -UCII, 23 II 1 II -COC11, 11 2,t 11 -OC., II~, l 2J II II II II -OC.,IIo II
L
2G II ll il -COCII, II
-UC, II, i m.,r,i~
g 6 ntermedia R R' R R R
a R ' z 27 11 H H S i tBuMez H
OCzlls 2$ ~ H Il H S i tBuhlez 11 OC~Hs t 2g 11 H H -CO -~O - H
NO z OC113 H -CH(CHa)OCzlls 11 H H OCIl3 31 -NHCOCI13 H H -COCH3 OCtl3 II
4 -OCO-OQ H Br -CO-QO -OCO-QO I1 -OCO-QO II H -CO-QO -0 ll 35 .
36 -OCOC,Het H H -OC113 H
-COC~Hot 37 -NIICOOCHz-~H H H -OC113 11 0 Me -OCHz H
3g -OCH3 H II CH3 Me0 hle ht a 3g -OCOCHa H H -COCH3 -OCOCiIa II , H C113 H -CO-QO -OCzHs I1 40 H CH, H Tr -OCZHs H
42 - O~ C113 I! H Singly: bond 11 43 H CH3 I1 Single bond II
44 -CH=Cllz H fl Single bond 1 45 -C= CIl H H Single bond II
II
46 -CHzCHz H Il Single bond II
47 -(CHz)aCH3 II 11 Single bond II
II Single bond 4g -CIIzOC113 11 H/OH and OH/H
for RS
and R6 mean that either RS or is an OH group.
SitBuMe2 represents a tert-butyl dimethylsilyl group, C4H9t represents a tert-butyl group, and C3H~i represents 25 an iso-propyl group.
Tr represents a triphenylmethyl group, and -~H~
represents a cyclohexyl group.
Preparation of 1.6-anhydro-3.4-dideoxy-3-iodo-Q-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 5) 150 ml of a dry pyridine-carbon tetrachloride (1:1) solution containing 40 g of iodine, was gradually added at 0°C to 150 ml of a dry pyridine-carbon tetrachloride (1:1) solution containing 5 g of 1,6-anhydro-3,4-dideoxy-(~-D-glycero-hex-3-enopyranos-2-ulose (disclosed in US
Patent 3,926,947) under an inert atmosphere of nitrogen gas. The mixture was stirred at room temperature for two hours. Then, disappearance of the starting material was confirmed by thin layer chromatography, and 200 ml of ethyl acetate was added thereto. The mixture was washed twice with 200 ml of a saturated sodium chloride aqueous solution and once with 209 m~ of 20~ sodium thiosulfate.
The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:3) to obtain 6.1 g of the desired product (Intermediate No. 5) as slightly yellow crystals.
The NMR analytical data and physical data of this product are as follows.
1H NMR (CDC13, 400MHz): 3.81(lH,d,J=6.8Hz);
3.87(lH,dd,J=6.8,5.OHz; 4.93(lH,t,J=S.OHz); 5.57(lH,s);
7.96(lH,d,J=5.OHz) m.p. 66-67°C
20~~~~~
Preparation of 1,6-anhydro-3.4-dideoxy-3-methyl-Q-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 2) 5.3 g of tetramethyltin was added to 20 ml of a dry N-methylpyrrolidinone solution containing a mixture comprising 5 g of 1,6-anhydro-3,4-dideoxy-3-iodo-/3-D-glycero-hex-3-enopyranos-2-ulose, 0.4 g of copper(I) iodide, 0.6 g of triphenylarsine and 0.4 g of dichlorobis(benzonitrile)palladium(II) under an inert atmosphere of nitrogen gas. The mixture was stirred at 80°C for 4 hours. Then, 200 ml of ethyl acetate was added thereto, and the mixture was washed three times with 100 ml of a 10~ potassium fluoride aqueous solution.
The organic layer was dried:bver anhydrous sodium sulfate, and then the solver~t was distilled off under reduced pressure. The obtained syrup product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:3) and then distilled under reduced pressure to obtain 1.61 g of the desired product (Intermediate No. 2) as a colorless transparent liquid.
The NMR analytical data of this product are as follows.
1 H N M R (CDC13. 400MHz) : 1. 79 (3H, s) ; 3. 68 (llt, d. J=6. 8Hz) ; 3. 83 (1H, dd. J
=6. 8. 4. 8Hz) ; 4. 95 (1H, t. J=4. 8Hz) ; 5. 36 (1H, s) : 6. 96 (1H. dq. J=4.
8. 1. 6ftz) b. p. 150-170°C (40mmttg) The following compounds were prepared in the same manner as in the above Intermediate Preparation Example 2, and their physical properties will be given.
Intermediate No. 42 1 H N M R (CDC13. 400MHz) : 2. 36 (3H, s) ; 3. 85 (1H, d, J=6. 6Hz) ; 3. 95 (1H, dd, J
=6. 6, 4. 8Hz) ; 5. 15 (1H, t, J=4. 8Hz) : 5. 50 (1H, s) ; 7. 19 (2H, br, d.
J=8. 1Hz) ; 7. 23 (1H, d, J=4. 8Hz) ; 7. 32 (2H, br, d, J=8. 1Hz) m. p. 117-119°C
Intermediate No. 9 1 H N M R (CDC13, 400MHz) : 1. 82 (1H, dt. J=11. 5, 4. 8Hz) ; 1. 90 (1H, m) ;
1. 98 (1 H, dt, J=11. 5. 3. 3Hz) ; 2. 22 (1H, m) ; 2. 64 (1H, dddd, J=20. 0. 3. 5. 3.
5, 3. 5Hz) ; 3. 15 (1H, m) ; 3. 62(1H, d, J=6. 9Hz) ;3.68 (1H, d, J=7. 3Hz) ; 3. 79(1H, dd, J=7.
3. 4. 7flz) ;
3. 87 (1H, dd, J=6. 9, 4. 3Hz) ; 4. 40 (llf, d, J=4. 7Hz) ; 5. O1 (1H, t. J=4.
7Hz) ; 5. 17 (1 H, s) ; 5. 35(1H, s) ; 6. 80(llf, dd, J=4. 7,~1. 2fiz) ; 6. 93(1H, q, J=3.
5Hz) Preparation of methyl 3.4-dideoxy-3-methyl-a-D-glycero-hex 3 enopyranos-2-ulose (Intermediate No. 20) 0.1 ml of concentrated sulfuric acid was added to 30 ml of a dry methanol solution containing 500 mg of 1,6-anhydro-3,4-dideoxy-3-methyl-(3-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 2), and the mixture was stirred at room temperature for 48 hours. Then, 30 ml of a saturated sodium hydrogencarbonate aqueous solution was added thereto, and the mixture was stirred at room temperature for 15 minutes and then concentrated under reduced pressure. Then, 200 ml of ethyl acetate was added thereto, and the mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 2:3) to obtain 350 mg of the desired compound (Intermediate No. 20) as a colorless liquid.
The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 1. 86 (3H, m) ; 1. 95 (1H, t, J=6. OHz) ; 3. 54 (3H, s) ;
3. 76 (1H, ddd. J=11. Z, 6. 8, 6. OHz) : 3. 84 (1H, ddd; J=11. 2, 6. 0. 3.
6Hz) ; 4. 63 (1H. m, 4. 80 (1H, s) ; 6. 68 (1H, m) Preparation of 1,6-di-0-propionyl-3,4-dideoxy-a-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 19) 100 mg of 1,6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose was dissolved in 3 ml of propionic anhydride, and the solution_was cooled to -20°C. Then, 0.06 ml of concentrated snl~~tric acid was added thereto, and the mixture was stirred for 30 minutes. Then, the~~
reaction mixture was added to 100 ml of an ice-cooled saturated sodium hydrogencarbonate aqueous solution. The mixture was stirred for 30 minutes and then extracted with 100 ml of ethyl acetate. The extract was washed three times with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:2) to obtain 100 mg of the desired product (Intermediate No. 19) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
Intermediate No. 19 1 H N M R (CDC13, 400h1Hz) : 1. 14 (3H, t, J=5. 2Hz) ; 1. 16 (3H, t. J=5. 2Hz) ; 2. 38 (4H, m) ; 4. 22 (1H, dd. J=11. 4. 4. 6Hz) ; 4. 41 (1H. dd, J=11. 4, 4. 7Hz) ;
4. 81 (1H, m, ) ;
6. 20 (1H, s) ; 6. 28 (1H, dd, J=10. 6, 2. 4Hz) ; 7. 05 (1H, dd, J=10. 6, 1.
9Hz) The following compound was prepared in the same manner as in the above Intermediate Preparation Example 4, and its physical properties will be given.
Intermediate No. 16 1 H N M R (CDC13, 400h1Hz) : 2. 10 (3H, s) ; 2. 13 (3H. s) ; 4. 20 (1H, dd, J=11. 4, 5.
OHz) ; 4. 38 (1H, dd, J=11. 4, 5. OHz) ; 4. 88 (1H, td, J=5. 0, 1. 9Hz) ; 6.
34 (1H, s) ; 7. 4 3 (1H, d. J=1. 9Hz) Preparation of 6 0-acetyl-3-bromo-3,4-dideoxy-D-alYcero-hex 3 enopyranos-2-ulose (Intermediate No. 18) 200 mg of 1,6-di-O-acetyl-3-bromo-3,4-dideoxy-a-D-glycero-hex-3-enopyranos-2-ulose prepared in the same manner as in the above Intermediate Preparation Example 4 from 1,6-anhydro-3-bromo-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 4) prepared by the method disclosed in Carbohydrate Research (1981), Vol.
93, 284-287. was dissolved in 6 ml of tetrahydrofuran-water (5:1), and 70 mg of lithium hydroxide monohydrate was added thereto. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 100 ml of ethyl acetate was added. The mixture was 2~~~~~~
washed three times with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by thin layer chromatography for separation (NO-5744, manufactured by Merck, ethyl acetate: hexane = 1:1) to obtain 40 mg of the desired product (Intermediate No. 18) as a slightly yellow liquid. The NMR analytical data of this product are as follows.
. 1 H N M R (CDC13, 400hiHz) : 2. 12 (0. 9H, s) ; 2. 13 (0. 1H. s) ; 4. 24 (0.
1H, dd. J=1 1. 2, 5. OHz) ; 4. 26 (0. 9H, dd, J=11. 5, 5. OHz) : 4. 35 (0. 9H, dd, J=11.
5, 5. OHz) ; 4. 47 (0. 1H, dd, J=11. 2, 6. 5Hz) ; 4. 78 (0. 1H, dddd, J=6. 5, 5. 0, 1. 9, 1. OHz) ; 5. 00 (0. 9H, t d, J=5. 0, 2. 2Hz) ; 5. 31 (0. 1H, br, s) : 5. 46 (0. 9H, br, s) ; 7. 38 (0.
9H, d, J=2. 2Hz) ;
9Hz) The following compound was prepared in the same manner as in the above Intermediate Preparation Example 4, and its physical properties will be given.
Intermediate No. 16 1 H N M R (CDC13, 400h1Hz) : 2. 10 (3H, s) ; 2. 13 (3H. s) ; 4. 20 (1H, dd, J=11. 4, 5.
OHz) ; 4. 38 (1H, dd, J=11. 4, 5. OHz) ; 4. 88 (1H, td, J=5. 0, 1. 9Hz) ; 6.
34 (1H, s) ; 7. 4 3 (1H, d. J=1. 9Hz) Preparation of 6 0-acetyl-3-bromo-3,4-dideoxy-D-alYcero-hex 3 enopyranos-2-ulose (Intermediate No. 18) 200 mg of 1,6-di-O-acetyl-3-bromo-3,4-dideoxy-a-D-glycero-hex-3-enopyranos-2-ulose prepared in the same manner as in the above Intermediate Preparation Example 4 from 1,6-anhydro-3-bromo-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 4) prepared by the method disclosed in Carbohydrate Research (1981), Vol.
93, 284-287. was dissolved in 6 ml of tetrahydrofuran-water (5:1), and 70 mg of lithium hydroxide monohydrate was added thereto. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 100 ml of ethyl acetate was added. The mixture was 2~~~~~~
washed three times with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by thin layer chromatography for separation (NO-5744, manufactured by Merck, ethyl acetate: hexane = 1:1) to obtain 40 mg of the desired product (Intermediate No. 18) as a slightly yellow liquid. The NMR analytical data of this product are as follows.
. 1 H N M R (CDC13, 400hiHz) : 2. 12 (0. 9H, s) ; 2. 13 (0. 1H. s) ; 4. 24 (0.
1H, dd. J=1 1. 2, 5. OHz) ; 4. 26 (0. 9H, dd, J=11. 5, 5. OHz) : 4. 35 (0. 9H, dd, J=11.
5, 5. OHz) ; 4. 47 (0. 1H, dd, J=11. 2, 6. 5Hz) ; 4. 78 (0. 1H, dddd, J=6. 5, 5. 0, 1. 9, 1. OHz) ; 5. 00 (0. 9H, t d, J=5. 0, 2. 2Hz) ; 5. 31 (0. 1H, br, s) : 5. 46 (0. 9H, br, s) ; 7. 38 (0.
9H, d, J=2. 2Hz) ;
7. 44 (0. 1H, d, J=1. 9Hz) The following compound was prepared in the same manner as the above Intermediate Preparation Example 5, and its physical properties will be given.
Intermediate No. 17 1 H N M R (CDC13, 400MHz) :2. 09(2. 25H, s); 2. 10 (0. 75H, s) ; 4. 26 (0.
25H, dd, J
=11. 5, 5. OHz) ; 4. 27 (0. 75H, dd, J=11. 5, 4. 3Hz) ; 4. 34 (0. 75H, dd, J=11. 5, 5. 3Hz) ;
4. 42 (0. 25H, dd, J=11. 5, 6. 2Hz) ; 4. 79 (0. 25H, m) ; 4. 93 (0. 75H, m) ;
5. 19 (0. 25H, br d, J=5. 7Hz) ; 5. 26 (0. 75H, br, d, J=3. 3Hz) : 6. 19 (0. 75H, dd. J=10. 4, 2. 5Hz) ; 6. 27 (0. 25H, dd, J=10. 0, 2. 8Hz) ; 6. 99 (0. 75H, dd. J=10. 4. 1. 7Hz) : 6. 99 (0. 2511, dd. J=10 . 0, 1. 9Hz) Preparation of 1,6-anhydro-3-0-p-toluenesulfonyl-4-deoxy-20~78~~
~3 D c~lycero hex-3-enopyranos-2-ulose (Intermediate No. 3) 360 mg of pyridinium chlorochromate was added to 20 ml of a dry methylene chloride solution containing 50 mg of 1,6-anhydro-3-0-p-toluenesulfonyl-4-deoxy-~-D-erythro-hex-3-enopyranose, and the mixture was stirred at room temperature for 48 hours. Disappearance of the starting material was confirmed by thin layer chromatography, and then 60 ml of diethyl ether was added thereto. The mixture was further stirred at room temperature for 15 minutes. Then, the reaction mixture was filtered by silica gel and washed with 200 ml of diethyl ether. The washing solution was concentrated under reduced pressure together with the filtrate. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = ~:~) to obtain 34 mg of the desired product (Intermediate No. 3) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
1 H N Vf R (CDC13, 400MHz) : 2. 45 (3H, s) ; 3. 83 (1H, d. J=7. 211z) ; 3. 92 (l li, dd. J
=7. 2, 4. 8Hz) ; 5. 14 (1H, t. J=4. 8llz) : 5. 36 (1H, s) : 7. 17 (111, d.
J=4. 811z) : 7. 35 (21( br, d, J=8. OHz) : 7. 82 (211, dt, J=8. 8, 2. OHz) m. p. 81-86°C
Preparation of 1,6 anhydro-3,4-dideoxy-4-methyl-a-D-lycero hex 3 enopyranos-2-ulose (Intermediate No. 43) 1 ml of a tetrahydrofuran solution containing 300 mg of 1,6-anhydro-3,4-dideoxy-4-C-methyl-~3-D-erythro-~o~~~~~
hexopyranose-2-ulose (disclosed in Carbohydrate Res., 71, (1979) 169), was added at -78°C to a lithium amide solution prepared by a conventional method from 0.45 ml of diisopropylamine and 1.75 ml of butyl lithium in 25 ml of dry tetrahydrofuran, under an inert atmosphere of nitrogen gas. The mixture was stirred for one hour, and then 3 ml of a tetrahydrofuran solution containing 500 mg of phenyl serenyl chloride and 0.75 ml of phosphoric acid hexamethyl triamide, was added. The mixture was stirred at -78°C for 30 minutes. Then, a saturated ammonium chloride aqueous solution was added thereto, and the solvent was distilled off under reduced pressure. Then, the mixture was extracted with ethyl acetate. The extract was washed twice with a saturated sodium chloride aqueous solution and then_dried over anhydrous sodium sulfate. The solvent~was distilled off under reduced ' pressure to obtain a syrup crude product. This crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:10) to obtain 106 mg of a serenium derivative.
The serenium derivative obtained by the above reaction was dissolved in 20 ml of dry methylene chloride under an inert atmosphere of nitrogen gas, and 60 mg of m-chloroperbenzoic acid was added thereto at -78°C. The mixture was stirred for 20 minutes and then a saturated sodium hydrogencarbonate aqueous solution was added. The mixture was extracted twice with methylene chloride. The 2~~7~0~
organic layers were put together and washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel thin layer chromatography (methylene chloride) to obtain 1.7 mg of desired 1,6-anhydro-3,4-dideoxy-4-methyl-f3-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 43) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
1 H N M R (CDC13. 400MHz) : . 2. 08 (3H, d. J=1. 2Hz) ; 3. 71 (1H, d. J=6.
8Hz) ; 3. 91 (1H, dd, J=6. 8, 4. 8Hz) ; 4. 80 (1H. d, J=4. 8Hz) ; 5. 32 (1H, d, J=1. 2Hz) :
5. 87 (1H, m) Preparation of 1,6-anhydro-~',4-dideoxy-3-ethyl-a-D-glycero-hex-3-enopyranos =2-i~-lose (Intermediate No. 46) (1) 22 g of 1,6-anhydro-3-bromo-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose was dissolved in 500 ml of dry benzene, and 66 g of ethylene glycol and 3 g of p-toluenesulfQnic acid monohydrate were added thereto. The mixture was refluxed under heating while removing formed water. 19 hours later, disappearance of the starting material was confirmed by TLC, and the reaction mixture was cooled to room temperature. Then, 500 ml of ethyl acetate was added thereto, and the mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was 2~8'~8~~
distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (ethyl acetate: hexane = 1:1) to obtain 20 g of 1,6-anhydro-3-bromo-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal as white crystals.
The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 3. 71 (1H, dd. J=6. 8, 4. 4Hz) ; 3. 79 (1H, d, J=6. 8Hz) ;
4. 04 (1H, m) ; 4. 17 (1H, m) ; 4. 28 (2H, m) ; 4. 75 (1H, t, J=4. 4Hz) ; 5.
28 (1H, s) ; 6. 60 (1H, d, J=4. 4Hz) m. p. 111-112 °C
(2) 3 g of 1,6-anhydro-3-bromo-3,4-dideoxy-(~-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal obtained in the above step (1) was dissolved in 200 ml of dry tetrahydrofuran. Then, 1.2:equivalent of n-butyl lithium was added thereto under s~i~=ring at -78°C under a nitrogen atmosphere. The mixture was stirred for 20 minutes, and then 10 ml of a dry tetrahydrofuran solution containing 1.9 ml of ethyl iodide and 5.2 ml of hexamethyl phosphoamide, was added thereto. The mixture was stirred for 30 minutes, and then gradually heated to room temperature. Completion of the reaction was confirmed by TLC, and then a small amount of water was added. The solvent was distilled off under reduced pressure. To the residue, 300 ml of ethyl acetate was added, and the mixture was washed three times with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate.
2~~"~8~~
The so3:vent was distilled off under reduced pressure, and then the obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane - 1:2) to obtain 1.48 g of 1,6-anhydro-3,4-dideoxy-3-ethyl-(~-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal as white crystals. The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 1. 03 (3H, t, J=7. 2Hz) ; 2. 03 (1H, m) ; 2. 11 (1H, dqd, J=16. 6, 7. 2, 2. OHz) ; 3. 70 (2H, m) ; 4. 00-4. 10 (3H, m) ; 4. 16 (1H, m) ;
4. 74 (1H, m) ;
5. 19 (1H, s) ; 5. 94 (1H, dt, J=4. 4, 2. OHz) (3) 1.47 g of 1,6-anhydro-3,4-dideoxy-3-ethyl-(~-D-glycero-hexo-3-enopyranos-2-ulose ethylene acetal obtained in the above step (2) was dissolved in 150 ml of dry tetrahydrofuran-water (21). and 2 g of p-toluenesulfonic acid monohyd~'ate was added thereto. The obtained mixture was refluxed under heating for two hours, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was dissolved in 200 ml of ethyl acetate, and the solution was washed three times with 100 ml of a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:2) to obtain 1.1 g of the desired product (Intermediate No. 46). The NMR analytical data of this product are as follows.
2Q~'~80~
1 H N M R (CDC13, 400MHz) : 1. 16 (3H, t, J=7. 6Hz) ; Z. 35 (2H, qd, J=7. 6, 1. 5f(z) 3. 81 (1H, d. J=6. 6Hz) ; 3. 95 (1H, dd, J=6. 6, 4. 6flz) ; 5. 12 (1H. t, J=4.
6Hz) ; 5. 48 1H, s) ; 7. 03(1H, dt. J=4. 6, 1. 5Hz) The following compound was prepared in the same manner as in the above Intermediate Preparation Example 8 and its physical properties will be given.
Intermediate No. 47 1 H N M R (CDC13, 400hfHz) : 0. 90 (3H. t. J=7. 2lfz) : 1. 30-1. 50 (4H, m) ;
2. 17 (111 ddd, J=14. 4, 6. 8, 1. 6Hz) ; 2. 23 (1H, dd, J=14. 4, 6. 8Hz) ; 3. 69 (1H, d, J=6. 8Hz) ; 3.
86 (1H, dd, J=6. 8, 4. 4Hz) ; 4. 98 (1H, t, J=4. 4Hz) : 5. 36 (1H, s) ; 6. 92 (1H, dt, J=4. 4, 1. 6Hz) Preparation of 1.6-anhydro-3,4-dideoxy-3-methoxymethyl-~3 D glycero-hex-3-enopyranos-2=ulose (Intermediate No. 48) ( 1 ) 1. 65 g of 1, 6-anl~.yd-zo-3-bromo-3, 4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal obtained in the above Intermediate Preparation Example 8 (1), was dissolved in 200 ml of dry tetrahydrofuran, and the solution was cooled to -78°C. Then, 5 ml (1.6N) of n-butyl lithium was gradually added thereto, and the mixture was further stirred for 20 minutes. To the obtained reaction mixture, formaldehyde gas was introduced in large excess, and the temperature was raised to room temperature. Termination of the reaction was confirmed by TLC, and then the reaction mixture was filtered through Celite~ to remove the precipitate. The filtrate was concentrated under reduced pressure, and the 2~~'~~~5 obtained syrup crude product was purified by silica gel column chromatography (ethyl aceta-te: hexane = 1:1) to obtain 0.7 g of 1,6-anhydro-3,4-dideoxy-3-hydroxymethyl-(3-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal.
The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 2. 04 (1H, br. s) ; 3. 73 (2H, m) ; 4. 00-4. 20 (SH, m) ;
4. 17 (1H, dd, J=12. 0, 1. 2Hz) ; 4. 79 (1H, m) ; 5. 19 (1H, s) ; 6. 32 (1H, dt, J=4. 8, 1. 2Hz 2 g of p-toluene sulfonic acid monohydrate was added to 150 ml of a methanol solution containing 2.8 g of 1,6-anhydro-3,4-dideoxy-3-hydroxymethyl-~3-D-glycero-hex-3-enopyranos-2-ulose obtained in the above step (1), and the mixture was refluxed under heating for one hour.
Disappearance of the starting material was confirmed by TLC, and then the solvent=was distilled off under reduced pressure. The obtained crude product was purified by ~~
silica gel column chromatography (ethyl acetate: hexane - 1:2) to obtain 0.8 g of the desired product (Intermediate No. 48). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400hiHz) : 3. 40 (3H, s) ; 3. 73 (lf(, d. J=6. 8Hz) ; 3. 89 (lll, dd, J
=6. 8, 4. 4Hz) ; 4. 07 (1H, br, d, J=lSHz) ; 4. 11 (1H, dd, J=14. 4, 1. 6Hz) ;
5. 06 (lli, t, J
=4. 4Hz) ; 5. 36 (1H, s) : 7. 20 (1H, dt, J=4. 4. 1. 6) Now, specific Preparation Examples for the compounds of the formula (I) will be described.
Preparation of 1,6-anhydro-3,4-dideoxy-(3-D-threo-hex-3-20~'~~~5 enopyranose (Compound No. 1) 50 ml of a dry diethyl ether solution containing 20 g of 1,6-anhydro-3,4-dideoxy-/~-D-glycero-hex-3-enopyranos-2-ulose, was gradually dropwise added to 500 ml of a dry diethyl ether suspension containing 3.0 g of lithium aluminum hydride, at 0°C under an inert atmosphere of nitrogen gas. After completion of the dropwise addition, the mixture was immediately returned to room temperature, and stirring was continued for 30 minutes. Disappearance of the starting material was confirmed by thin layer chromatography, and then a small amount of water was added to inactivate an excess amount of lithium aluminum hydride. The mixture was further stirred for 30 minutes, and the reaction mixture was~~filtered through Celite~ to remove the precipitate. ~h~-precipitate was washed a few times with diethyl ether, and the washing solutions were concentrated under reduced pressure together with the filtrate. Precipitated crude crystals were recrystallized from diethyl ether to obtain 14.5 g of the desired product (Compound No. 1). The NMR analytical data and physical properties of this product were as follows.
1 H N M R (CDC13, 400h1Hz) : 3. 73 (1H, dd, J=6. 4, 4. OHz) : 3. 82 (1H, d, J=6. 4Hz) ;
4. 32(1H, br. s) : 4. 65(1H, t, J=4. OHz) : 5. 51 (1H, t, J=2. 2Hz) ; 5.
69(11(, dt, J=10.
0, 2. 2Hz) ; 6. 09 (11i, dd, J=10. 0, 4. OHz) m. p. 69-71°C
20~7~0~
Preparation of 1,6-anhydro-3,4-dideoxy-2-0-isovaleryl-a-D threo-hex-3-enopyranose (Compound No. 2; an isovaleric acid ester of Compound No. 1) 0.7 g of isovaleryl chloride was gradually added to 30 ml of a dry pyridine solution containing 0.5 g of 1,6-anhydro-3,4-dideoxy-(~-D-threo-hex-3-enopyranose obtained in the above Preparation Example 1, at 0°C under an inert atmosphere of nitrogen gas. The mixture was stirred for about 10 minutes. Then, the ice bath was removed, and the mixture was further stirred at room temperature for two hours. To the reaction mixture, a small amount of water was added, and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in 200 ml of ethyl'acetate, and the solution was washed three times with'200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:5) to obtain 0.85 g of the desired product (Compound No. 2) as a colorless liquid. The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400h1Hz) : 0. 97 (6H, d, J=6. 9Hz) : 2. 12 (1H. QQt J=6. 9, 6. 9. 6.
gHz) ; 2. 27 (2H, d, J=6. 9Hz) ; 3. 79 (1H, dd, J=6. 6, 4. OHz) : 3. 97 (1H, d, J=6. 6Hz) ; 4.
68 (1H, t, J=4. OHz) ; 5. 53 (111, br. s) : 5. 61 (1H, dt, J=9. 6. 2. 01(z) :
~. 63 (1H, m) : 6.
19 (lll, ddd, J=9. 6, 4. 0, 1. 2Hz) The following compounds were prepared in the same manner as in the above Preparation Example 2, and their physical properties will be given.
Compound No 3 (Crotonic acid ester of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 1. 95 (3H, dd, J=6. 8, 1. 6Hz) ; 3. 80 (1H, ddd, J=6. 5, 4 . 2, 1. 2Hz) ; 3. 98 (1H, d, J=6. 5Hz) ; 4. 69 (111, t, J=4. 2Hz) : 5. 55 (1H, m) ; 5. 65 (1H, d t, J=9. 2, 2. 3Hz) ; 5. 66 (1H, m) ; 5. 92 (1H, dq, J=15. 5, 1. 6Hz) ; 6. 19 (1H, ddt, J=9. 2.
4. 2, 1. 2Hz) ; 7. 04 (1H, dq, J=15. 5, 6. 8Hz) Com ound No 4 (Cyclohexanoic acid ester of Compound No. 1 1 H N M R (CDC13, 400D1Hz) : 1. 15-1. 30 (3H, m) ; 1. 43 (211, m) ; 1. 61 (11I, m) ; 1. 7 3 (2H, m) ; 1. 90 (2H, m) ; 2. 37 (1H, tt, J=11. 4, 3. 3llz) ; 3. 76 (1H, ddd.
J=6. 5, 4. 1, 1. 2 Hz) ; 3. 94 (lli, d, J=6. 5Hz) ; 4. 66 (lli, t, J=4. lltz) ; 5. 47 (1H, m) ;
5. 58 (1H, dt, J=9.
7, 2. 2Hz) : 5. 60 (1H, m) ; 6. 17 (1H, ddd,=J=9. 7, 3. 7, 1. 2Hz) Compound No 5 (Benzoic aoid=ester of Compound No. 1) 1 H N M R (CDC13. 400MHz) : 3. 84 (1H, ddd, J=6. S, 4. 2. 1. 1Hz) : 4. 03 (111, d. J=6.
5Hz) ; 4. 74 (1H, t, J=4. 2Hz) ; 5. 74 (2H, m) ; 5. 78 (11t, m) ; 6. 26 (111.
dd. J=9. 2, 4. 2Hz 7. 44 (2H, t, J=7. SHz) ; 7. 57 (1H, tt, J=7. 5, 1. 5Hz) ; 8. 09 (2H, m) m. p. 116-I1T°~C
Compound No 6 (n Hexanoic acid ester of Compound No. 1) 1 H N M R (CDC13, 400h1Hz) : 0. 88 (3H, t, J=6. 6Hz) ; 1. 32 (4H, m) : 1. 64 (2H, m) ;
2. 38 (2H, t, J=7. 7Hz) ; 3. 80 (1H, m) ; 3. 98 (1H, d, J=7. 1Hz) ; 4. 68 (1H, t, J=4. 8llz) ;
5. 52 (1H, br. s) ; 5. 61 (1H, m) ; 5. 64 (1H, br. s) ; 6. ~19 (1H, dd, J=11.
1, 4. 8liz) ~0~'~~~~_ Compound No 7 (Palmitic acid ester of Compound No. 1) 1 H N M R (CDC13, 400NHz) : 0. 88 (3H, t, J=6. 8Hz) ; 1. 25 (24H, br. s) ; 1.
60-1. 7 0 (2H, m) ; 2. 38 (2H, dd, J=7. 6, 6. 8Hz) ; 3.. 80 (1H, ddd. J=6. 4, 4. 0. 1.
OHz) ; 3. 98 (1H, d, J=6. 4Hz) ; 4. 69 (1H, t, J=4. OHz) ; 5. 52 (1H, m) ; 5. 62 (1H, dt, J=10.
0, 2. 2Hz) ; 5.
64 (1H, m) ; 6. 20 (1H, m) m. p. 39-41°C
20 --17. 4 (c=0. 402, chloroform ) D
Compound No 109 (Palmitic acid ester of Compound No. 103) 1 H N M R (CDC13, 400MHz) : 0. 88 (3H, t, J=6. 8Hz) ; 1. 25 (24H, br. s) ; 1.
63 (2H, quin, J=7. 2Hz) ; 2. 35 (2H, t, J=7. 2Hz) ; 3. 72 (2H, m) ; 4. 76 (1H, t, J=4.
4Hz) ; 4. 78 1H, br. d. J=4. OHz) ; 5. 53 (1H, m) ; 5. 78 (1H, ddd. J=9. 6, 4. 0, 2. OHz) ;
6. 31 (1H, ddd.
J=9. 6, 4. 4, 0. 8Hz) Compound No 8 (Oleic acid ester of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 0. 90 (3~1, t. J=7. 6Hz) : 1. 35-1. 23 (20H, m) ;
1. 64 (2 H, m) ; 1. 98 (4H, m) ; 2. 38 (2H, t, J=7. 7Hz) ; 3. 79 (llf. ddd. J=6. 5, 4.
2, 1. 5llz) ; 3. 97 (llt, d, J=fi. 5Hz) ; 4. 68 (1H, t, J=4. 211z) ; 5. 85 (21t, m) : 5. 52 (1 H, br. s) ; 5. 62 (1 fl, d t, J=9. 9. 1. 6Hz) ; 5. 63(1H, m) ; 6. 29(1H, dd, J=9. 9, 4. 2Hz) Com ound No~ 9 (Acetic acid ester of Compound No. 1) 1 H N M R (CDCI3. 400MHz) : 2. 14 (3H, s) : 3. 80 (1H, ddd, J=6. 8, 4. 4, 0.
8Hz) : 3.
98 (1H, d, J=6. 8liz) : 4. 69 (1H, t, J=4. 4Hz) : 5. 52 (1H. m) : 5. 63 (1H, m) ; 5. 65 (1H, d, J=2. 8Hz) ; 6. 20(1H, ddt. J=9. 2, 4. 4. 0. 8Hz) ."~.~
Compound No 10 (a-chloroacetic acid ester of Compound No. 1 1 H N M R (CDC13, 400b1Hz) :3~ 81(lH,ddd,a=6. 8, 4. 0,1. O~z);~, 97 (1H, d, J=6. 8H
z) ; 4. 13 (1H, d, J=15. 2Hz) ; 4. 17 (1H, d, J=15. 2Hz) ; 4. 71 (11i, t, J=4.
OHz) ; 5. 59 (1 H, m) ; 5. 64 (1H, dt, J=10. 0, Z. 2Hz) ; 5. 67 (1H, t, J=2. 2Hz) ; 6. 25 (1H, ddd, J=10. 0, 4 . 0. 1. OHZ) ( a ~ 20D =-43. 1 (c=0. 627, chloroform ) Compound No 11 (0- -acetylsalicylic acid ester of Compound N_ 01 ) 1 H N M R (CDC13, 400MHz) : 2. 36 (3H, s) ; 3. 83 (lli, ddd. J=6. 8, 4. 4. 1.
6Hz) : 3.
98 (1H, d, J=6. 8Hz) ; 4. 72 (1H, t, J=4. 4Hz) ; 5. 72 (3H, m) ; 6. 24 (1H, ddd, J=10. 8, 4. 4 1. 6Hz) ; 7. 10 (1H, dd, J=7. 6, 1. 2Hz) ; 7. 31 (1H, td, J=7. 6, 1. 2Hz) ; 7.
56 (1H, td, J=
7. 6, 1. 2Hz) ; 8. 08 (1H, dd, J=7. 6, 1. 2Hz) PREPARATION EXAMPLE 3 -' Preparation of 1,6-anhydre-2;0-decanoyl-3,4-dideoxy-a-D-threo hex-3-enopyranose (Compound No. 12; decanoic acid ester of Compound No. 1) 0.6 g of decanoic acid, 0.97 g of dicyclohexylcarbodiimide and 28 mg of N,N-dimethylaminopyridine were added to 50 ml of a dry methylene chloride solution containing 0.3 g of 1,6-anhydro-3,4-dideoxy-(3-D-threo-hex-3-enopyranose obtained in the above Preparation Example 1, while stirring under an inert atmosphere of nitrogen gas. The reaction mixture was stirred for 12 hours at room temperature.
Then, the formed precipitate was filtered off by Celite~, and the filtrate was concentrated under reduced pressure.
2~7~~5 The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:3) to obtain 0.38 g of the desired product (Compound No.
12). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 0. 87 (3H, t, J=6. 8Hz) : 1. 26 (12H, m) ; 1. 64 (2H, qui n. . J=7. 5Hz) ; 2. 36 (1H, dt, J=16. 8, 7. 5Hz) ; 2. 40 (1H, dt, J=16. 8, 7.
5Hz) ; 3. 97 (1H
ddd, J=6. 4, 4. 0, 1. OHz) ; 3. 98 (1H, d, J=6. 4Hz) ; 4. 69 (1H, t. J=4. OHz) ; 5. 52 (1H, m 5. 63 (1H, dt, J=9. 6. 2. ZHz) ; 5. 65 (1H, m) ; 6. 19 (1H, ddd, J=9. 6, 4. 0, 1. OHz) The following compounds were prepared in the same manner as in the above Preparation Example 3, and their physical properties will be given.
Compound No 13 (6-Bromohexanoic acid ester of Compound NO. 1 1 H N M R (CDC13, 400MHz) : 1. 49 (Z)I; tt, J=8. 0, 6. 8Hz) ; 1. 68 (2H, quin.
J=8. OH
z) ; 1. 88 (2H, quin. J=6. 8Hz) ; 2. 41 (2H, td. J=8. 0, 1. 6Hz) ; 3. 40 (2H, t, J=6. 8Hz) ;
3. 79 (1H, ddd, J=6. 8, 4. 4, 1. 6Hz) : 3. 97 (1H, d, J=6. 8Hz) ; 4. 69 (1H, t, J=4. 4Hz) ; 5.
52 (1H, m) ; 5. 62 (1H, dt, J=10. 0, Z. OHz) ; 5. 64 (1H, m) ; 6. 20 (lH, ddd.
J=10. 0, 4. 4, 1 . 6Hz) ' Com aund No. 14 2-Thio henecarbox lic acid ester of Compound No. l~
1 H N M R (CDC13, 400MHz) : 3. 83 (1H, ddd. J=6. 8, 4. 5, 1. OHz) ; 4. 02 (1H, d. J=6.
8Hz) ; 4. 73 (1H, t, J=4. 5Hz) ; 5. 69 (1H, m) ; 5. 75 (1H, dt, J=9. 9, 2.
3Hz) ; 5. 77 (1H, m 6. 25 (1H, ddd, J=9. 9, 4. 5. 1. OHz) ; 7. 11 (1H, dd, J=4. 8. 3. 8Hz) ; 7. 59 (1H, dd, J=4 . 8. 0. 9llz) ; 7. 86 (1H, dd, J=3. 8, 0. 9Hz) m. p. 69-71°C
Compound No 15 (Nicotinic acid ester of Compound No. 1) 1 H N M R (CDC1~, 400h1Hz) : 3. 84 (1H, ddd, J=6. 4, 4. 4, 1. 2Hz) ; 4. 02 (1H, d, J=6.
4Hz) ; 4. 75 (1H, t, J=4. 4Hz) ; 5. 74 (2H, m) ; 5. 77 (1H, dt, J=9. 6, 2.
4Hz) ; 6. 29 (1H, d dd; J=9. 6, 4. 4, 1. 2Hz) ; 7. 40 (1H, ddd, J=8. 0, 5. 0, 1. 2Hz) ; 8. 35 (1H, dt, J=8. 0, 1. 2H
z) ; 8. 79 (1H, dd, J=5. 0, 1. 2Hz) ; 9. 27 (1H, br. d, J=1. Zlfz) m. p. 76-81°C
Compound No 16 (p-Chlorobenzoic acid ester of Compound No. 1 1 H N M R (CDC13, 400MHz) : 3. 83 (1H, ddd, J=6. 4, 4. 0, 1. 2Hz) ; 4. 02 (1H, d, J=6.
4Hz) ; 4. 74 (1H, t, J=4. OHz) : 5. 72 (1H, m) ; 5. 74 (1H, dt, J=9. 2, 2.
4Hz) ; 5. 76 (1H, m 6. 26 (1H, ddd, J=9. 2, 4. 0, 1. 2Hz) ; 7. 41 (2H, dt, J=8. 8, 2. OHz) ; 8. 02 (2H, dt, J=8 8, 2. OHz) m. p. 57-59°C
Compound No 17 (2-Furancarlioxylic acid ester of Compound No. 1 1 H N M R (CDC13, 400MHz) : 3. 82 (1H, dd, J=6. 4, 4. 4Hz) : 4. OZ (1H, d, J=6~. 4Hz) ;
4. 72 (1H, t, J=4. 4Hz) ; 5. 71 (1H, m) ; 5. 72 (1H, m) ; 5. 75 (111, m) ; 6.
25 (1H, dd. J=9.
6, 4. 4Hz) ; 6. 51 (1H, dd, J=3. 4, 2. OHz) ; 7. 26 (1H, dd, J=3. 4, 1. OHz) ;
7. 59 (1H, m) m. p. 86-88°C
Compound No. 18 (Cinnamic acid ester of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 3. 83 (1H, ddd, J=6. 8, 4. 2, 1. 6Hz) ; 4. 02 (1H, d, J=6.
SHz) ; 4. 73 (1H, t, J=4. 2Hz) ; 5. 66 (.1H, m) : 5. 71 (1H, dt, J=10. 0, 2.
2Hz) : 5. 73 (1H.
m) ; 6. 24 (1H, ddd, J=10. 0, 4. 4, 1. 6Hz) ; 6. 54 (1H, d, J=16. OHz) ; 7. 39 (3H, m) ; 7. 53 (2H, m) ; 7. 25 (1H, d, J=16. OHz) m. p. 147-153°C
20~78~~
Compound No 19 (Anthranic acid ester of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 3. 83 (1H, ddd. J=6. 8, 4. 2, 0. 8Hz) ; 4. 02 (1H.
d, J=6.
8Hz) ; 4. 73 (1H, t. J=4. 2Hz) ; 5. 71 (1H, m) : 5. 75 (2H, m) ; 6. 25 (1H, ddd, J=10. 2, 4. 2 0. 8Hz) ; 6. 66 (1H, ddd, J=8. 4, 6. 8, 1. 6Hz) ; 6. 67 (1H, br. d, J=8. 4Hz) ; 7. 28 (1H, dd d, J=8. 4, 6. 8, 1. 6Hz) ; 7. 94 (1H, dd, J=8. 4, 1. 6Hz) m. p. 95-100 °C
Com ound No 20 (Arachidic acid ester of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 0. 88 (31i, t, J=7. 211z) ; 1. 26 (3211, br. s) ;
1. 65 (2H.
m) : 2. 38 (2H, t. J=7. 8Hz) ; 3. 80 (1H. ddd. J=6. 4, 4. 3. 1. OHz) ; 3. 98 (1H, d, J=6. 4llz) , 4. 69 (1H, t, J=4. 3Hz) ; 5. 52 (1H, m) ; 5. 62 (1H, dt, J=9. 6, 2. 2Hz) ;
5. 64 (1H, mY; 6 . 19 (1H, dddd, J=9. 6, 4. 3, 1. 2, 1. OHz) Compound No 50 (o-Methylbenzoic acid ester of Compound No. 1 1 H N M R (CDC13, 400MHz) : 2. 61 E~H, s) ; 3. 83 (1H, m) ; 4. O1 (1H, d, J=6.
4Hz) ;
4. 73 (1H, t, J=4. 1Hz) : 5. 72 (1H, m) ; 576 (1H, dt, J=9. 5, 2. 2Hz) ; 5. 79 (1H, m) ; 6. 2 5 (1H, dd, J=9. 5, 4. 1Hz) ; 7. 24 (2H, m) ; 7. 40 (1H, td,. J=7. 4, 1. 4Hz) ;
7. 97 (1H, dd, J=
8. 3, 1. 4Hz) P_re aration of 1,6-anhydro-3,4-dideoxy-2-0-methoxycarbonyl Q D-threo-hex-3-enopyranose (Compound No.
_21, methyl carbonate ester of Compound No. 1) 0.33 g of methyl chlorocarbonate was gradually added to 30 ml of a dry pyridine solution containing 0.3 g of 1,6-anhydro-3~4-dideoxy-~3-D-threo-hexo-3-enopyranose under an inert atmosphere of nitrogen gas. The reaction mixture was stirred at room temperature for 12 hours, and 0.33 g of methyl chlorocarbonate was further added 2~~'~~a~
thereto. The mixture was stirred for 30 minutes. A
small amount of water was added thereto to inactivate methyl chlorocarbonate. Then, the solvent was distilled off under reduced pressure. To the residue, 200 ml of ethyl acetate was added, and the mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:3) to obtain 0.33 g of the desired product (Compound No. 21). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 3. 80 (1H, m) : 3. 81 (3H, s) ; 3. 96 (1H, d, J=6.
8Hz) 4. 70 (1H, t, J=4. 411z) ; 5. 37 (1H, m)~ 5:-68 (1H, dt, J=10. 0, 2. Olfz) ;
5. 71 (lli, t. J=2.
2Hz) ; 6. 23 (1H, ddd, J=10. 0. 4. 4, 1. ZHz) The following compounds were prepared in the same manner as in the above Preparation Example 4, and their physical properties will be given.
Compound No 22 (Phenyl carbonate ester of Compound No.
1 H N M R (CDC13, 400MHz) : 3. 85 (1H, ddd, J=6. 8. 4. 3, 1. 3Hz) ; 4. 02 (1H, d, J=6.
8Hz) ; 4. 74 (1H, t, J=4. 3Hz) ; 5. 47 (111, m) ; 5. 77 (1H, dt, J=9. 3, 2.
4Hz) ; 5. 79 (1H, m 6. 29 (1H, ddt, J=9. 3, 4. 3. 1. 3llz) ; 7. ZO (2H, m) : 7. 26 (1H, m) ; 7. 39 (2H, m) m. p. 98-99°C
Compound No 26 (Phenyl thiocarbonate ester of Com op and No. 1) 2~3~'~~~
1 H N M R (CDC13, 400MHz) : 3. 86 (1H, ddd, J=6. 8, 4. 0, 1. OHz) ; 4. 05 (1H.
d. J=6.
8Hz) ; 4. 76 (1H, t, J=4. OHz) : 5. 84 (1H, dt, J=10. 0, 2. 4Hz) ; 5. 86 (1H, m) ; 6. 05 (1H, m) : 6. 31 (1H, ddd, J=10. 0, 4. 0, 1. OHz) : 7. 31 (2H, m) ; 7. 30(1H, tt, J=7. 6, 1. 1Hz) ;
7. 42 (2H, t t, J=7. 6, 2. 2Hz) Pre aration of 1,6-anhydro-3,4-dideoxy-2-0-_L_.~...,,_~_"_+.r"-Ar,-t,PY-~-enoovranose (Compound No_ phenyic:,at uai«~ r y N
23 phenyl carbamic acid ester of Compound No. 1) 0.56 g of phenyl isocyanate was added at room temperature to 30 ml of a dry toluene solution containing 0.3 g of 1,6-anhydro-3,4-dideoxy-/3-D-threo-hex-3-enopyranose under an inert atmosphere of nitrogen gas.
Further, 0.1 ml of triethylamine was added thereto, and the reaction mixture was refluxed under heating for two hours. Completion of the~reaction was confirmed by thin layer chromatography,~and then the solvent was immediately distilled off under reduced pressure to obtain a syrup crude product. This crude product was purified by silica gel chromatography (ethyl acetate:
hexane = 1:3) to obtain 0.5 g of the desired product (Compound No. 23). The NMR analytical data of this product are as follows.
1 H N M R (CDC13. 400MHz) : 3. 83 (11f, ddd, J=7. 6. 5. 2, 1. 9Hz) ; 3. 99 (111, d, J=7.
611z) : 4. 73 (lil, t, J=S. 2, Hz) ; 5. 57 (1H, m) ; 5. 71 (111, m) ; 5. 73 (1H, dt, J=10. 0, 2. 7 Hz) ; 6. 23 (11(, ddd, J=10. 0, 5. 2, 1. 9Hz) ; 6. 83 (1H. br. s) ; 7. 08 (111, t t, J=7. 6, 1. 0!1 z) ; 7. 32 (2H, t, J=7. 6Hz) ; 7. 37 (2H, d, J=7. 611z) m. p. 107-109°C
Preparation of 1,6-anhydro-3,4-dideoxy-2-0-methylthiocarbamoyl-Q-D-threo-hex-3-enopyranose (Compound No 24, methyl thiocarbonate ester of Compound No. 1) 0.4 g of methyl thioisocyanate was added to 30 ml of a dry toluene solution containing 0.35 g of 1,6-anhydro-3,4-dideoxy-~3-D-threo-hex-3-enopyranose under an inert atmosphere of nitrogen gas. Then, sodium hydride (60%
dispersion in mineral oil, 1.3 equivalent) was gradually added thereto. After confirming the termination of the generation of hydrogen (from 5 to 10 minutes), the stirring was further continued for one hour. Completion of the reaction was confirmed by thin layer chromatography, and then a small amount of water was added to inactivate sodiu~a hydride. Then, the formed precipitate was removed by filtration with Celite~-anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 2:3) to obtain 0.45 g of the desired product (Compound No. 24). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400hiHz) : 2. 92 (0. 9H. d, J=4. 6Hz) : 3. 07 (2. 1H, d.
J=4. 6Hz) ;
3. 79 (1H, m) ; 3. 94 (0. 7H, d. J=6. 5Hz) ; 3. 97 (0. 3H, d. J=6. 5Hz) ; 4.
70 (0. 7H, t. J=3.
7Hz) ; 4. 71 (0. 3H, t, J=3. 7Hz) : 5. 72 (21i, m) : 6. 19 (2H. m) ; 6. 61 (0.
7H, br. s) : 6. 7 9 (0. 3H, br. s) The following compound was prepared in the same manner as in the above Preparation Example 6, and its physical properties will be given.
Compound No 25 (N-tert-butyl carbamate of Compound No-1 ) 1 H N M R (CDC13, 400h1Hz) : 1. 31 (9H, s) ; 3. 79 (lH,.ddd, J=6. 4, 4. 4. 1.
5Hz) : 3.
95 (1H, d, J=6. 4Hz) ; 4. 68 (1H, t, J=4. 4Hz) ; 4. 87 (1H, br. s) ; 5. 41 (1H, br. s) : 5. 65 (1H, m) ; 5. 66 (1H, dt, J=9. 6, 2. 2Hz) ; 6. 16 (1H, ddd, J=9. 6. 4. 4, 1.
5Hz) m. p. 113-115°C
Pre aration of 1,6 anhydro-3,4-dideoxy-2-C-vinyl-/3-D-threo hex 3 enopyranose (Compound No. 27) 9.5 ml (1 mol) of vinyl magnesium bromide was gradually added to 50 m1 of a dry tetrahydrofuran solution containing 1 g of ~;6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ti~.ose under stirring at 0°C
under an inert atmosphere of nitrogen gas. 30 minutes ~~
later, the ice bath was removed, and stirring was further continued for 30 minutes at room temperature. Completion of the reaction was confirmed by thin layer chromatography, and then a small amount of water was added to inactivate any excess Grignard reagent. Then, the solvent was distilled off under reduced pressure.
The obtained crude product was dissolved in 200 ml of ethyl acetate and washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the 2~'~~~
obtained syrup product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:2) to obtain 0.9 g of the desired product (Compound No. 27). The NMR
analytical data of this product are as follows.
1 H N M R (CDC13, 400hiHz) : 3. 73 (1H, dd. J=6. 4, 3. 9Hz) ; 3. 82 (1H, d, J=6. 4Hz) 4. 68 (1H, t, J=3. 9Hz) : 5. 19 (1H, br. s) ; 5. 26 (1H, dt, J=10. 5, 1. 3Hz) ; 5. 36 (1H, dt J=17. 7, 1. 3Hz) : 5. 53 (1H, dt, J=9. 4, 1. 3Hz) ; 5. 92 (1H, ddd, J=17. 7, 10. 5. 1. OHz) ;
6. 09 (1H, dd, J=9. 9, 3. 9Hz) The following compounds were prepared in the same manner as in the above Preparation Example 7, and their physical properties will be given.
Compound No. 28 1 H N M R (CDC13. 400MHz) : 1. 26 (3H, s) : 3. 69 (1H, dd. J=7. 0, 4. 6Hz) :
3. 76 (1H
d, J=7. OHz) : 4. 62 (1H, t, J=4. 6Hz) : 5-17 (1H, d, J=2. 21(z) : 5. 67 (1H, dd, J=10. 0, 2 . 2Hz) : 5. 94 (1H, dd, J=10. 0. 4. 6Hz)~
Compound No. 29 1 H N M R (CDC13, 400MHz) : 2. 69 (1H, s) : 3. 76 (1H, dd, J=6. 8, 4. 4Hz) :
3. 82 (111 d, J=6. 8Hz) ; 4. 73(1H, t, J=4. 4Hz) ; 5. 49 (1H, d, J=2. Ollz) ; 5. 75 (111, dd, J=9. 8. 2.
OHz) : 6. 12 (1H, dd, J=9. 8, 4. 4liz) m~ p~ 64-67°C
~ 20D =-214.8 (c=0.433, chloroform ) Compound No. 30 1 H N M R (CDC13, 400MHz) : 0. 90 (3H, t, J=7. OHz) : 1. 35-1. 50 (4H, m) ; 1.
60-1.
75 (2H, m) ; 3. 70 (1H, dd. J=6. 8, 4. 4Hz) ; 3. 77 (1H, d, J=6. 8Hz) ; 4. 64 (1H, t, J=4. 4Hz ) ; 5, 22 (1H, d, J=2. OHz) ; 5. 61 (1H, dd, J=10. 0, 2. OHz) : 6. 00 (1H, dd, J=10. 0, 4. 4Hz m. p. 31-33°C
Compound No. 31 1H N M R (CDC13, 400MHz) : 0. 97 (3H, t, J=7. 2Hz) ; 1. 55 (2H, six, J=7. 2Hz) ; 2.
23 (2H, t, J=7. 2Hz) ; 2. 26 (1H, br. s) ; 3. 74 (1H, dd, J=6. 8, 4. 4Hz) ; 3.
80 (1H, d, J=6.
8Hz) ; 4. 71 (1H, t, J=4. 4Hz) ; 5. 44 (1H, d, J=2. 4Hz) ; 5. 74 (1H, dd,J=10.
0,2. 4Hz); 6.
05 (1H, dd, J=10. 0. 4. 4Hz) m. p. 43-46°C
Preparation of 2-0-acetyl-1,6-anhydro-3 4-dideox~-2-C-methyl a D threo-hex-3-enopyranose (Compound No. 32) 2.4 ml (1.5 mol) of methyl lithium was gradually added to 30 ml of a dry tetrahydrofuran solution containing 0.3 g of 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose under stirring at 0°C under an inert atmosphere of nitrogeri-gas. Completion of the reaction was confirmed by=tR~.n layer chromatography, and then 0.25 ml of acetyl chloride was added to the reaction mixture. The ice bath was removed, and the reaction solution was returned to room temperature and further stirred for one hour. The solvent was distilled off under reduced pressure. To the residue, 200 ml of ethyl acetate was added. The mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:5) to obtain 0.29 g of the desired 2~~'~~~~
product (Compound No. 32). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 1. 59 (3H, s) ; 2. OS (311, s) : 3. 76 (1 fl, dd, J=6. 8, 4. 4 Hz) ; 3. 89 (1H, d, J=6. 8Hz) ; 4. 63 (1H, t, J=4. 4Hz) ; 5. 78 (1H, dd, J=9.
6, 1. 6Hz) ; 5.
89 (1H, d, J=1. 6Hz) ; 6. 06 (1H, dd, J=9. 6, 4. 4Hz) 20D =-114. 7 (c=0. 654, chloroform ) The following compound was prepared in the same manner as in the above Preparation Example 8, and its physical properties will be given.
Compound No. 33 .
1 H N M R (CDC13, 400hIHz) : 0. 88 (3H, t, J=7. 2Hz) ; 1. 25 (24H, br. s) ; 1.
57 (2H, m) ; 1. 59 (3H, s) ; 2. 29 (2H, td, J=8. 0, 1. OHz) ; 3. 76 (1H, dd, J=6. 4, 4. 4Hz) ; 3. 87 (1 H, d, J=6. 4Hz) ; 4. 62 (1H, t, J=4. 4Hz) ;: 5. 77 (1H, dd, J=9. 6, 2. OHz) ;
5. 90 (1H, d. J=2 . OHz) ; 6. O6 (1H, dd, J=9. 6, 4. 4Hz) _ .
Preparation of 1,6-anhydro-3,4-dideoxy-/3-D-erythro-hex-3-enopyranose (Compound No. 103) (1) 15 g of p-toluenesulfonyl chloride was added to 50 ml of a dry pyridine solution containing 1,6-anhydro-3,4-dideoxy-(~-D-threo-hex-3-enopyranose obtained in the above Preparation Example 1, at room temperature under an inert atmosphere of nitrogen gas. The mixture was stirred for 12 hours, and then a small amount of water Was added thereto. Then, the mixture was extracted with 300 ml of toluene. The extract was washed once with 200 ml of 1N hydrochloric acid and then washed three times with 200 ml of a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:1) to obtain 10.5 g of 1,6-anhydro-3,4-dideoxy-2-O-(p-toluene)sulfonyl-(3-D-threo-hex-3-enopyranose (Compound No. 46). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400M1iz) : 2. 45 (3H, s) ; 3. 76 (1H, ddd, J=6. 8. 4. 0. 1.
2Hz) : 3.
94 (111, d, J=6. 8Hz) ; 4. 65 (1H, t, J=4. Oliz) ; 5. 22 (1H, m) ; 5. 45 (1H, t. 1=2. 4Hz) ; 5.
52(11(, dt, J=10. 4, 2. 4Hz) ; 6. 19(1H, ddd, J=10. 4, 4. 0, 1. 211z) ; 7.
35(2H, br. d, J=8.
4Hz) : 7. 83(2H, dt. J=8. 4, 2. OHz) m. p. 81-83°C
(2) 10.5 g of 1,6-anhydr~-3,4-dideoxy-2-0-(p-toluene)sulfonyl-~3-D-threo-hex-3-enopyranose obtained in the above reaction, was dissolved in 100 ml of dried dimethylformamide, and 6 g of sodium benzoate was added thereto. Thd mixture was refluxed under heating for 30 minutes. The solvent was distilled off under reduced pressure, and 200 ml of water was added to the residue.
The mixture was extracted with 300 ml of chloroform. The organic layer was washed once with 200 ml of a saturated sodium hydrogencarbonate aqueous solution and then washed twice with 200 m1 of a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off ~Q8'~~Q~
under reduced pressure, and then the obtained syrup crude product was dissolved in 100 ml of dry methanol. Then, 2 ml of a methanol solution of sodium methoxide (28 wt$) was added thereto. The mixture was stirred for 25 minutes at room temperature. The reaction solution was neutralyzed with a 20~ citric acid aqueous solution and then filtered through Celite~ to remove the precipitate.
The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate.~ hexane = 1:2) to obtain 1.1 g of the desired product (Compound No. 103).
The NMR analytical data of this product are as follows.
1 H N M R (CDC13. 400MHz) : 3. 50 (1H, br. d, J=3. 6Hz) ; 3. 64 (2H, m) ; 4.
69 (1H, d dd. J=5. 0. 4. 0. 1. 8Hz) ; 5. 53(1H, t. J=~. 8Hz) ; 5. 82(1H, ddd. J=9. 6. 4.
0. 1. 8Hz) ; 6 . 19 (1H, ddd. J=9. 6. 5. 0. 0. 8Hz) -m. p. 50-54°C
Preparation of 1,6 anhydro-3 4-dideoxy-2-O-methyl-a-D-threo hex 3 enopyranose (Compound No. 41) 0.3 g of 1,6-anhydro-3,4-dideoxy-(3-D-threo-hex-3-enoyranose was gradually added to 30 ml of a dry tetrahydrofuran solution of sodium hydride (60~
dispersion in mineral oil, 1.3 equivalent) under an inert atmosphere of nitrogen gas. Stirring was continued for 15 minutes, and then 0.45 ml of methyl iodide was added.
This reaction solution was stirred at room temperature for 12 hours. A small amount of water was added to inactivate excess sodium hydride, and the reaction solution was concentrated under reduced pressure. To the obtained syrup crude product, 200 ml of ethyl acetate was added, and the mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. Then, the mixture was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained syrup product was purified by silica gel column chromatography (ethyl acetate: hexane = 2:3) to obtain 0.25 g of the desired product (Compound No. 41). The NMR
analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 3. 44 (3H, s) ; 3. 74 (1H, ddd, J=6. 7, 4. 1, 1.
3Hz) ; 3.
91 (1H, d, J=6. 7Hz) ; 4. 07 (1H, m) ; 4. 62 (1H, t, J=4. 1Hz) ; 5. 61 (1H, t, J=2. 2Hz) ; 5.
72 (1H, dt, J=9. 8, 2. 2Hz) ; 6. 09 (1H, ddd: J=9. 8, 4. 1, 1. 3Hz) The following compounds';were prepared in the same manner as in the above Preparation Example 10, and their physical properties will be given.
Compound No 40 (n-Butyl ether of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 0. 92 (3H, t, J=7. 2Hz) ; 1. 39 (2H, m) ; 1. 60 (2H, m) ;
3.57(lH,dt,J=9.2,6.8Hz);3. 60 (1H, dt, J=9. 2. 6. 8Hz) ; 3. 77 (1H, ddd, J=6.
8, 4. 0, 1 . 2Hz) ; 3. 97 (1H, d, J=6. 8Hz) ; 4. 17 (1H, m) ; 4. 63 (1H, t, J=4. OHz) ;
5. 62 (1H, t. J=2 . 2Hz) ; 5. 72(1H, dt, J=9. 6, 2. 2Hz) ; 6. 08 (1H, ddd, J=9. 6. 4. 0, 1. 2Hz) Compound No 48 (Benzyl ether of Compound No. 1) 1 H N M R (CDC13, 900h1Hz) : 3. 78 (1H, ddd, J=6. 4, 4. 0, 1. 2Hz) : 3. 98 (1H, d. J=6.
4Hz) : 4. 28 (11I, m) ; 4. 63 (1H, t, J=4. OHz) ; 4. 66 (lfl, d, J=12. OHz) ;
4. 70 (1H, d. J=1 2. OHz) ; 5. 56 (1H, t, J=2. 4Hz) : 5. 71 (1H. dt. J=10. 0. 2. 4llz) : 6. 10 (1H. ddd. J=10. 0 4. 0. 1. 2Hz) ; 7. 29 (1H, tt, J=6. 8, 2. OIIz) ; 7. 34 (2H, m) ; 7. 38 (2H, m) 2a87~~
Preparation of 1.6-anhydro-3,4-dideoxy-2-O-(16-hydroxy)hexadecanoyl-a-D-threo-hex-3-enopyranose (Compound No. 49) 50 ml of a dry tetrahydrofuran solution containing 1 g of 16-hydroxyhexadecanoic acid, 1.1 g of tert-butyldimethylsilyl chloride and 0.75 g of imidazole, was stirred at room temperature for 12 hours under an inert atmosphere of nitrogen gas. The solvent was distilled off under reduced pressure, and then 200 ml of ethyl acetate was added. The mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrup product. Then, 40 ml of diethyl ether. 30 ml of methanol and 30 ml of 1N
hydrochloric acid were added thereto, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and then 200 ml of ethyl acetate was added. The mixture was washed once with 200 ml of a saturated sodium hydrogencarbonate aqueous solution and then washed twice with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrup product. This product was purified by silica gel column chromatography (ethyl acetate: hexane - 1:1) to obtain 1.4 g of 16-tert-butyldimethylsilyloxyhexadecanoic acid.
A condensation reaction of 16-tert-butyldimethylsilyloxyhexadecanoic acid obtained by the above reaction and Compound No. 1, was conducted in the same manner as in the above Preparation Example 3. Post-treatment was conducted by a conventional method, and then purification was conducted by silica gel column chromatography (ethyl acetate: hexane = 1:7). The product was dissolved in 50 ml of dry tetrahydrofuran, and 3 ml of a tetrahydrofurarl solution of 1N tetrabutyl ammonium fluoride, was added thereto at room temperature.
The mixture was stirred for 12 hours. The solvent was distilled off under reduced=pressure, and then 200 ml of ethyl acetate was added. =Tt~~ mixture was washed twice with 200 ml of a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was again distilled off under reduced pressure to obtain a syrup product. This product was purified by silica gel column chromatography (ethyl acetate: hexane - 2:3) to obtain 0.59 g of the desired product (Compound No. 49). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400htHz) : 1. 20-1. 37 (22H, m) : 1. 57 (211, quin. , J=T.
OHz) ; 1.
64 (2H, quin. , J=7. OHz) ; 2. 38 (21i, t. J=7. 4Hz) : Z. 64 (2H, td, J=5. 6.
5. 6Hz) : 3. 80 1H, ddd, J=6. 6. 4. 1, 1. lltz) ; 3. 98(1H, d, J=6. 611z) ; 4. 69(111, t. J=4.
1Hz) ; 5. 52(11( m) ; 5. 62(1H, dt, J=9. 5, 2. 1Hz) ; 5. 64(1H, m) ; 6. 20(1H, ddt, J=9. 5, 4.
1. 1. lllz) °
~.....
The following compounds were prepared in the same manner as in the above Preparation Example 1 or 2, and their physical properties will be given.
1 6-anhydro-3,4-dideoxy-3-methyl-~-D-threo-hex-3-enopyranose (Compound No. 51) 1 H N M R (CDC13, 400~t11z) : 1. 72 (3H, m) ; 2. 03 (11I, d, J=12. OIIz) : 3.
71 (1H, dd, J=6. 4. 4. 4Hz) ; 3. 78 (1H, d. J=6. 4Hz) ; 4. 11 (1H, m) ; 4. 60 (1H, t, J=4.
4Hz) ; 5. 51 (1 H, d. J=2. 8Hz) ; 5. 80 (1H, dd. J=4. 4,1, fiHz) m. p. 62. 5-64°C
1 6-anhydro-3,4-dideoxy-3-ethyl-!3-D-threo-hex-3-enopyranose (Compound No. 95) 1 H N M R (CDC13, 400h1Hz) : 1. 02 (3H, t, J=7. 21(z ) ; 1. 57 (1H, br. s) ;
2. 12 (2H, m 3. 73 (1H, dd, J=6. 0, 4. 4Hz) ; 3. 78 (1H, d, J=6. OHz) ; 4. 21 (1H, d, J= 3.
ZHz) ; 4. 6 5 (1H, t, J=4. 4Hz) ; 5. 53 (1H. d, J=3. 2Hz) ; 5. 80 (1H, m) m, p. 75-76°C
1,6 anhydro-3-butyl-3,4-dideoxy-(~-D-threo-hex-3-enopyranose (Compound No. 97) 1 H N M R (CDC13, 400MHz) : 0. 94 (3H, t, J=7. 2Hz) ; 1. 41 (4H, m) ; 1. 65 (1H, br. s 2. 06 (1H, ddd, J=15. 0. 9. 6, 6. OHz) ; 2. 18 (1H, ddd, J=15. 0, 8. 8, 5.
6Hz) ; 3. 72 (1H
, dd; J=6. 8, 4. OHz) ; 3. 78 (1H, d. J=6. 8Hz) ; 4. 19 (1H, d, J=2. 8Hz) ; 4.
63 (1H, t. J=4.
OHz) : 5. 52 (1H. d. J=2. 8Hz) ; 5. 79 (1H, br. d, J=5Hz) m. p. 43-44°C
2~~8'~BQ~ -1 6 anhydro 3,4-dideoxy-3-methoxymethyl-Q-D-threo-hex-3-enopyranose (Compound No. 96) . 1 H N M R (CDC13. 400MHz) : 3. 35 (3H, s) : 3. 75 (1H, dd, J=6. 8, 4. 4Hz) ;
3. 83 (11I
d, J=6. 8Hz) ; 3. 91 (1H, br. d, J=l3Hz) ; 4. O1 (1H, br. d, J=1311z) ; 4.
32(1H, br, d, J=
2llz) : 4. 70 (1H, t, J=4. 4Hz) ; 5. 53 (1H, d, J=2. 8Hz) ; 6. 09 (111, m) m. p. 53-56°C
Compound No. 98 1 H N M R (CDC13, 400htllz) : 1. 63 (3H, s) ; 3. 72 (111, dd, J=5. 6, 4. 4llz) ; 3. 92 (liI
. d. J=5. 6Hz) ; 4. 61 (1H, t. J=4. 4Hz) ; 5. 60 (11I, br. s) ; 5. 68 (1H, d, J=2. 41(z) : 5. 9 0 (1H, m) ; 6. 46 (1H, dd, J=3. 6, 2. OHz) ; 7. 21 (1H, d, J=3. 6Hz) ; 7. 54 (1H, s) Compound No. 99 1 H N M R (CDC13, 400MHz) : 2. 85 (1H, s) : 3. 82 (1H. dd, J=6. 8..4. 3Hz) ;
3. 94 (1H
. d, J=6. 8Hz) ; 4. 76 (1H, t, J=4. 3Hz) ; 6. Ol (1H, dd, J=9. 7, 2. OHz) ; 6.
18 (1H. d. J=2.
OHz) -; 6. 27 (1H, dd, J=9. 7, 4. 3Hz) ; 6. 51 (1H, dd, J=3. 3, 1. 3Hz) ; 7.
23 (1H, d, J=3. 3H
z) ; 7. 58 (1H, br. s) Compound No. 100 1 H N M R (CDC13, 400MHz) : 1. 57 (3H, s) : 3. 66 (1H, dd, J=5. 6. 4. 4Hz) :
3. 83 (111 d, J=5. 6Hz) ; 4. O6 (1H, br. s) ; 4. 50 (1H, t, J=4. 4Hz) ; 4. 54 (1H, d, J=13. OHz) : 4. 5 9 (1H, d, J=13. OHz) ; 5. 40 (1H, d, J=2. 4Hz) ; 5. 72 (1H. m) ; 6. 28 (1H, dd, J=3. 0, 2. OHz ) ; 6. 30 (1H, d. J=3. OHz) ; 7. 36 (1H, s) Compound No. 101 1 H N M R (CDC13, 400htHz) : 3. 77 (1H. ddd, J=7. 2. 4. 4, 1. ZHz) ; 3. 96 (1H, d. J=7.
2liz) ; 4. 31 (1H, m) ; 4. 60 (lll, d, J=13. 2llz) : 4. 63 (1H. m) ; 4. 64 (1H, d, J=13. 211z) :
5. 50 (1H, t, J=2. 4Hz) ; 5. 64 (1H, dt. J=9. 6, 2. 4Hz) : 6. 09 (lfi, ddd.
J=9. 6., 4. 4. 1. 2Hz ) ; 6. 36 (2H, m) ; 7. 41 (1H, dd, J=1. 6, 0. 8Hz) .2~~'~~~~
Compound No. 102 1 H N M R (CDC13, 400hiHz) : 2. 92 (1H, s) ; 3. 78 (1H, dd, J=6. 8. 4. 4Hz) ;
3. 95 (1H
. d. J=6. 8Hz) ; 4. 17 (1H, dt, J=4. 4Hz) : 4. 73 (1H, d, J=12. 6Hz) ; 4. 80 (lli, d. J=12. 6H
z) ; 5. 57 (1H, d, J=2. OHz) ; 5. 70 (1H, dd, J=9. 6. 2. OHz) ; 6. 12 (1H, dd.
J=9. 6. 4. 4Hz) : 6. 33 (2H, m) ; 7. 41 (1H, m) Now enopyranose derivatives of the formula (I-1) or (I-2) will be presented in Tables 3 to 11.
20878~'~
v ~~
~~~'R
s C
I -1 ) R w R
Com- R~ Rz R' R~ R5 RB X Z
ound 1 H H H Single H H H
bond H H H Single H -COCHzCfI(CH3)zII
2 bond II II H Single II -COCII=CHC113 II
bond II H H Single H -CO H II
bond H H H Single H -CO--~ H
bond .
6 H H H Single H -~0(Cllz)~CH3 H
~
bond 7 H H H Single H -CO (CH z ) H
i , CH a bond g If H H S-ingle H -CO(CHz),CH= H
bond CH(Cllz)7CHa g II H H Single H -COCH3 II
bond H H H Single H -COCHzCI II
bond II H H Single II -C0 I( 11 ~
d '~-~
bon 0C0CIla 12 II II il Single II -CO(Cllz) eCll3II
bond ~0~'~~~~i m .,v.,i~ n om- R' Rz R3 R4 R5 Rs X y pound No.
Intermediate No. 17 1 H N M R (CDC13, 400MHz) :2. 09(2. 25H, s); 2. 10 (0. 75H, s) ; 4. 26 (0.
25H, dd, J
=11. 5, 5. OHz) ; 4. 27 (0. 75H, dd, J=11. 5, 4. 3Hz) ; 4. 34 (0. 75H, dd, J=11. 5, 5. 3Hz) ;
4. 42 (0. 25H, dd, J=11. 5, 6. 2Hz) ; 4. 79 (0. 25H, m) ; 4. 93 (0. 75H, m) ;
5. 19 (0. 25H, br d, J=5. 7Hz) ; 5. 26 (0. 75H, br, d, J=3. 3Hz) : 6. 19 (0. 75H, dd. J=10. 4, 2. 5Hz) ; 6. 27 (0. 25H, dd, J=10. 0, 2. 8Hz) ; 6. 99 (0. 75H, dd. J=10. 4. 1. 7Hz) : 6. 99 (0. 2511, dd. J=10 . 0, 1. 9Hz) Preparation of 1,6-anhydro-3-0-p-toluenesulfonyl-4-deoxy-20~78~~
~3 D c~lycero hex-3-enopyranos-2-ulose (Intermediate No. 3) 360 mg of pyridinium chlorochromate was added to 20 ml of a dry methylene chloride solution containing 50 mg of 1,6-anhydro-3-0-p-toluenesulfonyl-4-deoxy-~-D-erythro-hex-3-enopyranose, and the mixture was stirred at room temperature for 48 hours. Disappearance of the starting material was confirmed by thin layer chromatography, and then 60 ml of diethyl ether was added thereto. The mixture was further stirred at room temperature for 15 minutes. Then, the reaction mixture was filtered by silica gel and washed with 200 ml of diethyl ether. The washing solution was concentrated under reduced pressure together with the filtrate. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = ~:~) to obtain 34 mg of the desired product (Intermediate No. 3) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
1 H N Vf R (CDC13, 400MHz) : 2. 45 (3H, s) ; 3. 83 (1H, d. J=7. 211z) ; 3. 92 (l li, dd. J
=7. 2, 4. 8Hz) ; 5. 14 (1H, t. J=4. 8llz) : 5. 36 (1H, s) : 7. 17 (111, d.
J=4. 811z) : 7. 35 (21( br, d, J=8. OHz) : 7. 82 (211, dt, J=8. 8, 2. OHz) m. p. 81-86°C
Preparation of 1,6 anhydro-3,4-dideoxy-4-methyl-a-D-lycero hex 3 enopyranos-2-ulose (Intermediate No. 43) 1 ml of a tetrahydrofuran solution containing 300 mg of 1,6-anhydro-3,4-dideoxy-4-C-methyl-~3-D-erythro-~o~~~~~
hexopyranose-2-ulose (disclosed in Carbohydrate Res., 71, (1979) 169), was added at -78°C to a lithium amide solution prepared by a conventional method from 0.45 ml of diisopropylamine and 1.75 ml of butyl lithium in 25 ml of dry tetrahydrofuran, under an inert atmosphere of nitrogen gas. The mixture was stirred for one hour, and then 3 ml of a tetrahydrofuran solution containing 500 mg of phenyl serenyl chloride and 0.75 ml of phosphoric acid hexamethyl triamide, was added. The mixture was stirred at -78°C for 30 minutes. Then, a saturated ammonium chloride aqueous solution was added thereto, and the solvent was distilled off under reduced pressure. Then, the mixture was extracted with ethyl acetate. The extract was washed twice with a saturated sodium chloride aqueous solution and then_dried over anhydrous sodium sulfate. The solvent~was distilled off under reduced ' pressure to obtain a syrup crude product. This crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:10) to obtain 106 mg of a serenium derivative.
The serenium derivative obtained by the above reaction was dissolved in 20 ml of dry methylene chloride under an inert atmosphere of nitrogen gas, and 60 mg of m-chloroperbenzoic acid was added thereto at -78°C. The mixture was stirred for 20 minutes and then a saturated sodium hydrogencarbonate aqueous solution was added. The mixture was extracted twice with methylene chloride. The 2~~7~0~
organic layers were put together and washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel thin layer chromatography (methylene chloride) to obtain 1.7 mg of desired 1,6-anhydro-3,4-dideoxy-4-methyl-f3-D-glycero-hex-3-enopyranos-2-ulose (Intermediate No. 43) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
1 H N M R (CDC13. 400MHz) : . 2. 08 (3H, d. J=1. 2Hz) ; 3. 71 (1H, d. J=6.
8Hz) ; 3. 91 (1H, dd, J=6. 8, 4. 8Hz) ; 4. 80 (1H. d, J=4. 8Hz) ; 5. 32 (1H, d, J=1. 2Hz) :
5. 87 (1H, m) Preparation of 1,6-anhydro-~',4-dideoxy-3-ethyl-a-D-glycero-hex-3-enopyranos =2-i~-lose (Intermediate No. 46) (1) 22 g of 1,6-anhydro-3-bromo-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose was dissolved in 500 ml of dry benzene, and 66 g of ethylene glycol and 3 g of p-toluenesulfQnic acid monohydrate were added thereto. The mixture was refluxed under heating while removing formed water. 19 hours later, disappearance of the starting material was confirmed by TLC, and the reaction mixture was cooled to room temperature. Then, 500 ml of ethyl acetate was added thereto, and the mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was 2~8'~8~~
distilled off under reduced pressure. The obtained crude crystals were purified by silica gel column chromatography (ethyl acetate: hexane = 1:1) to obtain 20 g of 1,6-anhydro-3-bromo-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal as white crystals.
The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 3. 71 (1H, dd. J=6. 8, 4. 4Hz) ; 3. 79 (1H, d, J=6. 8Hz) ;
4. 04 (1H, m) ; 4. 17 (1H, m) ; 4. 28 (2H, m) ; 4. 75 (1H, t, J=4. 4Hz) ; 5.
28 (1H, s) ; 6. 60 (1H, d, J=4. 4Hz) m. p. 111-112 °C
(2) 3 g of 1,6-anhydro-3-bromo-3,4-dideoxy-(~-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal obtained in the above step (1) was dissolved in 200 ml of dry tetrahydrofuran. Then, 1.2:equivalent of n-butyl lithium was added thereto under s~i~=ring at -78°C under a nitrogen atmosphere. The mixture was stirred for 20 minutes, and then 10 ml of a dry tetrahydrofuran solution containing 1.9 ml of ethyl iodide and 5.2 ml of hexamethyl phosphoamide, was added thereto. The mixture was stirred for 30 minutes, and then gradually heated to room temperature. Completion of the reaction was confirmed by TLC, and then a small amount of water was added. The solvent was distilled off under reduced pressure. To the residue, 300 ml of ethyl acetate was added, and the mixture was washed three times with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate.
2~~"~8~~
The so3:vent was distilled off under reduced pressure, and then the obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane - 1:2) to obtain 1.48 g of 1,6-anhydro-3,4-dideoxy-3-ethyl-(~-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal as white crystals. The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 1. 03 (3H, t, J=7. 2Hz) ; 2. 03 (1H, m) ; 2. 11 (1H, dqd, J=16. 6, 7. 2, 2. OHz) ; 3. 70 (2H, m) ; 4. 00-4. 10 (3H, m) ; 4. 16 (1H, m) ;
4. 74 (1H, m) ;
5. 19 (1H, s) ; 5. 94 (1H, dt, J=4. 4, 2. OHz) (3) 1.47 g of 1,6-anhydro-3,4-dideoxy-3-ethyl-(~-D-glycero-hexo-3-enopyranos-2-ulose ethylene acetal obtained in the above step (2) was dissolved in 150 ml of dry tetrahydrofuran-water (21). and 2 g of p-toluenesulfonic acid monohyd~'ate was added thereto. The obtained mixture was refluxed under heating for two hours, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was dissolved in 200 ml of ethyl acetate, and the solution was washed three times with 100 ml of a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:2) to obtain 1.1 g of the desired product (Intermediate No. 46). The NMR analytical data of this product are as follows.
2Q~'~80~
1 H N M R (CDC13, 400MHz) : 1. 16 (3H, t, J=7. 6Hz) ; Z. 35 (2H, qd, J=7. 6, 1. 5f(z) 3. 81 (1H, d. J=6. 6Hz) ; 3. 95 (1H, dd, J=6. 6, 4. 6flz) ; 5. 12 (1H. t, J=4.
6Hz) ; 5. 48 1H, s) ; 7. 03(1H, dt. J=4. 6, 1. 5Hz) The following compound was prepared in the same manner as in the above Intermediate Preparation Example 8 and its physical properties will be given.
Intermediate No. 47 1 H N M R (CDC13, 400hfHz) : 0. 90 (3H. t. J=7. 2lfz) : 1. 30-1. 50 (4H, m) ;
2. 17 (111 ddd, J=14. 4, 6. 8, 1. 6Hz) ; 2. 23 (1H, dd, J=14. 4, 6. 8Hz) ; 3. 69 (1H, d, J=6. 8Hz) ; 3.
86 (1H, dd, J=6. 8, 4. 4Hz) ; 4. 98 (1H, t, J=4. 4Hz) : 5. 36 (1H, s) ; 6. 92 (1H, dt, J=4. 4, 1. 6Hz) Preparation of 1.6-anhydro-3,4-dideoxy-3-methoxymethyl-~3 D glycero-hex-3-enopyranos-2=ulose (Intermediate No. 48) ( 1 ) 1. 65 g of 1, 6-anl~.yd-zo-3-bromo-3, 4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal obtained in the above Intermediate Preparation Example 8 (1), was dissolved in 200 ml of dry tetrahydrofuran, and the solution was cooled to -78°C. Then, 5 ml (1.6N) of n-butyl lithium was gradually added thereto, and the mixture was further stirred for 20 minutes. To the obtained reaction mixture, formaldehyde gas was introduced in large excess, and the temperature was raised to room temperature. Termination of the reaction was confirmed by TLC, and then the reaction mixture was filtered through Celite~ to remove the precipitate. The filtrate was concentrated under reduced pressure, and the 2~~'~~~5 obtained syrup crude product was purified by silica gel column chromatography (ethyl aceta-te: hexane = 1:1) to obtain 0.7 g of 1,6-anhydro-3,4-dideoxy-3-hydroxymethyl-(3-D-glycero-hex-3-enopyranos-2-ulose ethylene acetal.
The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 2. 04 (1H, br. s) ; 3. 73 (2H, m) ; 4. 00-4. 20 (SH, m) ;
4. 17 (1H, dd, J=12. 0, 1. 2Hz) ; 4. 79 (1H, m) ; 5. 19 (1H, s) ; 6. 32 (1H, dt, J=4. 8, 1. 2Hz 2 g of p-toluene sulfonic acid monohydrate was added to 150 ml of a methanol solution containing 2.8 g of 1,6-anhydro-3,4-dideoxy-3-hydroxymethyl-~3-D-glycero-hex-3-enopyranos-2-ulose obtained in the above step (1), and the mixture was refluxed under heating for one hour.
Disappearance of the starting material was confirmed by TLC, and then the solvent=was distilled off under reduced pressure. The obtained crude product was purified by ~~
silica gel column chromatography (ethyl acetate: hexane - 1:2) to obtain 0.8 g of the desired product (Intermediate No. 48). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400hiHz) : 3. 40 (3H, s) ; 3. 73 (lf(, d. J=6. 8Hz) ; 3. 89 (lll, dd, J
=6. 8, 4. 4Hz) ; 4. 07 (1H, br, d, J=lSHz) ; 4. 11 (1H, dd, J=14. 4, 1. 6Hz) ;
5. 06 (lli, t, J
=4. 4Hz) ; 5. 36 (1H, s) : 7. 20 (1H, dt, J=4. 4. 1. 6) Now, specific Preparation Examples for the compounds of the formula (I) will be described.
Preparation of 1,6-anhydro-3,4-dideoxy-(3-D-threo-hex-3-20~'~~~5 enopyranose (Compound No. 1) 50 ml of a dry diethyl ether solution containing 20 g of 1,6-anhydro-3,4-dideoxy-/~-D-glycero-hex-3-enopyranos-2-ulose, was gradually dropwise added to 500 ml of a dry diethyl ether suspension containing 3.0 g of lithium aluminum hydride, at 0°C under an inert atmosphere of nitrogen gas. After completion of the dropwise addition, the mixture was immediately returned to room temperature, and stirring was continued for 30 minutes. Disappearance of the starting material was confirmed by thin layer chromatography, and then a small amount of water was added to inactivate an excess amount of lithium aluminum hydride. The mixture was further stirred for 30 minutes, and the reaction mixture was~~filtered through Celite~ to remove the precipitate. ~h~-precipitate was washed a few times with diethyl ether, and the washing solutions were concentrated under reduced pressure together with the filtrate. Precipitated crude crystals were recrystallized from diethyl ether to obtain 14.5 g of the desired product (Compound No. 1). The NMR analytical data and physical properties of this product were as follows.
1 H N M R (CDC13, 400h1Hz) : 3. 73 (1H, dd, J=6. 4, 4. OHz) : 3. 82 (1H, d, J=6. 4Hz) ;
4. 32(1H, br. s) : 4. 65(1H, t, J=4. OHz) : 5. 51 (1H, t, J=2. 2Hz) ; 5.
69(11(, dt, J=10.
0, 2. 2Hz) ; 6. 09 (11i, dd, J=10. 0, 4. OHz) m. p. 69-71°C
20~7~0~
Preparation of 1,6-anhydro-3,4-dideoxy-2-0-isovaleryl-a-D threo-hex-3-enopyranose (Compound No. 2; an isovaleric acid ester of Compound No. 1) 0.7 g of isovaleryl chloride was gradually added to 30 ml of a dry pyridine solution containing 0.5 g of 1,6-anhydro-3,4-dideoxy-(~-D-threo-hex-3-enopyranose obtained in the above Preparation Example 1, at 0°C under an inert atmosphere of nitrogen gas. The mixture was stirred for about 10 minutes. Then, the ice bath was removed, and the mixture was further stirred at room temperature for two hours. To the reaction mixture, a small amount of water was added, and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in 200 ml of ethyl'acetate, and the solution was washed three times with'200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:5) to obtain 0.85 g of the desired product (Compound No. 2) as a colorless liquid. The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400h1Hz) : 0. 97 (6H, d, J=6. 9Hz) : 2. 12 (1H. QQt J=6. 9, 6. 9. 6.
gHz) ; 2. 27 (2H, d, J=6. 9Hz) ; 3. 79 (1H, dd, J=6. 6, 4. OHz) : 3. 97 (1H, d, J=6. 6Hz) ; 4.
68 (1H, t, J=4. OHz) ; 5. 53 (111, br. s) : 5. 61 (1H, dt, J=9. 6. 2. 01(z) :
~. 63 (1H, m) : 6.
19 (lll, ddd, J=9. 6, 4. 0, 1. 2Hz) The following compounds were prepared in the same manner as in the above Preparation Example 2, and their physical properties will be given.
Compound No 3 (Crotonic acid ester of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 1. 95 (3H, dd, J=6. 8, 1. 6Hz) ; 3. 80 (1H, ddd, J=6. 5, 4 . 2, 1. 2Hz) ; 3. 98 (1H, d, J=6. 5Hz) ; 4. 69 (111, t, J=4. 2Hz) : 5. 55 (1H, m) ; 5. 65 (1H, d t, J=9. 2, 2. 3Hz) ; 5. 66 (1H, m) ; 5. 92 (1H, dq, J=15. 5, 1. 6Hz) ; 6. 19 (1H, ddt, J=9. 2.
4. 2, 1. 2Hz) ; 7. 04 (1H, dq, J=15. 5, 6. 8Hz) Com ound No 4 (Cyclohexanoic acid ester of Compound No. 1 1 H N M R (CDC13, 400D1Hz) : 1. 15-1. 30 (3H, m) ; 1. 43 (211, m) ; 1. 61 (11I, m) ; 1. 7 3 (2H, m) ; 1. 90 (2H, m) ; 2. 37 (1H, tt, J=11. 4, 3. 3llz) ; 3. 76 (1H, ddd.
J=6. 5, 4. 1, 1. 2 Hz) ; 3. 94 (lli, d, J=6. 5Hz) ; 4. 66 (lli, t, J=4. lltz) ; 5. 47 (1H, m) ;
5. 58 (1H, dt, J=9.
7, 2. 2Hz) : 5. 60 (1H, m) ; 6. 17 (1H, ddd,=J=9. 7, 3. 7, 1. 2Hz) Compound No 5 (Benzoic aoid=ester of Compound No. 1) 1 H N M R (CDC13. 400MHz) : 3. 84 (1H, ddd, J=6. S, 4. 2. 1. 1Hz) : 4. 03 (111, d. J=6.
5Hz) ; 4. 74 (1H, t, J=4. 2Hz) ; 5. 74 (2H, m) ; 5. 78 (11t, m) ; 6. 26 (111.
dd. J=9. 2, 4. 2Hz 7. 44 (2H, t, J=7. SHz) ; 7. 57 (1H, tt, J=7. 5, 1. 5Hz) ; 8. 09 (2H, m) m. p. 116-I1T°~C
Compound No 6 (n Hexanoic acid ester of Compound No. 1) 1 H N M R (CDC13, 400h1Hz) : 0. 88 (3H, t, J=6. 6Hz) ; 1. 32 (4H, m) : 1. 64 (2H, m) ;
2. 38 (2H, t, J=7. 7Hz) ; 3. 80 (1H, m) ; 3. 98 (1H, d, J=7. 1Hz) ; 4. 68 (1H, t, J=4. 8llz) ;
5. 52 (1H, br. s) ; 5. 61 (1H, m) ; 5. 64 (1H, br. s) ; 6. ~19 (1H, dd, J=11.
1, 4. 8liz) ~0~'~~~~_ Compound No 7 (Palmitic acid ester of Compound No. 1) 1 H N M R (CDC13, 400NHz) : 0. 88 (3H, t, J=6. 8Hz) ; 1. 25 (24H, br. s) ; 1.
60-1. 7 0 (2H, m) ; 2. 38 (2H, dd, J=7. 6, 6. 8Hz) ; 3.. 80 (1H, ddd. J=6. 4, 4. 0. 1.
OHz) ; 3. 98 (1H, d, J=6. 4Hz) ; 4. 69 (1H, t, J=4. OHz) ; 5. 52 (1H, m) ; 5. 62 (1H, dt, J=10.
0, 2. 2Hz) ; 5.
64 (1H, m) ; 6. 20 (1H, m) m. p. 39-41°C
20 --17. 4 (c=0. 402, chloroform ) D
Compound No 109 (Palmitic acid ester of Compound No. 103) 1 H N M R (CDC13, 400MHz) : 0. 88 (3H, t, J=6. 8Hz) ; 1. 25 (24H, br. s) ; 1.
63 (2H, quin, J=7. 2Hz) ; 2. 35 (2H, t, J=7. 2Hz) ; 3. 72 (2H, m) ; 4. 76 (1H, t, J=4.
4Hz) ; 4. 78 1H, br. d. J=4. OHz) ; 5. 53 (1H, m) ; 5. 78 (1H, ddd. J=9. 6, 4. 0, 2. OHz) ;
6. 31 (1H, ddd.
J=9. 6, 4. 4, 0. 8Hz) Compound No 8 (Oleic acid ester of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 0. 90 (3~1, t. J=7. 6Hz) : 1. 35-1. 23 (20H, m) ;
1. 64 (2 H, m) ; 1. 98 (4H, m) ; 2. 38 (2H, t, J=7. 7Hz) ; 3. 79 (llf. ddd. J=6. 5, 4.
2, 1. 5llz) ; 3. 97 (llt, d, J=fi. 5Hz) ; 4. 68 (1H, t, J=4. 211z) ; 5. 85 (21t, m) : 5. 52 (1 H, br. s) ; 5. 62 (1 fl, d t, J=9. 9. 1. 6Hz) ; 5. 63(1H, m) ; 6. 29(1H, dd, J=9. 9, 4. 2Hz) Com ound No~ 9 (Acetic acid ester of Compound No. 1) 1 H N M R (CDCI3. 400MHz) : 2. 14 (3H, s) : 3. 80 (1H, ddd, J=6. 8, 4. 4, 0.
8Hz) : 3.
98 (1H, d, J=6. 8liz) : 4. 69 (1H, t, J=4. 4Hz) : 5. 52 (1H. m) : 5. 63 (1H, m) ; 5. 65 (1H, d, J=2. 8Hz) ; 6. 20(1H, ddt. J=9. 2, 4. 4. 0. 8Hz) ."~.~
Compound No 10 (a-chloroacetic acid ester of Compound No. 1 1 H N M R (CDC13, 400b1Hz) :3~ 81(lH,ddd,a=6. 8, 4. 0,1. O~z);~, 97 (1H, d, J=6. 8H
z) ; 4. 13 (1H, d, J=15. 2Hz) ; 4. 17 (1H, d, J=15. 2Hz) ; 4. 71 (11i, t, J=4.
OHz) ; 5. 59 (1 H, m) ; 5. 64 (1H, dt, J=10. 0, Z. 2Hz) ; 5. 67 (1H, t, J=2. 2Hz) ; 6. 25 (1H, ddd, J=10. 0, 4 . 0. 1. OHZ) ( a ~ 20D =-43. 1 (c=0. 627, chloroform ) Compound No 11 (0- -acetylsalicylic acid ester of Compound N_ 01 ) 1 H N M R (CDC13, 400MHz) : 2. 36 (3H, s) ; 3. 83 (lli, ddd. J=6. 8, 4. 4. 1.
6Hz) : 3.
98 (1H, d, J=6. 8Hz) ; 4. 72 (1H, t, J=4. 4Hz) ; 5. 72 (3H, m) ; 6. 24 (1H, ddd, J=10. 8, 4. 4 1. 6Hz) ; 7. 10 (1H, dd, J=7. 6, 1. 2Hz) ; 7. 31 (1H, td, J=7. 6, 1. 2Hz) ; 7.
56 (1H, td, J=
7. 6, 1. 2Hz) ; 8. 08 (1H, dd, J=7. 6, 1. 2Hz) PREPARATION EXAMPLE 3 -' Preparation of 1,6-anhydre-2;0-decanoyl-3,4-dideoxy-a-D-threo hex-3-enopyranose (Compound No. 12; decanoic acid ester of Compound No. 1) 0.6 g of decanoic acid, 0.97 g of dicyclohexylcarbodiimide and 28 mg of N,N-dimethylaminopyridine were added to 50 ml of a dry methylene chloride solution containing 0.3 g of 1,6-anhydro-3,4-dideoxy-(3-D-threo-hex-3-enopyranose obtained in the above Preparation Example 1, while stirring under an inert atmosphere of nitrogen gas. The reaction mixture was stirred for 12 hours at room temperature.
Then, the formed precipitate was filtered off by Celite~, and the filtrate was concentrated under reduced pressure.
2~7~~5 The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:3) to obtain 0.38 g of the desired product (Compound No.
12). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 0. 87 (3H, t, J=6. 8Hz) : 1. 26 (12H, m) ; 1. 64 (2H, qui n. . J=7. 5Hz) ; 2. 36 (1H, dt, J=16. 8, 7. 5Hz) ; 2. 40 (1H, dt, J=16. 8, 7.
5Hz) ; 3. 97 (1H
ddd, J=6. 4, 4. 0, 1. OHz) ; 3. 98 (1H, d, J=6. 4Hz) ; 4. 69 (1H, t. J=4. OHz) ; 5. 52 (1H, m 5. 63 (1H, dt, J=9. 6. 2. ZHz) ; 5. 65 (1H, m) ; 6. 19 (1H, ddd, J=9. 6, 4. 0, 1. OHz) The following compounds were prepared in the same manner as in the above Preparation Example 3, and their physical properties will be given.
Compound No 13 (6-Bromohexanoic acid ester of Compound NO. 1 1 H N M R (CDC13, 400MHz) : 1. 49 (Z)I; tt, J=8. 0, 6. 8Hz) ; 1. 68 (2H, quin.
J=8. OH
z) ; 1. 88 (2H, quin. J=6. 8Hz) ; 2. 41 (2H, td. J=8. 0, 1. 6Hz) ; 3. 40 (2H, t, J=6. 8Hz) ;
3. 79 (1H, ddd, J=6. 8, 4. 4, 1. 6Hz) : 3. 97 (1H, d, J=6. 8Hz) ; 4. 69 (1H, t, J=4. 4Hz) ; 5.
52 (1H, m) ; 5. 62 (1H, dt, J=10. 0, Z. OHz) ; 5. 64 (1H, m) ; 6. 20 (lH, ddd.
J=10. 0, 4. 4, 1 . 6Hz) ' Com aund No. 14 2-Thio henecarbox lic acid ester of Compound No. l~
1 H N M R (CDC13, 400MHz) : 3. 83 (1H, ddd. J=6. 8, 4. 5, 1. OHz) ; 4. 02 (1H, d. J=6.
8Hz) ; 4. 73 (1H, t, J=4. 5Hz) ; 5. 69 (1H, m) ; 5. 75 (1H, dt, J=9. 9, 2.
3Hz) ; 5. 77 (1H, m 6. 25 (1H, ddd, J=9. 9, 4. 5. 1. OHz) ; 7. 11 (1H, dd, J=4. 8. 3. 8Hz) ; 7. 59 (1H, dd, J=4 . 8. 0. 9llz) ; 7. 86 (1H, dd, J=3. 8, 0. 9Hz) m. p. 69-71°C
Compound No 15 (Nicotinic acid ester of Compound No. 1) 1 H N M R (CDC1~, 400h1Hz) : 3. 84 (1H, ddd, J=6. 4, 4. 4, 1. 2Hz) ; 4. 02 (1H, d, J=6.
4Hz) ; 4. 75 (1H, t, J=4. 4Hz) ; 5. 74 (2H, m) ; 5. 77 (1H, dt, J=9. 6, 2.
4Hz) ; 6. 29 (1H, d dd; J=9. 6, 4. 4, 1. 2Hz) ; 7. 40 (1H, ddd, J=8. 0, 5. 0, 1. 2Hz) ; 8. 35 (1H, dt, J=8. 0, 1. 2H
z) ; 8. 79 (1H, dd, J=5. 0, 1. 2Hz) ; 9. 27 (1H, br. d, J=1. Zlfz) m. p. 76-81°C
Compound No 16 (p-Chlorobenzoic acid ester of Compound No. 1 1 H N M R (CDC13, 400MHz) : 3. 83 (1H, ddd, J=6. 4, 4. 0, 1. 2Hz) ; 4. 02 (1H, d, J=6.
4Hz) ; 4. 74 (1H, t, J=4. OHz) : 5. 72 (1H, m) ; 5. 74 (1H, dt, J=9. 2, 2.
4Hz) ; 5. 76 (1H, m 6. 26 (1H, ddd, J=9. 2, 4. 0, 1. 2Hz) ; 7. 41 (2H, dt, J=8. 8, 2. OHz) ; 8. 02 (2H, dt, J=8 8, 2. OHz) m. p. 57-59°C
Compound No 17 (2-Furancarlioxylic acid ester of Compound No. 1 1 H N M R (CDC13, 400MHz) : 3. 82 (1H, dd, J=6. 4, 4. 4Hz) : 4. OZ (1H, d, J=6~. 4Hz) ;
4. 72 (1H, t, J=4. 4Hz) ; 5. 71 (1H, m) ; 5. 72 (1H, m) ; 5. 75 (111, m) ; 6.
25 (1H, dd. J=9.
6, 4. 4Hz) ; 6. 51 (1H, dd, J=3. 4, 2. OHz) ; 7. 26 (1H, dd, J=3. 4, 1. OHz) ;
7. 59 (1H, m) m. p. 86-88°C
Compound No. 18 (Cinnamic acid ester of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 3. 83 (1H, ddd, J=6. 8, 4. 2, 1. 6Hz) ; 4. 02 (1H, d, J=6.
SHz) ; 4. 73 (1H, t, J=4. 2Hz) ; 5. 66 (.1H, m) : 5. 71 (1H, dt, J=10. 0, 2.
2Hz) : 5. 73 (1H.
m) ; 6. 24 (1H, ddd, J=10. 0, 4. 4, 1. 6Hz) ; 6. 54 (1H, d, J=16. OHz) ; 7. 39 (3H, m) ; 7. 53 (2H, m) ; 7. 25 (1H, d, J=16. OHz) m. p. 147-153°C
20~78~~
Compound No 19 (Anthranic acid ester of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 3. 83 (1H, ddd. J=6. 8, 4. 2, 0. 8Hz) ; 4. 02 (1H.
d, J=6.
8Hz) ; 4. 73 (1H, t. J=4. 2Hz) ; 5. 71 (1H, m) : 5. 75 (2H, m) ; 6. 25 (1H, ddd, J=10. 2, 4. 2 0. 8Hz) ; 6. 66 (1H, ddd, J=8. 4, 6. 8, 1. 6Hz) ; 6. 67 (1H, br. d, J=8. 4Hz) ; 7. 28 (1H, dd d, J=8. 4, 6. 8, 1. 6Hz) ; 7. 94 (1H, dd, J=8. 4, 1. 6Hz) m. p. 95-100 °C
Com ound No 20 (Arachidic acid ester of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 0. 88 (31i, t, J=7. 211z) ; 1. 26 (3211, br. s) ;
1. 65 (2H.
m) : 2. 38 (2H, t. J=7. 8Hz) ; 3. 80 (1H. ddd. J=6. 4, 4. 3. 1. OHz) ; 3. 98 (1H, d, J=6. 4llz) , 4. 69 (1H, t, J=4. 3Hz) ; 5. 52 (1H, m) ; 5. 62 (1H, dt, J=9. 6, 2. 2Hz) ;
5. 64 (1H, mY; 6 . 19 (1H, dddd, J=9. 6, 4. 3, 1. 2, 1. OHz) Compound No 50 (o-Methylbenzoic acid ester of Compound No. 1 1 H N M R (CDC13, 400MHz) : 2. 61 E~H, s) ; 3. 83 (1H, m) ; 4. O1 (1H, d, J=6.
4Hz) ;
4. 73 (1H, t, J=4. 1Hz) : 5. 72 (1H, m) ; 576 (1H, dt, J=9. 5, 2. 2Hz) ; 5. 79 (1H, m) ; 6. 2 5 (1H, dd, J=9. 5, 4. 1Hz) ; 7. 24 (2H, m) ; 7. 40 (1H, td,. J=7. 4, 1. 4Hz) ;
7. 97 (1H, dd, J=
8. 3, 1. 4Hz) P_re aration of 1,6-anhydro-3,4-dideoxy-2-0-methoxycarbonyl Q D-threo-hex-3-enopyranose (Compound No.
_21, methyl carbonate ester of Compound No. 1) 0.33 g of methyl chlorocarbonate was gradually added to 30 ml of a dry pyridine solution containing 0.3 g of 1,6-anhydro-3~4-dideoxy-~3-D-threo-hexo-3-enopyranose under an inert atmosphere of nitrogen gas. The reaction mixture was stirred at room temperature for 12 hours, and 0.33 g of methyl chlorocarbonate was further added 2~~'~~a~
thereto. The mixture was stirred for 30 minutes. A
small amount of water was added thereto to inactivate methyl chlorocarbonate. Then, the solvent was distilled off under reduced pressure. To the residue, 200 ml of ethyl acetate was added, and the mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:3) to obtain 0.33 g of the desired product (Compound No. 21). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 3. 80 (1H, m) : 3. 81 (3H, s) ; 3. 96 (1H, d, J=6.
8Hz) 4. 70 (1H, t, J=4. 411z) ; 5. 37 (1H, m)~ 5:-68 (1H, dt, J=10. 0, 2. Olfz) ;
5. 71 (lli, t. J=2.
2Hz) ; 6. 23 (1H, ddd, J=10. 0. 4. 4, 1. ZHz) The following compounds were prepared in the same manner as in the above Preparation Example 4, and their physical properties will be given.
Compound No 22 (Phenyl carbonate ester of Compound No.
1 H N M R (CDC13, 400MHz) : 3. 85 (1H, ddd, J=6. 8. 4. 3, 1. 3Hz) ; 4. 02 (1H, d, J=6.
8Hz) ; 4. 74 (1H, t, J=4. 3Hz) ; 5. 47 (111, m) ; 5. 77 (1H, dt, J=9. 3, 2.
4Hz) ; 5. 79 (1H, m 6. 29 (1H, ddt, J=9. 3, 4. 3. 1. 3llz) ; 7. ZO (2H, m) : 7. 26 (1H, m) ; 7. 39 (2H, m) m. p. 98-99°C
Compound No 26 (Phenyl thiocarbonate ester of Com op and No. 1) 2~3~'~~~
1 H N M R (CDC13, 400MHz) : 3. 86 (1H, ddd, J=6. 8, 4. 0, 1. OHz) ; 4. 05 (1H.
d. J=6.
8Hz) ; 4. 76 (1H, t, J=4. OHz) : 5. 84 (1H, dt, J=10. 0, 2. 4Hz) ; 5. 86 (1H, m) ; 6. 05 (1H, m) : 6. 31 (1H, ddd, J=10. 0, 4. 0, 1. OHz) : 7. 31 (2H, m) ; 7. 30(1H, tt, J=7. 6, 1. 1Hz) ;
7. 42 (2H, t t, J=7. 6, 2. 2Hz) Pre aration of 1,6-anhydro-3,4-dideoxy-2-0-_L_.~...,,_~_"_+.r"-Ar,-t,PY-~-enoovranose (Compound No_ phenyic:,at uai«~ r y N
23 phenyl carbamic acid ester of Compound No. 1) 0.56 g of phenyl isocyanate was added at room temperature to 30 ml of a dry toluene solution containing 0.3 g of 1,6-anhydro-3,4-dideoxy-/3-D-threo-hex-3-enopyranose under an inert atmosphere of nitrogen gas.
Further, 0.1 ml of triethylamine was added thereto, and the reaction mixture was refluxed under heating for two hours. Completion of the~reaction was confirmed by thin layer chromatography,~and then the solvent was immediately distilled off under reduced pressure to obtain a syrup crude product. This crude product was purified by silica gel chromatography (ethyl acetate:
hexane = 1:3) to obtain 0.5 g of the desired product (Compound No. 23). The NMR analytical data of this product are as follows.
1 H N M R (CDC13. 400MHz) : 3. 83 (11f, ddd, J=7. 6. 5. 2, 1. 9Hz) ; 3. 99 (111, d, J=7.
611z) : 4. 73 (lil, t, J=S. 2, Hz) ; 5. 57 (1H, m) ; 5. 71 (111, m) ; 5. 73 (1H, dt, J=10. 0, 2. 7 Hz) ; 6. 23 (11(, ddd, J=10. 0, 5. 2, 1. 9Hz) ; 6. 83 (1H. br. s) ; 7. 08 (111, t t, J=7. 6, 1. 0!1 z) ; 7. 32 (2H, t, J=7. 6Hz) ; 7. 37 (2H, d, J=7. 611z) m. p. 107-109°C
Preparation of 1,6-anhydro-3,4-dideoxy-2-0-methylthiocarbamoyl-Q-D-threo-hex-3-enopyranose (Compound No 24, methyl thiocarbonate ester of Compound No. 1) 0.4 g of methyl thioisocyanate was added to 30 ml of a dry toluene solution containing 0.35 g of 1,6-anhydro-3,4-dideoxy-~3-D-threo-hex-3-enopyranose under an inert atmosphere of nitrogen gas. Then, sodium hydride (60%
dispersion in mineral oil, 1.3 equivalent) was gradually added thereto. After confirming the termination of the generation of hydrogen (from 5 to 10 minutes), the stirring was further continued for one hour. Completion of the reaction was confirmed by thin layer chromatography, and then a small amount of water was added to inactivate sodiu~a hydride. Then, the formed precipitate was removed by filtration with Celite~-anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 2:3) to obtain 0.45 g of the desired product (Compound No. 24). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400hiHz) : 2. 92 (0. 9H. d, J=4. 6Hz) : 3. 07 (2. 1H, d.
J=4. 6Hz) ;
3. 79 (1H, m) ; 3. 94 (0. 7H, d. J=6. 5Hz) ; 3. 97 (0. 3H, d. J=6. 5Hz) ; 4.
70 (0. 7H, t. J=3.
7Hz) ; 4. 71 (0. 3H, t, J=3. 7Hz) : 5. 72 (21i, m) : 6. 19 (2H. m) ; 6. 61 (0.
7H, br. s) : 6. 7 9 (0. 3H, br. s) The following compound was prepared in the same manner as in the above Preparation Example 6, and its physical properties will be given.
Compound No 25 (N-tert-butyl carbamate of Compound No-1 ) 1 H N M R (CDC13, 400h1Hz) : 1. 31 (9H, s) ; 3. 79 (lH,.ddd, J=6. 4, 4. 4. 1.
5Hz) : 3.
95 (1H, d, J=6. 4Hz) ; 4. 68 (1H, t, J=4. 4Hz) ; 4. 87 (1H, br. s) ; 5. 41 (1H, br. s) : 5. 65 (1H, m) ; 5. 66 (1H, dt, J=9. 6, 2. 2Hz) ; 6. 16 (1H, ddd, J=9. 6. 4. 4, 1.
5Hz) m. p. 113-115°C
Pre aration of 1,6 anhydro-3,4-dideoxy-2-C-vinyl-/3-D-threo hex 3 enopyranose (Compound No. 27) 9.5 ml (1 mol) of vinyl magnesium bromide was gradually added to 50 m1 of a dry tetrahydrofuran solution containing 1 g of ~;6-anhydro-3,4-dideoxy-~3-D-glycero-hex-3-enopyranos-2-ti~.ose under stirring at 0°C
under an inert atmosphere of nitrogen gas. 30 minutes ~~
later, the ice bath was removed, and stirring was further continued for 30 minutes at room temperature. Completion of the reaction was confirmed by thin layer chromatography, and then a small amount of water was added to inactivate any excess Grignard reagent. Then, the solvent was distilled off under reduced pressure.
The obtained crude product was dissolved in 200 ml of ethyl acetate and washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the 2~'~~~
obtained syrup product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:2) to obtain 0.9 g of the desired product (Compound No. 27). The NMR
analytical data of this product are as follows.
1 H N M R (CDC13, 400hiHz) : 3. 73 (1H, dd. J=6. 4, 3. 9Hz) ; 3. 82 (1H, d, J=6. 4Hz) 4. 68 (1H, t, J=3. 9Hz) : 5. 19 (1H, br. s) ; 5. 26 (1H, dt, J=10. 5, 1. 3Hz) ; 5. 36 (1H, dt J=17. 7, 1. 3Hz) : 5. 53 (1H, dt, J=9. 4, 1. 3Hz) ; 5. 92 (1H, ddd, J=17. 7, 10. 5. 1. OHz) ;
6. 09 (1H, dd, J=9. 9, 3. 9Hz) The following compounds were prepared in the same manner as in the above Preparation Example 7, and their physical properties will be given.
Compound No. 28 1 H N M R (CDC13. 400MHz) : 1. 26 (3H, s) : 3. 69 (1H, dd. J=7. 0, 4. 6Hz) :
3. 76 (1H
d, J=7. OHz) : 4. 62 (1H, t, J=4. 6Hz) : 5-17 (1H, d, J=2. 21(z) : 5. 67 (1H, dd, J=10. 0, 2 . 2Hz) : 5. 94 (1H, dd, J=10. 0. 4. 6Hz)~
Compound No. 29 1 H N M R (CDC13, 400MHz) : 2. 69 (1H, s) : 3. 76 (1H, dd, J=6. 8, 4. 4Hz) :
3. 82 (111 d, J=6. 8Hz) ; 4. 73(1H, t, J=4. 4Hz) ; 5. 49 (1H, d, J=2. Ollz) ; 5. 75 (111, dd, J=9. 8. 2.
OHz) : 6. 12 (1H, dd, J=9. 8, 4. 4liz) m~ p~ 64-67°C
~ 20D =-214.8 (c=0.433, chloroform ) Compound No. 30 1 H N M R (CDC13, 400MHz) : 0. 90 (3H, t, J=7. OHz) : 1. 35-1. 50 (4H, m) ; 1.
60-1.
75 (2H, m) ; 3. 70 (1H, dd. J=6. 8, 4. 4Hz) ; 3. 77 (1H, d, J=6. 8Hz) ; 4. 64 (1H, t, J=4. 4Hz ) ; 5, 22 (1H, d, J=2. OHz) ; 5. 61 (1H, dd, J=10. 0, 2. OHz) : 6. 00 (1H, dd, J=10. 0, 4. 4Hz m. p. 31-33°C
Compound No. 31 1H N M R (CDC13, 400MHz) : 0. 97 (3H, t, J=7. 2Hz) ; 1. 55 (2H, six, J=7. 2Hz) ; 2.
23 (2H, t, J=7. 2Hz) ; 2. 26 (1H, br. s) ; 3. 74 (1H, dd, J=6. 8, 4. 4Hz) ; 3.
80 (1H, d, J=6.
8Hz) ; 4. 71 (1H, t, J=4. 4Hz) ; 5. 44 (1H, d, J=2. 4Hz) ; 5. 74 (1H, dd,J=10.
0,2. 4Hz); 6.
05 (1H, dd, J=10. 0. 4. 4Hz) m. p. 43-46°C
Preparation of 2-0-acetyl-1,6-anhydro-3 4-dideox~-2-C-methyl a D threo-hex-3-enopyranose (Compound No. 32) 2.4 ml (1.5 mol) of methyl lithium was gradually added to 30 ml of a dry tetrahydrofuran solution containing 0.3 g of 1,6-anhydro-3,4-dideoxy-(3-D-glycero-hex-3-enopyranos-2-ulose under stirring at 0°C under an inert atmosphere of nitrogeri-gas. Completion of the reaction was confirmed by=tR~.n layer chromatography, and then 0.25 ml of acetyl chloride was added to the reaction mixture. The ice bath was removed, and the reaction solution was returned to room temperature and further stirred for one hour. The solvent was distilled off under reduced pressure. To the residue, 200 ml of ethyl acetate was added. The mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:5) to obtain 0.29 g of the desired 2~~'~~~~
product (Compound No. 32). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 1. 59 (3H, s) ; 2. OS (311, s) : 3. 76 (1 fl, dd, J=6. 8, 4. 4 Hz) ; 3. 89 (1H, d, J=6. 8Hz) ; 4. 63 (1H, t, J=4. 4Hz) ; 5. 78 (1H, dd, J=9.
6, 1. 6Hz) ; 5.
89 (1H, d, J=1. 6Hz) ; 6. 06 (1H, dd, J=9. 6, 4. 4Hz) 20D =-114. 7 (c=0. 654, chloroform ) The following compound was prepared in the same manner as in the above Preparation Example 8, and its physical properties will be given.
Compound No. 33 .
1 H N M R (CDC13, 400hIHz) : 0. 88 (3H, t, J=7. 2Hz) ; 1. 25 (24H, br. s) ; 1.
57 (2H, m) ; 1. 59 (3H, s) ; 2. 29 (2H, td, J=8. 0, 1. OHz) ; 3. 76 (1H, dd, J=6. 4, 4. 4Hz) ; 3. 87 (1 H, d, J=6. 4Hz) ; 4. 62 (1H, t, J=4. 4Hz) ;: 5. 77 (1H, dd, J=9. 6, 2. OHz) ;
5. 90 (1H, d. J=2 . OHz) ; 6. O6 (1H, dd, J=9. 6, 4. 4Hz) _ .
Preparation of 1,6-anhydro-3,4-dideoxy-/3-D-erythro-hex-3-enopyranose (Compound No. 103) (1) 15 g of p-toluenesulfonyl chloride was added to 50 ml of a dry pyridine solution containing 1,6-anhydro-3,4-dideoxy-(~-D-threo-hex-3-enopyranose obtained in the above Preparation Example 1, at room temperature under an inert atmosphere of nitrogen gas. The mixture was stirred for 12 hours, and then a small amount of water Was added thereto. Then, the mixture was extracted with 300 ml of toluene. The extract was washed once with 200 ml of 1N hydrochloric acid and then washed three times with 200 ml of a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then the obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1:1) to obtain 10.5 g of 1,6-anhydro-3,4-dideoxy-2-O-(p-toluene)sulfonyl-(3-D-threo-hex-3-enopyranose (Compound No. 46). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400M1iz) : 2. 45 (3H, s) ; 3. 76 (1H, ddd, J=6. 8. 4. 0. 1.
2Hz) : 3.
94 (111, d, J=6. 8Hz) ; 4. 65 (1H, t, J=4. Oliz) ; 5. 22 (1H, m) ; 5. 45 (1H, t. 1=2. 4Hz) ; 5.
52(11(, dt, J=10. 4, 2. 4Hz) ; 6. 19(1H, ddd, J=10. 4, 4. 0, 1. 211z) ; 7.
35(2H, br. d, J=8.
4Hz) : 7. 83(2H, dt. J=8. 4, 2. OHz) m. p. 81-83°C
(2) 10.5 g of 1,6-anhydr~-3,4-dideoxy-2-0-(p-toluene)sulfonyl-~3-D-threo-hex-3-enopyranose obtained in the above reaction, was dissolved in 100 ml of dried dimethylformamide, and 6 g of sodium benzoate was added thereto. Thd mixture was refluxed under heating for 30 minutes. The solvent was distilled off under reduced pressure, and 200 ml of water was added to the residue.
The mixture was extracted with 300 ml of chloroform. The organic layer was washed once with 200 ml of a saturated sodium hydrogencarbonate aqueous solution and then washed twice with 200 m1 of a saturated sodium chloride aqueous solution. Then, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off ~Q8'~~Q~
under reduced pressure, and then the obtained syrup crude product was dissolved in 100 ml of dry methanol. Then, 2 ml of a methanol solution of sodium methoxide (28 wt$) was added thereto. The mixture was stirred for 25 minutes at room temperature. The reaction solution was neutralyzed with a 20~ citric acid aqueous solution and then filtered through Celite~ to remove the precipitate.
The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate.~ hexane = 1:2) to obtain 1.1 g of the desired product (Compound No. 103).
The NMR analytical data of this product are as follows.
1 H N M R (CDC13. 400MHz) : 3. 50 (1H, br. d, J=3. 6Hz) ; 3. 64 (2H, m) ; 4.
69 (1H, d dd. J=5. 0. 4. 0. 1. 8Hz) ; 5. 53(1H, t. J=~. 8Hz) ; 5. 82(1H, ddd. J=9. 6. 4.
0. 1. 8Hz) ; 6 . 19 (1H, ddd. J=9. 6. 5. 0. 0. 8Hz) -m. p. 50-54°C
Preparation of 1,6 anhydro-3 4-dideoxy-2-O-methyl-a-D-threo hex 3 enopyranose (Compound No. 41) 0.3 g of 1,6-anhydro-3,4-dideoxy-(3-D-threo-hex-3-enoyranose was gradually added to 30 ml of a dry tetrahydrofuran solution of sodium hydride (60~
dispersion in mineral oil, 1.3 equivalent) under an inert atmosphere of nitrogen gas. Stirring was continued for 15 minutes, and then 0.45 ml of methyl iodide was added.
This reaction solution was stirred at room temperature for 12 hours. A small amount of water was added to inactivate excess sodium hydride, and the reaction solution was concentrated under reduced pressure. To the obtained syrup crude product, 200 ml of ethyl acetate was added, and the mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. Then, the mixture was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained syrup product was purified by silica gel column chromatography (ethyl acetate: hexane = 2:3) to obtain 0.25 g of the desired product (Compound No. 41). The NMR
analytical data of this product are as follows.
1 H N M R (CDC13, 400MHz) : 3. 44 (3H, s) ; 3. 74 (1H, ddd, J=6. 7, 4. 1, 1.
3Hz) ; 3.
91 (1H, d, J=6. 7Hz) ; 4. 07 (1H, m) ; 4. 62 (1H, t, J=4. 1Hz) ; 5. 61 (1H, t, J=2. 2Hz) ; 5.
72 (1H, dt, J=9. 8, 2. 2Hz) ; 6. 09 (1H, ddd: J=9. 8, 4. 1, 1. 3Hz) The following compounds';were prepared in the same manner as in the above Preparation Example 10, and their physical properties will be given.
Compound No 40 (n-Butyl ether of Compound No. 1) 1 H N M R (CDC13, 400MHz) : 0. 92 (3H, t, J=7. 2Hz) ; 1. 39 (2H, m) ; 1. 60 (2H, m) ;
3.57(lH,dt,J=9.2,6.8Hz);3. 60 (1H, dt, J=9. 2. 6. 8Hz) ; 3. 77 (1H, ddd, J=6.
8, 4. 0, 1 . 2Hz) ; 3. 97 (1H, d, J=6. 8Hz) ; 4. 17 (1H, m) ; 4. 63 (1H, t, J=4. OHz) ;
5. 62 (1H, t. J=2 . 2Hz) ; 5. 72(1H, dt, J=9. 6, 2. 2Hz) ; 6. 08 (1H, ddd, J=9. 6. 4. 0, 1. 2Hz) Compound No 48 (Benzyl ether of Compound No. 1) 1 H N M R (CDC13, 900h1Hz) : 3. 78 (1H, ddd, J=6. 4, 4. 0, 1. 2Hz) : 3. 98 (1H, d. J=6.
4Hz) : 4. 28 (11I, m) ; 4. 63 (1H, t, J=4. OHz) ; 4. 66 (lfl, d, J=12. OHz) ;
4. 70 (1H, d. J=1 2. OHz) ; 5. 56 (1H, t, J=2. 4Hz) : 5. 71 (1H. dt. J=10. 0. 2. 4llz) : 6. 10 (1H. ddd. J=10. 0 4. 0. 1. 2Hz) ; 7. 29 (1H, tt, J=6. 8, 2. OIIz) ; 7. 34 (2H, m) ; 7. 38 (2H, m) 2a87~~
Preparation of 1.6-anhydro-3,4-dideoxy-2-O-(16-hydroxy)hexadecanoyl-a-D-threo-hex-3-enopyranose (Compound No. 49) 50 ml of a dry tetrahydrofuran solution containing 1 g of 16-hydroxyhexadecanoic acid, 1.1 g of tert-butyldimethylsilyl chloride and 0.75 g of imidazole, was stirred at room temperature for 12 hours under an inert atmosphere of nitrogen gas. The solvent was distilled off under reduced pressure, and then 200 ml of ethyl acetate was added. The mixture was washed three times with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrup product. Then, 40 ml of diethyl ether. 30 ml of methanol and 30 ml of 1N
hydrochloric acid were added thereto, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and then 200 ml of ethyl acetate was added. The mixture was washed once with 200 ml of a saturated sodium hydrogencarbonate aqueous solution and then washed twice with 200 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a syrup product. This product was purified by silica gel column chromatography (ethyl acetate: hexane - 1:1) to obtain 1.4 g of 16-tert-butyldimethylsilyloxyhexadecanoic acid.
A condensation reaction of 16-tert-butyldimethylsilyloxyhexadecanoic acid obtained by the above reaction and Compound No. 1, was conducted in the same manner as in the above Preparation Example 3. Post-treatment was conducted by a conventional method, and then purification was conducted by silica gel column chromatography (ethyl acetate: hexane = 1:7). The product was dissolved in 50 ml of dry tetrahydrofuran, and 3 ml of a tetrahydrofurarl solution of 1N tetrabutyl ammonium fluoride, was added thereto at room temperature.
The mixture was stirred for 12 hours. The solvent was distilled off under reduced=pressure, and then 200 ml of ethyl acetate was added. =Tt~~ mixture was washed twice with 200 ml of a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was again distilled off under reduced pressure to obtain a syrup product. This product was purified by silica gel column chromatography (ethyl acetate: hexane - 2:3) to obtain 0.59 g of the desired product (Compound No. 49). The NMR analytical data of this product are as follows.
1 H N M R (CDC13, 400htHz) : 1. 20-1. 37 (22H, m) : 1. 57 (211, quin. , J=T.
OHz) ; 1.
64 (2H, quin. , J=7. OHz) ; 2. 38 (21i, t. J=7. 4Hz) : Z. 64 (2H, td, J=5. 6.
5. 6Hz) : 3. 80 1H, ddd, J=6. 6. 4. 1, 1. lltz) ; 3. 98(1H, d, J=6. 611z) ; 4. 69(111, t. J=4.
1Hz) ; 5. 52(11( m) ; 5. 62(1H, dt, J=9. 5, 2. 1Hz) ; 5. 64(1H, m) ; 6. 20(1H, ddt, J=9. 5, 4.
1. 1. lllz) °
~.....
The following compounds were prepared in the same manner as in the above Preparation Example 1 or 2, and their physical properties will be given.
1 6-anhydro-3,4-dideoxy-3-methyl-~-D-threo-hex-3-enopyranose (Compound No. 51) 1 H N M R (CDC13, 400~t11z) : 1. 72 (3H, m) ; 2. 03 (11I, d, J=12. OIIz) : 3.
71 (1H, dd, J=6. 4. 4. 4Hz) ; 3. 78 (1H, d. J=6. 4Hz) ; 4. 11 (1H, m) ; 4. 60 (1H, t, J=4.
4Hz) ; 5. 51 (1 H, d. J=2. 8Hz) ; 5. 80 (1H, dd. J=4. 4,1, fiHz) m. p. 62. 5-64°C
1 6-anhydro-3,4-dideoxy-3-ethyl-!3-D-threo-hex-3-enopyranose (Compound No. 95) 1 H N M R (CDC13, 400h1Hz) : 1. 02 (3H, t, J=7. 21(z ) ; 1. 57 (1H, br. s) ;
2. 12 (2H, m 3. 73 (1H, dd, J=6. 0, 4. 4Hz) ; 3. 78 (1H, d, J=6. OHz) ; 4. 21 (1H, d, J= 3.
ZHz) ; 4. 6 5 (1H, t, J=4. 4Hz) ; 5. 53 (1H. d, J=3. 2Hz) ; 5. 80 (1H, m) m, p. 75-76°C
1,6 anhydro-3-butyl-3,4-dideoxy-(~-D-threo-hex-3-enopyranose (Compound No. 97) 1 H N M R (CDC13, 400MHz) : 0. 94 (3H, t, J=7. 2Hz) ; 1. 41 (4H, m) ; 1. 65 (1H, br. s 2. 06 (1H, ddd, J=15. 0. 9. 6, 6. OHz) ; 2. 18 (1H, ddd, J=15. 0, 8. 8, 5.
6Hz) ; 3. 72 (1H
, dd; J=6. 8, 4. OHz) ; 3. 78 (1H, d. J=6. 8Hz) ; 4. 19 (1H, d, J=2. 8Hz) ; 4.
63 (1H, t. J=4.
OHz) : 5. 52 (1H. d. J=2. 8Hz) ; 5. 79 (1H, br. d, J=5Hz) m. p. 43-44°C
2~~8'~BQ~ -1 6 anhydro 3,4-dideoxy-3-methoxymethyl-Q-D-threo-hex-3-enopyranose (Compound No. 96) . 1 H N M R (CDC13. 400MHz) : 3. 35 (3H, s) : 3. 75 (1H, dd, J=6. 8, 4. 4Hz) ;
3. 83 (11I
d, J=6. 8Hz) ; 3. 91 (1H, br. d, J=l3Hz) ; 4. O1 (1H, br. d, J=1311z) ; 4.
32(1H, br, d, J=
2llz) : 4. 70 (1H, t, J=4. 4Hz) ; 5. 53 (1H, d, J=2. 8Hz) ; 6. 09 (111, m) m. p. 53-56°C
Compound No. 98 1 H N M R (CDC13, 400htllz) : 1. 63 (3H, s) ; 3. 72 (111, dd, J=5. 6, 4. 4llz) ; 3. 92 (liI
. d. J=5. 6Hz) ; 4. 61 (1H, t. J=4. 4Hz) ; 5. 60 (11I, br. s) ; 5. 68 (1H, d, J=2. 41(z) : 5. 9 0 (1H, m) ; 6. 46 (1H, dd, J=3. 6, 2. OHz) ; 7. 21 (1H, d, J=3. 6Hz) ; 7. 54 (1H, s) Compound No. 99 1 H N M R (CDC13, 400MHz) : 2. 85 (1H, s) : 3. 82 (1H. dd, J=6. 8..4. 3Hz) ;
3. 94 (1H
. d, J=6. 8Hz) ; 4. 76 (1H, t, J=4. 3Hz) ; 6. Ol (1H, dd, J=9. 7, 2. OHz) ; 6.
18 (1H. d. J=2.
OHz) -; 6. 27 (1H, dd, J=9. 7, 4. 3Hz) ; 6. 51 (1H, dd, J=3. 3, 1. 3Hz) ; 7.
23 (1H, d, J=3. 3H
z) ; 7. 58 (1H, br. s) Compound No. 100 1 H N M R (CDC13, 400MHz) : 1. 57 (3H, s) : 3. 66 (1H, dd, J=5. 6. 4. 4Hz) :
3. 83 (111 d, J=5. 6Hz) ; 4. O6 (1H, br. s) ; 4. 50 (1H, t, J=4. 4Hz) ; 4. 54 (1H, d, J=13. OHz) : 4. 5 9 (1H, d, J=13. OHz) ; 5. 40 (1H, d, J=2. 4Hz) ; 5. 72 (1H. m) ; 6. 28 (1H, dd, J=3. 0, 2. OHz ) ; 6. 30 (1H, d. J=3. OHz) ; 7. 36 (1H, s) Compound No. 101 1 H N M R (CDC13, 400htHz) : 3. 77 (1H. ddd, J=7. 2. 4. 4, 1. ZHz) ; 3. 96 (1H, d. J=7.
2liz) ; 4. 31 (1H, m) ; 4. 60 (lll, d, J=13. 2llz) : 4. 63 (1H. m) ; 4. 64 (1H, d, J=13. 211z) :
5. 50 (1H, t, J=2. 4Hz) ; 5. 64 (1H, dt. J=9. 6, 2. 4Hz) : 6. 09 (lfi, ddd.
J=9. 6., 4. 4. 1. 2Hz ) ; 6. 36 (2H, m) ; 7. 41 (1H, dd, J=1. 6, 0. 8Hz) .2~~'~~~~
Compound No. 102 1 H N M R (CDC13, 400hiHz) : 2. 92 (1H, s) ; 3. 78 (1H, dd, J=6. 8. 4. 4Hz) ;
3. 95 (1H
. d. J=6. 8Hz) ; 4. 17 (1H, dt, J=4. 4Hz) : 4. 73 (1H, d, J=12. 6Hz) ; 4. 80 (lli, d. J=12. 6H
z) ; 5. 57 (1H, d, J=2. OHz) ; 5. 70 (1H, dd, J=9. 6. 2. OHz) ; 6. 12 (1H, dd.
J=9. 6. 4. 4Hz) : 6. 33 (2H, m) ; 7. 41 (1H, m) Now enopyranose derivatives of the formula (I-1) or (I-2) will be presented in Tables 3 to 11.
20878~'~
v ~~
~~~'R
s C
I -1 ) R w R
Com- R~ Rz R' R~ R5 RB X Z
ound 1 H H H Single H H H
bond H H H Single H -COCHzCfI(CH3)zII
2 bond II II H Single II -COCII=CHC113 II
bond II H H Single H -CO H II
bond H H H Single H -CO--~ H
bond .
6 H H H Single H -~0(Cllz)~CH3 H
~
bond 7 H H H Single H -CO (CH z ) H
i , CH a bond g If H H S-ingle H -CO(CHz),CH= H
bond CH(Cllz)7CHa g II H H Single H -COCH3 II
bond H H H Single H -COCHzCI II
bond II H H Single II -C0 I( 11 ~
d '~-~
bon 0C0CIla 12 II II il Single II -CO(Cllz) eCll3II
bond ~0~'~~~~i m .,v.,i~ n om- R' Rz R3 R4 R5 Rs X y pound No.
13 H H H 5iryle fl -CO(CHz)5Br H
' bond 14 I( H H Single ll -CO -~ II
bond Single N H
' bond 14 I( H H Single ll -CO -~ II
bond Single N H
bond 16 fl H H Single II -CO - Q~- C ft I
bond H
bond H
17 H H H Single H -CO -d b on H
g H H H Single H -CO-CIl=CH~ fl 1 bond 19 H H H Single H -C0~ fl d Y
bon _ NHz H
20 H H H Single fl -CO(CHz) i H
eCfla bond -21 II H H Single, H -COOC113 H
bond 22 H H If b~~ H -C00--~Q fl H
23 H H H Single H -CONII--~Q
bond H
24 H H H Single H -CSNHCH3 H
bond 25 H II ~f Single H -CONIIC (Cll II
a ) a bond 26 H If H Single fl -C(S)0-~O II
bond 2D-87~~
- s8 -T able 5 Com- Ri Rz R3 R~ R5 Rc X ~' pound No.
27 H H 11 Single H II -CH=CHz bond 28 H H H Single H H -Ctl, bond 29 H II H Single H 11 -C = CII
bond 30 H FI H Single }I H -(CHz)3CIla bond 31 H H H Single II II -C=CCHzCHzCH3 bond 32 H It II Single H -COCH3 -0113 bond 33 H H H Single H -CO(CHz) ~ -CHa ~CHa bond 34 H H II Single H -CflO d bond 35 H It H Single H H -CHzOH
bond 36 H II H Single H _ H -CtIzNHz bond 37 It 11 H Singh H _ H -CIIzOCOCHa bond 38 H H H Single H H -(CHz) aCH3 bond 39 11 H H Single H H -(CHz) ~ ~CH3 bond 40 ~ H H H Single H -(CHz) aCH3 tl bond T able 6 Com- R i Rz R3 R~ RS Rs X Y
pound No.
41 H H H Single H CH3 H
bond 42 II H II Single H II -CIlzN3 bond 43 H H H Single I1 I[ -CHz bond NOz 44 H H H Single I[ -C0~ H
bond NOz 45 H H H Single H -SOzCH3 H
bond 46 H H H Single H -SOz--O- CH3 H
bond 47 H. H H Single H II -CHzNHz ~
HCl bond Single H -CHz--O II
bond 49 II H H Single II -CO(CHz) ~ ~CHz011I1 bond 50 11 H H Single II -CO ~ II
bond CHa If 51 CHa ll H Single II II II
bond 52 -OSOz-~CEI3 H H nale H II II
53 Br II H o II II II
dle 54 I II II o H II II
dle T able 7 Com- R~ Rz Ra R4 RS R~ X Y
pound No.
55 -OCOCH3 Il H Single H H H
bond 56 H H Il Single -CH z Il II
bond OH
5? H H H Single CHs Il II
bond 5g H H Single II 11 H
bond 59 H H H H H/OH OH/Il H H
60 H H H H I~ -OCIIa ll II
61 H H H -COCIIs -OClls II If ll 62 H H H SitBuMez -OCHs H II
H
63 H H H H -OCH3 If ll H
' II
65 Br H H -COCH3 -OCOClIa tI H
H
H/OII
67 Br H H -COCIIa OII/H II fi II/Oll 68 H H H -COCzHs -OCOCzHs II If ll 69 CtI3 H H 11 ll -OC113 ll II
70 H I( I~ C113 -OCII~ fl I( Il -OCII~
72 H H II Tr if -OC113 II If 73 II If H -COCII~ II II II
-OC., Ilo t 74 ll Il ll II -OC., II Il II
II" t 75 II II II -COCII;, II II II
-OC~I(, i 2~~ ~~0~ _ TahlP 8 Com- R~ Rz R' R RS R X Y
pound 76 H H H C113 H/OH 011/lH H
77 H H l~ SitBullez (~ H H
OCzl~s 78 H H H S i tBuhtez Il II ll OC Ilo t 79 H H H -CO -~p-N02 II H H
OCIf3 80 H 1-I H -CH(CH3)OCzHs H E( II
OCHs 81 -NHCOCH3 H H -COCH, OCH3 H H 1( 82 -OCOCH3 Il H -COCf~3 OC113 ll H I( 83 -OCO-QO H B -CO-0 -OC0~0 H H (~
r 84 -OCO-QO H H -CO-QO -0 H H Il H
85 -OCOCIia H H -COCtls t 11 H Il t -OC1I3 86 -NHCOOCHz-~OH H H _ -OClla H H H
0 Oh a -OCHz 87 -OC113 H I~ CH3 II II H
hle0 01 a ht a 88 -OCOC113 H H -COCH, -OCOCH3 H II H
89 II C1~3II -CO-QO -OCZHS H I1 If 90 II CliaII Tr -OCzlls H If I( 91 -DO - C113 I( H Single bond (( II II
92 I1 CH3 I( Sinble bond fl ll ll 93 -CII=Cllz fl II Single bond II II II
94 -C= CII EI II Single bond II II II
T~hlo 4 Com-~ R~ RZ R3 R" Rs R X Y
pound i -CHZOCHa H H ge fl H Il bond Single H
96 -CzHs H IF bond Il fl 97 -(CFIz)3CH3H li Single H Il 11 bond 98 -CH3 H H Single H -CO-~ IF
bond 99 H H H Single IF -CO ~ -Cif = CH
bond 100 -CH3 H H dle II CFI2-~ II
bon 101 H H H dle fl -CHZ-~ II
' bon 102 H H H dle H -CH2~ -C1F= CH
bon 15 H/OH and OH/H for RS and-R6 mean that either R5 or R6 is an OH group. ' SitBuMe2 represents a tert-butyl dimethylsilyl group, C4H9t represents a tert-butyl group, and C3H~i represents an iso-propyl group.
Tr represents a triphenylmethyl group. and -represents a cyclohexyl group.
T able 10 0 Rq '~~.
R R
.",~u0 - X
R
Com- R~ Rz R3 R RS Rs X Y
pound 103 Ff H H mngie H 11 H
bond H H Single H -COCHzCH(CHa)zH
104 H bond fi H Single li -COCH=CI1CH3 H
105 H bond 106 H H H Single ){ -CO- H~ If bond 107 H H H Single H ; -CO-~O H
bond 108 H H H Single H =,CO(CHz)CHa II
bond 109 H H H S''ngle H -CO(Cllz) H
~.,Cfls bond 110 H H H Single If -CO (Cll z fl ) z CH=
bond CIl (CIl z ) ; Clla 111 H H H Single II -COC113 II
bond 112 H H H Single II -COCA z C II
l bond S~'gl~ II -C0 II
113 II H 11 d ~
bo ~,=~
n 114 II II II Slngle II -CO (CII 2 II
) a CII, bond T able 11 Com- R~ Rz R3 R4 Rs Rs X
pound No 115 H fl H Single Ll -CO(Cllz)sBr H
bond 116 H H H Single I1 -CO ~ 11 bond 117 H H H Single H -CO -~ H
bond 118 H H H Single H -CO -~- C H
bond H
Single H -CO -~
bond H
120 H H H Single H -CO-CH=CH-~Q H
bond 121 li II li S'~~le II -C0~ if d 7-' bon _ NHz 122 H fI H ~i~gy'~ H -CO(CIIz)n H
aCII3 bond 123 I1 I1 H Single fl -COOCll3 H
bond 124 H H H Single ll -C00~ H
bond Bangle t( 125 El H H H -CONK-- Q
bond p 126 fl H H Single H -CSNHCH3 I( bond 127 II ll H Single ll -COMIC (CIl3 II
) ~
bond 128 ll lI if Single H -C (S) 0-O II
d bon -72~~~~0 Now, pharmacological tests will be given which show that the enopyranose derivative of the above formula (I) or its salt is useful as an effective component for an immuno-suppressive agent.
Pharmacological Tests (1) Inhibiting effects on collagen-induced arthritis model Male DBA/lJNCrj mice of from 4 to 6 weeks old were used ~n groups each consisting of four mice. An emulsion of bovine collagen type II (Product No. K41, manufactured by Collagen Gijutsu-Kenshukai) (3 mg/ml) in the same amount by volume of complete Freund's adjuvant (Product No. 642851, manufactured by ICN Immunobiologicals) was injected intradermally at the base of the tail of each mouse (150 ,ug/0.1 ml/mous~)-to induce collagen-induced arthritis. The degree of arthritis was evaluated unde r the following standards and represented by scores (from 0 to 3 points per foot, the maximum of 12 points as the total score of four feet):
0 Point: No change 1 Point: Detectable swelling in one or more digital joints 2 Points: Mild swelling in one more joints 3 Points: Severe swelling of the entire paw and/or ankylosis For the basic procedure of the above test, reference was made to the Journal of Immunology, Vol. 140, 1477-~Q~~~~
1484, (1988).
(a) Inhibiting effects on collacten-induced arthritis model From the 18th day after inoculation of the antigen, administration of the compound of the formula (I) (50 mg/kg) was started. Administration was conducted continuously for four weeks intraperitoneally or orally once a day, whereby the state of arthritis was observed.
As a control, saline was used, and the test was conducted in the same manner. The results are shown in Figure 1.
(2) Effects on various cultured cells (a) Effects on the mitogenic response by murine thymocytes Using BALB/c murine thymocytes, the effect of the compound of the formula (I)-on the mitogenic response of lymphocytes to the stimulation by concanavalin A w (hereinafter referred to simply as Con A, Product No. L-1000, manufactured by Vector Laboratories) was studied.
Namely, 4 x 105 murine thymocytes were cultured for 48 hours on a microplate with 96 wells in a RPMI1640 solution containing 10~ of a fetal bovine serum (hereinafter referred to simply as a 10~ FCS-RPMI
solution) together with Con A (5 ~g/ml) and the compound of the formula (I) (in an incubator, 5~ C02, at 37°C).
Then, 0.5 ~Ci of 3H-thymidine (hereinafter referred to simply as 3H-TdR) was added thereto, and the mixture was further cultured for 4 hours. Then, cells were collected _ 77 _ by a cell harvester, and the radioactivity (dpm) of 3H-TdR uptaken into cells was measured. Such measured amounts of 3H-TdR uptaken into the cells were used as indices of the mitogenic response of the murine thymocytes, and the radioactivity at each concentration (from 0.001 to 1,000 ,ug/ml) of the compound of the formula (I) was compared with the control value treated solely by Con A, to calculate ICSO value. The results are shown in Tables 12 and 13. In these Tables 12 and 13, the results of murine thymocytes are shown by (a).
For the basic procedure of this test, reference was made to Selected methods in cellular immunology, p. 144-146 (translated by Katsuyuki Imai et al., published by Rikogakusha, (1982)): -(b) -Effects on the murine mixed lymphocyte reaction Using spleen cells of BALB/c and C57BL/6 mice, the~
effect of the compound of the formula (I) on the murine mixed lymphocyte reaction in both sides, was studied.
Namely, spleen cells of both types of mice were mixed in an equal amount of 5 x 105 cells each, and the mixed cells were cultured together with the compound of the formula (I) for 48 hours on a microplate with 96 wells by a 10~ FCS-RPMI solution (in an incubator, 5~ C02, at 37°C). Then, 0.5 ~cCi of 3H-TdR was added thereto, and the mixture was further cultured for from 16 to l8 hours.
Then, cells were collected by a cell harvester, and the radioactivity (dpm) of 3H-TdR uptaken into the cells, was ~Q~~~O~
_ 78 _ measured. Such measured amounts of 3H-TdR uptaken into the cells were used as indices for the mixed lymphocyte reaction, and the radioactivity at each concentration (from 0.001 to 1,000 ,ug/ml) of the compound of the formula (I) was compared with the non-treated control value, to calculate the Ic5o value. The results are shown in Tables 12 and 13. In these Tables 12 and 13, the results of the mixed lymphocyte reaction are shown by (b).
For the basic procedure for this test, reference was made to Selected methods in cellular immunology, p. 147-149 (translated by Katsuyuki Imai et al., published by Rikogakusha, (1982)).
(c) Effects on the murine bone mallow cells Bone mallow cells were rQmoved from the femur of a BALB/c mouse and suspended in a 10% FCS-RPMI solution. ' The cell suspension was put into a plastic Petri dish having a diameter of 10 cm and left to stand still (in an incubator, 5% COz, at 37°C). Two hours later, only floating cells were recovered, and adhesion cells were removed. 1 x 105 floating cells were cultured for 48 hours together with a 20% culture supernatant of L929 fibroblastoma and the compound of the formula (I) on a microplate with 96 wells by a 10% FCS-RPMI solution (in an incubator, 5% C02, at 37°C). Then, 0.5 ~cCi of 3H-TdR
was added thereto, and the mixture was further cultured for 4 hours. Then, cells were collected by a cell ~~$'~$~~
harvester, and the radioactivity (dpm) of 3H-TdR uptaken into the cells, was measured. Such measured amounts of 3H-TdR uptaken into the cells were used as indices for the proliferation of bone mallow cells, and the radioactivity at each concentration (from 0.001 to 1,000 ~cg/ml) of the compound of the formula (I) was compared with the control value where the L929 culture supernatant was added alone, to calculate the ICSO value. The results are shown in Tables 12 and 13. In these Tables 12 and 13, the results of the bone mallow cells are shown by (c).
For the basic procedure of this test, reference was made to Seikagakujikken Koza compiled by Japan Biochemistry Association, Vol. 5, p. 266-270 (published by Tokyo Kagaku Dojin in 1986).
T able 12 om- 1C50 value ( ,~ g /ml) ound -o.
2 350 560 > 1000 g 0.0044 0.0044 130 10 1. 4 18 68 11 110 170, 210 12 110 5~0=: 560 19 0. 39 > 1000 160 22 300 130 > 1000 25 0.32 430 340 ,~,.,.
T able 13 Com- ICSp value ( ,~ g /m 1 ) .
pound No.
Zg 76 280 150 29 35 > 1000 > 1000 40 160 > 1000 > 1000 48 120 > 1000.= ~ 430 49 11 32=. 41 103 780 > 1000 > 1000 109 550 740 > 1000 (d) Effects on the antibody production from murine spleen cells Using murine spleen B cells, the effects of the compound of the formula (I) on the IgGl, IgM and IgE
antibody production induced by the stimulation by LPS
(lipopolysaccharide; Product No. 520.02051, manufactured by Wako Junyaku) and IL4 (interleukin 4), were studied.
Namely, spleen cells of a BALB/c mouse were treated with a murine anti-Thy-1 antibody (obtained from Chiba University) and a rabbit complement (Product No. 3051, manufactured by cedarlane) to remove T cells, and 3 x 105 spleen B cells were cultured for 7 days together with 10 ,ug/ml of LPS, 100 U/ml of mouse-recombinant IL4 (Product No. MIL-4C, manufactured by-Genzyme) and each concentration (from 0.001_to_1,000 ,um/ml) of the compound of the formula (I) on'a microplate with 96 wells by a Yfl%
FCS-RPMI solution (in an incubator, 5% C02, at 37°C).
For the basic procedure of this test, reference was made to The Journal of Immunology, Vol. 136, p. 4538, (1986).
The amount of each antibody in the cell culture supernatant hereby obtained, was measured by the following enzyme-immunoassay. Firstly, on a microplate with 96 wells, 1 ~g/ml of a rabbit anti-mouse IgGl antibody (Product No. 36243. manufactured by Cappel), 1 ~g/ml of a goat anti-mouse IgM antibody (Product No.
0611-0201, manufactured by Cappel) or 10 ,~g/ml of a rat anti-mouse IgE monoclonal antibody (Product No. LO-ME-2, manufactured by Experimental Immunology) was coated (50 ,u2/well, at room temperature for 60 minutes), and then a nonspecific bond was blocked by a 0.1% bovine serum albumin-containing 10 mM sodium phosphate buffer (pH7.2) (at room temperature for 60 minutes). Then, the above-mentioned cell culture supernatant or its diluted solution was added in an amount of 50 ,u2/well and reacted at room temperature for 60 minutes. Further, an alkaline phosphatase-labeled rabbit anti-mouse IgGl antibody (Product No. 61-0122, manufactured by Zymet) diluted 1,000 times, an alkaline phosphatase-labeled rabbit anti-mouse IgM antibody (Product No. 61-6822, manufactured by Zymet) diluted 2,000 times, or an alkaline phosphatase-labeled goat anti-mouse IgE-antibody (Product No. PA-284, manufactured by Binding Site) diluted 500 times was addEd in an amount of 50 ~c2/well and reacted at room temperature for 60 minutes. 100 ,u2/well of a 10%
diethanol amine buffer solution (pH9.8) containing p-nitrophenyl phosphate as an enzyme substrate, was reacted, and the absorbance at 405 nm was measured. The amount of each antibody was calculated from the calibration curve of each standard antibody, and the ICSo value of the compound of the formula (I) on the antibody production was calculated using as the control value a value obtained in the absence of the compound of the formula (I). The results are shown in Tables 14 and 15 2~~~~~~
together with the above-mentioned results of the effect on the murine bone mallow cells. In these Tables 14 and 15. the ICSO value of the effect on the antibody production was shown by each antibody i.e. IgGl, IgM or IgE, and the above-mentioned results of the murine bone mallow cells are shown by (c).
20~~~~5 Table 14 Value ( ~ g /m ~
IC ) Com- 50 pound I gGl I gM I gL c No.
2 300 250 370 > 1000 3 2.4 < 0.001 0.024 130 8 810 340 310 > 1000 9 790 720 _ 320 > 1000 < 0. 001 < 0. s < 0. 001 68 12 24 0.11 28 560 13 < 0.001 < 0.001 0.32 330 14 10 0.89 3.7 500 17 1. 0 100 3. 2 510 18 < 0.001 0.68 < 0.001 370 5.2 500 3.2 400 21 500 130 17 > 1000 22 670 230 4. 0 > 1000 ~o~~~o~
r 86 -T able 15 Com- ICS value ( ,u g /ml) d poun No. I gGl I gM I g~ c 24 17 10 0. 22 620 25 0.0015 78 0.0034 340 26 23 110 4.5 200 29 380 > 1000 320 > 1000 31 1.5 10 _ 140 520 32 400 350 _ 2.8 540 33 340 5. 6 460 > 1000 40 0. 067 110 0. 0026 > 1000 41 670 > 1000 0. 95 > 1000 46 0.25 0.35 0.32 190 49 < 0.1 0.43 < 0.1 41 50 < 0.001 < 0.001 < 0.001 380 103 0. 45 1. 3 2. 1 > 1000 109 < 0. 1 31 < 0. 1 > 1000 ~0~'~8~
Table 16 Carrageenan~$nduced acute inflammation in rats Com- Dose Number Swelling of paw d (m of rats(x 10 cm's) /K
) poun g tested Average Slj p ~
No. g ~omroi group - 4 1 4 4 8 2 9 5 0 4 9 72 2 0. 0 1 1 5 0 4 1 0 03 3 0. 0 5 1 7 5 0 4 9 52 6 0. 0 5 ~ 24~7~4~_ ~~~,.
_88_ Toxicity test Male DBA1/J mice of 6 weeks old were used in groups each consisting of four mice. The compound of the formula (I) (50 mg/kg) was administered every day for 4 weeks intraperitonially or orally once a day, whereby the change in the body weight and the mortality were examined. As a result, there was no remarkable change in the body weight, and there was no case of death. Thus, the LD5o value of the compound of the above formula (I) is 50 mg/kg at the minimum.
The enopyranose derivative of the formula (I) or its salt has an anti-inflammatory activity, and a test example for the anti-inflammatory activity will be given below. -Test for anti-inflammatory activity A test for an anti-inflammatory activity was conducted by means of carrageenan-induced paw edema model which is commonly used for evaluation of the effectiveness of a common anti-inflammatory agent (NSAID).
0.1 ml of a 1~ ~-carrageenan solution was injected intradermally at the sole of the right paw of a SD male rat (six weeks old). Three hours later, the sole volumes of paws on both sides were measured, and the difference in the volume between the right paw and the left paw was taken as the degree of edema. The test compound was orally administered in an amount of 1 ml/100 g (body 2~~'~~~~a _ 89 _ weight) one hour prior to the administration of carrageenan. To the control group, a physiological saline was administered in the same amount. The results are shown in Table 16.
As is apparent from Table 16. the test compounds showed statistically significant suppressing effects against carrageenan-induced paw edema, whereby the effectiveness as anti-inflammatory agents was confirmed.
When the enopyranose derivative of the formula (I) or its salt is to be used as an effective component of an immuno-suppressive agent, it is administered orally or non-orally usually at a dose of from about 50 mg to 5,000 mg per day for an adult, although the dose may vary depending upon the conditions for administration, etc.
The administration of the_dr-ug can be conducted per orally, intravenously, intramuscularly, intradermally ar permucassaly. Formulations for administration include, for example, powders, microgranules, granules, tablets, pills, capsules, injection solutions, nose drops, suspensions, intravenous drips, ointments, syrups and gradually releasing agents. These formulations can be prepared by conventional methods by using pharmaceutically acceptable common carriers in the same manner as for usual drug formulations.
The present invention provides an immuno-suppressive agent containing a compound of the formula (I) as an effective component. More specifically, the immuno-~~~~a suppressive agent of the present invention is effective for treatment of a disease caused by abnormal sthenia of an immunological function, for example, an autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, chronic nephritis, chronic thyroiditis or autoimmune hemolytic anemia as well as for suppressing a rejection at the time of transplantation of an organ. Further, it is effective for treatment of an allergy disease or an inflammatory disease, particularly for treatment of an autoimmune disease such as rheumatoid arthritis.
For practical use, the immuno-suppressive agent, is usually put in a container and the container is put in a commercial package. The commercial package often includes a written matter which states that the agent can or should be used as an immuno-suppressive agent, e.g., for the treatment of a disease caused by abnormal sthenia of an immunological function: such as rheumatoid arthritis, systemic lupus erythematosus, chronic nephritis, chronic thyroiditis, autoimmune hemolytic anemia, allergy diseases, inflammatory diseases, as well as for suppressing a rejection at the time of transplantation of an organ.
g H H H Single H -CO-CIl=CH~ fl 1 bond 19 H H H Single H -C0~ fl d Y
bon _ NHz H
20 H H H Single fl -CO(CHz) i H
eCfla bond -21 II H H Single, H -COOC113 H
bond 22 H H If b~~ H -C00--~Q fl H
23 H H H Single H -CONII--~Q
bond H
24 H H H Single H -CSNHCH3 H
bond 25 H II ~f Single H -CONIIC (Cll II
a ) a bond 26 H If H Single fl -C(S)0-~O II
bond 2D-87~~
- s8 -T able 5 Com- Ri Rz R3 R~ R5 Rc X ~' pound No.
27 H H 11 Single H II -CH=CHz bond 28 H H H Single H H -Ctl, bond 29 H II H Single H 11 -C = CII
bond 30 H FI H Single }I H -(CHz)3CIla bond 31 H H H Single II II -C=CCHzCHzCH3 bond 32 H It II Single H -COCH3 -0113 bond 33 H H H Single H -CO(CHz) ~ -CHa ~CHa bond 34 H H II Single H -CflO d bond 35 H It H Single H H -CHzOH
bond 36 H II H Single H _ H -CtIzNHz bond 37 It 11 H Singh H _ H -CIIzOCOCHa bond 38 H H H Single H H -(CHz) aCH3 bond 39 11 H H Single H H -(CHz) ~ ~CH3 bond 40 ~ H H H Single H -(CHz) aCH3 tl bond T able 6 Com- R i Rz R3 R~ RS Rs X Y
pound No.
41 H H H Single H CH3 H
bond 42 II H II Single H II -CIlzN3 bond 43 H H H Single I1 I[ -CHz bond NOz 44 H H H Single I[ -C0~ H
bond NOz 45 H H H Single H -SOzCH3 H
bond 46 H H H Single H -SOz--O- CH3 H
bond 47 H. H H Single H II -CHzNHz ~
HCl bond Single H -CHz--O II
bond 49 II H H Single II -CO(CHz) ~ ~CHz011I1 bond 50 11 H H Single II -CO ~ II
bond CHa If 51 CHa ll H Single II II II
bond 52 -OSOz-~CEI3 H H nale H II II
53 Br II H o II II II
dle 54 I II II o H II II
dle T able 7 Com- R~ Rz Ra R4 RS R~ X Y
pound No.
55 -OCOCH3 Il H Single H H H
bond 56 H H Il Single -CH z Il II
bond OH
5? H H H Single CHs Il II
bond 5g H H Single II 11 H
bond 59 H H H H H/OH OH/Il H H
60 H H H H I~ -OCIIa ll II
61 H H H -COCIIs -OClls II If ll 62 H H H SitBuMez -OCHs H II
H
63 H H H H -OCH3 If ll H
' II
65 Br H H -COCH3 -OCOClIa tI H
H
H/OII
67 Br H H -COCIIa OII/H II fi II/Oll 68 H H H -COCzHs -OCOCzHs II If ll 69 CtI3 H H 11 ll -OC113 ll II
70 H I( I~ C113 -OCII~ fl I( Il -OCII~
72 H H II Tr if -OC113 II If 73 II If H -COCII~ II II II
-OC., Ilo t 74 ll Il ll II -OC., II Il II
II" t 75 II II II -COCII;, II II II
-OC~I(, i 2~~ ~~0~ _ TahlP 8 Com- R~ Rz R' R RS R X Y
pound 76 H H H C113 H/OH 011/lH H
77 H H l~ SitBullez (~ H H
OCzl~s 78 H H H S i tBuhtez Il II ll OC Ilo t 79 H H H -CO -~p-N02 II H H
OCIf3 80 H 1-I H -CH(CH3)OCzHs H E( II
OCHs 81 -NHCOCH3 H H -COCH, OCH3 H H 1( 82 -OCOCH3 Il H -COCf~3 OC113 ll H I( 83 -OCO-QO H B -CO-0 -OC0~0 H H (~
r 84 -OCO-QO H H -CO-QO -0 H H Il H
85 -OCOCIia H H -COCtls t 11 H Il t -OC1I3 86 -NHCOOCHz-~OH H H _ -OClla H H H
0 Oh a -OCHz 87 -OC113 H I~ CH3 II II H
hle0 01 a ht a 88 -OCOC113 H H -COCH, -OCOCH3 H II H
89 II C1~3II -CO-QO -OCZHS H I1 If 90 II CliaII Tr -OCzlls H If I( 91 -DO - C113 I( H Single bond (( II II
92 I1 CH3 I( Sinble bond fl ll ll 93 -CII=Cllz fl II Single bond II II II
94 -C= CII EI II Single bond II II II
T~hlo 4 Com-~ R~ RZ R3 R" Rs R X Y
pound i -CHZOCHa H H ge fl H Il bond Single H
96 -CzHs H IF bond Il fl 97 -(CFIz)3CH3H li Single H Il 11 bond 98 -CH3 H H Single H -CO-~ IF
bond 99 H H H Single IF -CO ~ -Cif = CH
bond 100 -CH3 H H dle II CFI2-~ II
bon 101 H H H dle fl -CHZ-~ II
' bon 102 H H H dle H -CH2~ -C1F= CH
bon 15 H/OH and OH/H for RS and-R6 mean that either R5 or R6 is an OH group. ' SitBuMe2 represents a tert-butyl dimethylsilyl group, C4H9t represents a tert-butyl group, and C3H~i represents an iso-propyl group.
Tr represents a triphenylmethyl group. and -represents a cyclohexyl group.
T able 10 0 Rq '~~.
R R
.",~u0 - X
R
Com- R~ Rz R3 R RS Rs X Y
pound 103 Ff H H mngie H 11 H
bond H H Single H -COCHzCH(CHa)zH
104 H bond fi H Single li -COCH=CI1CH3 H
105 H bond 106 H H H Single ){ -CO- H~ If bond 107 H H H Single H ; -CO-~O H
bond 108 H H H Single H =,CO(CHz)CHa II
bond 109 H H H S''ngle H -CO(Cllz) H
~.,Cfls bond 110 H H H Single If -CO (Cll z fl ) z CH=
bond CIl (CIl z ) ; Clla 111 H H H Single II -COC113 II
bond 112 H H H Single II -COCA z C II
l bond S~'gl~ II -C0 II
113 II H 11 d ~
bo ~,=~
n 114 II II II Slngle II -CO (CII 2 II
) a CII, bond T able 11 Com- R~ Rz R3 R4 Rs Rs X
pound No 115 H fl H Single Ll -CO(Cllz)sBr H
bond 116 H H H Single I1 -CO ~ 11 bond 117 H H H Single H -CO -~ H
bond 118 H H H Single H -CO -~- C H
bond H
Single H -CO -~
bond H
120 H H H Single H -CO-CH=CH-~Q H
bond 121 li II li S'~~le II -C0~ if d 7-' bon _ NHz 122 H fI H ~i~gy'~ H -CO(CIIz)n H
aCII3 bond 123 I1 I1 H Single fl -COOCll3 H
bond 124 H H H Single ll -C00~ H
bond Bangle t( 125 El H H H -CONK-- Q
bond p 126 fl H H Single H -CSNHCH3 I( bond 127 II ll H Single ll -COMIC (CIl3 II
) ~
bond 128 ll lI if Single H -C (S) 0-O II
d bon -72~~~~0 Now, pharmacological tests will be given which show that the enopyranose derivative of the above formula (I) or its salt is useful as an effective component for an immuno-suppressive agent.
Pharmacological Tests (1) Inhibiting effects on collagen-induced arthritis model Male DBA/lJNCrj mice of from 4 to 6 weeks old were used ~n groups each consisting of four mice. An emulsion of bovine collagen type II (Product No. K41, manufactured by Collagen Gijutsu-Kenshukai) (3 mg/ml) in the same amount by volume of complete Freund's adjuvant (Product No. 642851, manufactured by ICN Immunobiologicals) was injected intradermally at the base of the tail of each mouse (150 ,ug/0.1 ml/mous~)-to induce collagen-induced arthritis. The degree of arthritis was evaluated unde r the following standards and represented by scores (from 0 to 3 points per foot, the maximum of 12 points as the total score of four feet):
0 Point: No change 1 Point: Detectable swelling in one or more digital joints 2 Points: Mild swelling in one more joints 3 Points: Severe swelling of the entire paw and/or ankylosis For the basic procedure of the above test, reference was made to the Journal of Immunology, Vol. 140, 1477-~Q~~~~
1484, (1988).
(a) Inhibiting effects on collacten-induced arthritis model From the 18th day after inoculation of the antigen, administration of the compound of the formula (I) (50 mg/kg) was started. Administration was conducted continuously for four weeks intraperitoneally or orally once a day, whereby the state of arthritis was observed.
As a control, saline was used, and the test was conducted in the same manner. The results are shown in Figure 1.
(2) Effects on various cultured cells (a) Effects on the mitogenic response by murine thymocytes Using BALB/c murine thymocytes, the effect of the compound of the formula (I)-on the mitogenic response of lymphocytes to the stimulation by concanavalin A w (hereinafter referred to simply as Con A, Product No. L-1000, manufactured by Vector Laboratories) was studied.
Namely, 4 x 105 murine thymocytes were cultured for 48 hours on a microplate with 96 wells in a RPMI1640 solution containing 10~ of a fetal bovine serum (hereinafter referred to simply as a 10~ FCS-RPMI
solution) together with Con A (5 ~g/ml) and the compound of the formula (I) (in an incubator, 5~ C02, at 37°C).
Then, 0.5 ~Ci of 3H-thymidine (hereinafter referred to simply as 3H-TdR) was added thereto, and the mixture was further cultured for 4 hours. Then, cells were collected _ 77 _ by a cell harvester, and the radioactivity (dpm) of 3H-TdR uptaken into cells was measured. Such measured amounts of 3H-TdR uptaken into the cells were used as indices of the mitogenic response of the murine thymocytes, and the radioactivity at each concentration (from 0.001 to 1,000 ,ug/ml) of the compound of the formula (I) was compared with the control value treated solely by Con A, to calculate ICSO value. The results are shown in Tables 12 and 13. In these Tables 12 and 13, the results of murine thymocytes are shown by (a).
For the basic procedure of this test, reference was made to Selected methods in cellular immunology, p. 144-146 (translated by Katsuyuki Imai et al., published by Rikogakusha, (1982)): -(b) -Effects on the murine mixed lymphocyte reaction Using spleen cells of BALB/c and C57BL/6 mice, the~
effect of the compound of the formula (I) on the murine mixed lymphocyte reaction in both sides, was studied.
Namely, spleen cells of both types of mice were mixed in an equal amount of 5 x 105 cells each, and the mixed cells were cultured together with the compound of the formula (I) for 48 hours on a microplate with 96 wells by a 10~ FCS-RPMI solution (in an incubator, 5~ C02, at 37°C). Then, 0.5 ~cCi of 3H-TdR was added thereto, and the mixture was further cultured for from 16 to l8 hours.
Then, cells were collected by a cell harvester, and the radioactivity (dpm) of 3H-TdR uptaken into the cells, was ~Q~~~O~
_ 78 _ measured. Such measured amounts of 3H-TdR uptaken into the cells were used as indices for the mixed lymphocyte reaction, and the radioactivity at each concentration (from 0.001 to 1,000 ,ug/ml) of the compound of the formula (I) was compared with the non-treated control value, to calculate the Ic5o value. The results are shown in Tables 12 and 13. In these Tables 12 and 13, the results of the mixed lymphocyte reaction are shown by (b).
For the basic procedure for this test, reference was made to Selected methods in cellular immunology, p. 147-149 (translated by Katsuyuki Imai et al., published by Rikogakusha, (1982)).
(c) Effects on the murine bone mallow cells Bone mallow cells were rQmoved from the femur of a BALB/c mouse and suspended in a 10% FCS-RPMI solution. ' The cell suspension was put into a plastic Petri dish having a diameter of 10 cm and left to stand still (in an incubator, 5% COz, at 37°C). Two hours later, only floating cells were recovered, and adhesion cells were removed. 1 x 105 floating cells were cultured for 48 hours together with a 20% culture supernatant of L929 fibroblastoma and the compound of the formula (I) on a microplate with 96 wells by a 10% FCS-RPMI solution (in an incubator, 5% C02, at 37°C). Then, 0.5 ~cCi of 3H-TdR
was added thereto, and the mixture was further cultured for 4 hours. Then, cells were collected by a cell ~~$'~$~~
harvester, and the radioactivity (dpm) of 3H-TdR uptaken into the cells, was measured. Such measured amounts of 3H-TdR uptaken into the cells were used as indices for the proliferation of bone mallow cells, and the radioactivity at each concentration (from 0.001 to 1,000 ~cg/ml) of the compound of the formula (I) was compared with the control value where the L929 culture supernatant was added alone, to calculate the ICSO value. The results are shown in Tables 12 and 13. In these Tables 12 and 13, the results of the bone mallow cells are shown by (c).
For the basic procedure of this test, reference was made to Seikagakujikken Koza compiled by Japan Biochemistry Association, Vol. 5, p. 266-270 (published by Tokyo Kagaku Dojin in 1986).
T able 12 om- 1C50 value ( ,~ g /ml) ound -o.
2 350 560 > 1000 g 0.0044 0.0044 130 10 1. 4 18 68 11 110 170, 210 12 110 5~0=: 560 19 0. 39 > 1000 160 22 300 130 > 1000 25 0.32 430 340 ,~,.,.
T able 13 Com- ICSp value ( ,~ g /m 1 ) .
pound No.
Zg 76 280 150 29 35 > 1000 > 1000 40 160 > 1000 > 1000 48 120 > 1000.= ~ 430 49 11 32=. 41 103 780 > 1000 > 1000 109 550 740 > 1000 (d) Effects on the antibody production from murine spleen cells Using murine spleen B cells, the effects of the compound of the formula (I) on the IgGl, IgM and IgE
antibody production induced by the stimulation by LPS
(lipopolysaccharide; Product No. 520.02051, manufactured by Wako Junyaku) and IL4 (interleukin 4), were studied.
Namely, spleen cells of a BALB/c mouse were treated with a murine anti-Thy-1 antibody (obtained from Chiba University) and a rabbit complement (Product No. 3051, manufactured by cedarlane) to remove T cells, and 3 x 105 spleen B cells were cultured for 7 days together with 10 ,ug/ml of LPS, 100 U/ml of mouse-recombinant IL4 (Product No. MIL-4C, manufactured by-Genzyme) and each concentration (from 0.001_to_1,000 ,um/ml) of the compound of the formula (I) on'a microplate with 96 wells by a Yfl%
FCS-RPMI solution (in an incubator, 5% C02, at 37°C).
For the basic procedure of this test, reference was made to The Journal of Immunology, Vol. 136, p. 4538, (1986).
The amount of each antibody in the cell culture supernatant hereby obtained, was measured by the following enzyme-immunoassay. Firstly, on a microplate with 96 wells, 1 ~g/ml of a rabbit anti-mouse IgGl antibody (Product No. 36243. manufactured by Cappel), 1 ~g/ml of a goat anti-mouse IgM antibody (Product No.
0611-0201, manufactured by Cappel) or 10 ,~g/ml of a rat anti-mouse IgE monoclonal antibody (Product No. LO-ME-2, manufactured by Experimental Immunology) was coated (50 ,u2/well, at room temperature for 60 minutes), and then a nonspecific bond was blocked by a 0.1% bovine serum albumin-containing 10 mM sodium phosphate buffer (pH7.2) (at room temperature for 60 minutes). Then, the above-mentioned cell culture supernatant or its diluted solution was added in an amount of 50 ,u2/well and reacted at room temperature for 60 minutes. Further, an alkaline phosphatase-labeled rabbit anti-mouse IgGl antibody (Product No. 61-0122, manufactured by Zymet) diluted 1,000 times, an alkaline phosphatase-labeled rabbit anti-mouse IgM antibody (Product No. 61-6822, manufactured by Zymet) diluted 2,000 times, or an alkaline phosphatase-labeled goat anti-mouse IgE-antibody (Product No. PA-284, manufactured by Binding Site) diluted 500 times was addEd in an amount of 50 ~c2/well and reacted at room temperature for 60 minutes. 100 ,u2/well of a 10%
diethanol amine buffer solution (pH9.8) containing p-nitrophenyl phosphate as an enzyme substrate, was reacted, and the absorbance at 405 nm was measured. The amount of each antibody was calculated from the calibration curve of each standard antibody, and the ICSo value of the compound of the formula (I) on the antibody production was calculated using as the control value a value obtained in the absence of the compound of the formula (I). The results are shown in Tables 14 and 15 2~~~~~~
together with the above-mentioned results of the effect on the murine bone mallow cells. In these Tables 14 and 15. the ICSO value of the effect on the antibody production was shown by each antibody i.e. IgGl, IgM or IgE, and the above-mentioned results of the murine bone mallow cells are shown by (c).
20~~~~5 Table 14 Value ( ~ g /m ~
IC ) Com- 50 pound I gGl I gM I gL c No.
2 300 250 370 > 1000 3 2.4 < 0.001 0.024 130 8 810 340 310 > 1000 9 790 720 _ 320 > 1000 < 0. 001 < 0. s < 0. 001 68 12 24 0.11 28 560 13 < 0.001 < 0.001 0.32 330 14 10 0.89 3.7 500 17 1. 0 100 3. 2 510 18 < 0.001 0.68 < 0.001 370 5.2 500 3.2 400 21 500 130 17 > 1000 22 670 230 4. 0 > 1000 ~o~~~o~
r 86 -T able 15 Com- ICS value ( ,u g /ml) d poun No. I gGl I gM I g~ c 24 17 10 0. 22 620 25 0.0015 78 0.0034 340 26 23 110 4.5 200 29 380 > 1000 320 > 1000 31 1.5 10 _ 140 520 32 400 350 _ 2.8 540 33 340 5. 6 460 > 1000 40 0. 067 110 0. 0026 > 1000 41 670 > 1000 0. 95 > 1000 46 0.25 0.35 0.32 190 49 < 0.1 0.43 < 0.1 41 50 < 0.001 < 0.001 < 0.001 380 103 0. 45 1. 3 2. 1 > 1000 109 < 0. 1 31 < 0. 1 > 1000 ~0~'~8~
Table 16 Carrageenan~$nduced acute inflammation in rats Com- Dose Number Swelling of paw d (m of rats(x 10 cm's) /K
) poun g tested Average Slj p ~
No. g ~omroi group - 4 1 4 4 8 2 9 5 0 4 9 72 2 0. 0 1 1 5 0 4 1 0 03 3 0. 0 5 1 7 5 0 4 9 52 6 0. 0 5 ~ 24~7~4~_ ~~~,.
_88_ Toxicity test Male DBA1/J mice of 6 weeks old were used in groups each consisting of four mice. The compound of the formula (I) (50 mg/kg) was administered every day for 4 weeks intraperitonially or orally once a day, whereby the change in the body weight and the mortality were examined. As a result, there was no remarkable change in the body weight, and there was no case of death. Thus, the LD5o value of the compound of the above formula (I) is 50 mg/kg at the minimum.
The enopyranose derivative of the formula (I) or its salt has an anti-inflammatory activity, and a test example for the anti-inflammatory activity will be given below. -Test for anti-inflammatory activity A test for an anti-inflammatory activity was conducted by means of carrageenan-induced paw edema model which is commonly used for evaluation of the effectiveness of a common anti-inflammatory agent (NSAID).
0.1 ml of a 1~ ~-carrageenan solution was injected intradermally at the sole of the right paw of a SD male rat (six weeks old). Three hours later, the sole volumes of paws on both sides were measured, and the difference in the volume between the right paw and the left paw was taken as the degree of edema. The test compound was orally administered in an amount of 1 ml/100 g (body 2~~'~~~~a _ 89 _ weight) one hour prior to the administration of carrageenan. To the control group, a physiological saline was administered in the same amount. The results are shown in Table 16.
As is apparent from Table 16. the test compounds showed statistically significant suppressing effects against carrageenan-induced paw edema, whereby the effectiveness as anti-inflammatory agents was confirmed.
When the enopyranose derivative of the formula (I) or its salt is to be used as an effective component of an immuno-suppressive agent, it is administered orally or non-orally usually at a dose of from about 50 mg to 5,000 mg per day for an adult, although the dose may vary depending upon the conditions for administration, etc.
The administration of the_dr-ug can be conducted per orally, intravenously, intramuscularly, intradermally ar permucassaly. Formulations for administration include, for example, powders, microgranules, granules, tablets, pills, capsules, injection solutions, nose drops, suspensions, intravenous drips, ointments, syrups and gradually releasing agents. These formulations can be prepared by conventional methods by using pharmaceutically acceptable common carriers in the same manner as for usual drug formulations.
The present invention provides an immuno-suppressive agent containing a compound of the formula (I) as an effective component. More specifically, the immuno-~~~~a suppressive agent of the present invention is effective for treatment of a disease caused by abnormal sthenia of an immunological function, for example, an autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, chronic nephritis, chronic thyroiditis or autoimmune hemolytic anemia as well as for suppressing a rejection at the time of transplantation of an organ. Further, it is effective for treatment of an allergy disease or an inflammatory disease, particularly for treatment of an autoimmune disease such as rheumatoid arthritis.
For practical use, the immuno-suppressive agent, is usually put in a container and the container is put in a commercial package. The commercial package often includes a written matter which states that the agent can or should be used as an immuno-suppressive agent, e.g., for the treatment of a disease caused by abnormal sthenia of an immunological function: such as rheumatoid arthritis, systemic lupus erythematosus, chronic nephritis, chronic thyroiditis, autoimmune hemolytic anemia, allergy diseases, inflammatory diseases, as well as for suppressing a rejection at the time of transplantation of an organ.
Claims (13)
1. An immuno-suppressive or anti-inflammatory pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier and (ii) a therapeutically effective amount of an enopyranose derivative of formula (I):
(wherein:
R1 is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, (c) C2-C20 alkenyl, (d) C2-C20 alkynyl, (e) -OSO2R , (f) halogen, (g) -O-COR7, (h) -NHCOR8, (i) C1-C20 alkoxy, (j) phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro or (k) a saccharose residue, R2 is hydrogen or C1-C20 alkyl, R3 is hydrogen or halogen, R4 is (a) hydrogen, (b) -COR9, (c) silyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkyl and phenyl or (d) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, one of R5 and R6 is (a) hydroxyl, (b) C1-C20 alkoxy which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, (c) a saccharose residue, (d) C3-C8 cycloalkyloxy which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl or (e) -OCOR10 and the other is (a) hydrogen or (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, or R4 and R5 together form a single bond, while R6 is (a) hydrogen or (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, each of R7, R9 and R10 is (a) C1-C20 alkyl or (b) phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro, R8 is (a) C1-C20 alkyl, (b) phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro or (c) benzyloxy, X is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (c) C2-C20 alkenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (d) C2-C20 alkynyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (e) C3-C8 cycloalkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (f) phenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (g) pyridyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (h) furanyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (i) thienyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (j) formyl, (k) -COR11 (1) -C(W1)W2R11 or (m) -SO2R11, wherein:
R11 is (a) a chain hydrocarbon group which is selected from the group consisting of C1-C18 alkyl, C2-C18 alkenyl and C2-C18 alkynyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxy-carbonyl, carboxyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino and C1-C18 alkyl-substituted amino, wherein the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl, naphthyl, benzothienyl, benzofuranyl or quinolinyl, (b) a monocyclic hydrocarbon group which is selected from the group consisting of C3-C8 cycloalkyl, C5-C8 cycloalkenyl and phenyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18alkoxy, C1-C18 alkylthio, C3-C8-cycloalkyl, C3-C8cycloalkoxy, C5-C8cycloalkenyl, C5-C8-cycloalkenyloxy, C1-C18alkoxy-carbonyl, C1-C18 alkyl-carbonyl, C1-C18alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, (c) a polycyclic hydrocarbon group which is selected from the group consisting of naphthyl, tetrahydronaphthyl, indanyl, adamantyl, noradamantyl, norbornanyl and norbornonyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxycarbonyl, C1-C18 alkylcarbonyl, C1-C18 alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, (d) a monocyclic heterocycle group which is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrazolinyl, hydantoinyl, oxazolinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thioazolidinyl, dioxolanyl, dithiolanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydrooxopyridazinyl, tetrahydrooxapyridazinyl, dihydrooxopyrimidinyl, tetrahydrooxopyrimidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dihydrodithinyl, dithianyl and morpholinyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxycarbonyl, C1-C18 alkylcarbonyl, C1-C18 alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the anyloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, or (e) a polyacrylic heterocycle group which is selected from the group consisting of thienothienyl, dihydrocyclopentathienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, tetrahydrobenzothienyl, dihydrobenzofuranyl, tetrahydrobenzisoxazolyl, benzodioxolyl, quinolinyl, isoquinolinyl, benzodioxanyl, quinoxalinyl and quinuclidinyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxycarbonyl, C1-C18 alkylcarbonyl, C1-C18 alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, W1 is an oxygen atom or a sulfur atom, W2 is an oxygen atom, a sulfur atom or -NH-, and Y is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (c) C2-C20 alkenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino or (d) C2-C20 alkynyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino) or a pharmaceutically acceptable salt thereof.
(wherein:
R1 is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, (c) C2-C20 alkenyl, (d) C2-C20 alkynyl, (e) -OSO2R , (f) halogen, (g) -O-COR7, (h) -NHCOR8, (i) C1-C20 alkoxy, (j) phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro or (k) a saccharose residue, R2 is hydrogen or C1-C20 alkyl, R3 is hydrogen or halogen, R4 is (a) hydrogen, (b) -COR9, (c) silyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkyl and phenyl or (d) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, one of R5 and R6 is (a) hydroxyl, (b) C1-C20 alkoxy which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, (c) a saccharose residue, (d) C3-C8 cycloalkyloxy which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl or (e) -OCOR10 and the other is (a) hydrogen or (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, or R4 and R5 together form a single bond, while R6 is (a) hydrogen or (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, each of R7, R9 and R10 is (a) C1-C20 alkyl or (b) phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro, R8 is (a) C1-C20 alkyl, (b) phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro or (c) benzyloxy, X is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (c) C2-C20 alkenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (d) C2-C20 alkynyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (e) C3-C8 cycloalkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (f) phenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (g) pyridyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (h) furanyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (i) thienyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (j) formyl, (k) -COR11 (1) -C(W1)W2R11 or (m) -SO2R11, wherein:
R11 is (a) a chain hydrocarbon group which is selected from the group consisting of C1-C18 alkyl, C2-C18 alkenyl and C2-C18 alkynyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxy-carbonyl, carboxyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino and C1-C18 alkyl-substituted amino, wherein the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl, naphthyl, benzothienyl, benzofuranyl or quinolinyl, (b) a monocyclic hydrocarbon group which is selected from the group consisting of C3-C8 cycloalkyl, C5-C8 cycloalkenyl and phenyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18alkoxy, C1-C18 alkylthio, C3-C8-cycloalkyl, C3-C8cycloalkoxy, C5-C8cycloalkenyl, C5-C8-cycloalkenyloxy, C1-C18alkoxy-carbonyl, C1-C18 alkyl-carbonyl, C1-C18alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, (c) a polycyclic hydrocarbon group which is selected from the group consisting of naphthyl, tetrahydronaphthyl, indanyl, adamantyl, noradamantyl, norbornanyl and norbornonyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxycarbonyl, C1-C18 alkylcarbonyl, C1-C18 alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, (d) a monocyclic heterocycle group which is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrazolinyl, hydantoinyl, oxazolinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thioazolidinyl, dioxolanyl, dithiolanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydrooxopyridazinyl, tetrahydrooxapyridazinyl, dihydrooxopyrimidinyl, tetrahydrooxopyrimidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dihydrodithinyl, dithianyl and morpholinyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxycarbonyl, C1-C18 alkylcarbonyl, C1-C18 alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the anyloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, or (e) a polyacrylic heterocycle group which is selected from the group consisting of thienothienyl, dihydrocyclopentathienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, tetrahydrobenzothienyl, dihydrobenzofuranyl, tetrahydrobenzisoxazolyl, benzodioxolyl, quinolinyl, isoquinolinyl, benzodioxanyl, quinoxalinyl and quinuclidinyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxycarbonyl, C1-C18 alkylcarbonyl, C1-C18 alkylcarbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, W1 is an oxygen atom or a sulfur atom, W2 is an oxygen atom, a sulfur atom or -NH-, and Y is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (c) C2-C20 alkenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino or (d) C2-C20 alkynyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino) or a pharmaceutically acceptable salt thereof.
2. An immuno-suppressive or anti-inflammatory pharmaceutical composition according to Claim 1, wherein the enopyranose derivative of the formula (I) as defined in Claim 1 or its salt is a stereoisomer of the following formula (I-1) or (I-2):
3. An immuno-suppressive or anti-inflammatory pharmaceutical composition according to Claim 2, wherein the enopyranose derivative or its salt is a compound represented by the formula (I-1) as defined in Claim 2 in which R1 is hydrogen, the C1-C20 alkyl which may be substituted, C2-C20alkenyl or C2-C20alkynyl, R2 is hydrogen or C1-C20 alkyl, R3 and R6 each hydrogen and R4 and R5 together form a single bond.
4. An immuno-suppressive or anti-inflammatory pharmaceutical composition according to Claim 1, which comprises a compound selected from the group consisting of 1,6-anhydro-3,4-dideoxy-2-0-(2-furancarbonyl)-.beta.-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O-(2-furancarbonyl)-3-methyl-.beta.-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-C-ethynyl-2-O-(2-furancarbonyl)-.beta.-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O-(2-furfuryl)-3-methyl-.beta.-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O-(2-furfuryl)-.beta.-D-threo-hex-3-enopyranose and 1,6-anhydro-3,4-dideoxy-2-C-ethynyl-2-O-(2-furfuryl)-.beta.-D-threo-hex-3-enopyranose.
5. A compound of the following formula (I-1) or (I-2):
or its salt, wherein:
R1 is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, (c) C2-C20 alkenyl, (d) C2-C20 alkynyl, (e) -OSO2R7, (f) halogen, (g) -OCOR7, (h) -NHCOR8, (i) C2-C20 alkoxy, (j) phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro or (k) a saccharose residue, R2 is hydrogen atom or C1-C20 alkyl, R3 is hydrogen or halogen, R4 and R5 together form a single bond, R6 is hydrogen or C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, R7 is C1-C20 alkyl or phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro, R8 is (a) C1-C20 alkyl, (b) phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro or (c) benzyloxy, X is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl furanyl, thienyl, acetoxy, vareloxy, azide and amino, (c) C2-C20 alkenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (d) C2-C20 alkynyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (e) C3-C8 cycloalkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (f) phenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (g) pyridyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (h) furanyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (i) thienyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (j) formyl, (k) -COR11, (1) -C(W1)W2R11 or (m) -SO2R11, wherein:
R11 is (a) a chain hydrocarbon group which is selected from the group consisting of C1-C18 alkyl, C2-C18 alkenyl and C2-C18 alkynyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxy-carbonyl, carboxyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino and C1-C18 alkyl-substituted amino, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, (b) a monocyclic hydrocarbon group which is selected from the group consisting of C3-C8-cycloalkyl, C5-C8cycloalkenyl and phenyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo, C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxy-carbonyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the anyloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, (c) a polycyclic hydrocarbon group which is selected from the group consisting of naphthyl, tetrahydronaphthyl, indanyl, adamantyl, noradamantyl, norbornanyl and norbornonyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8-cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8-cycloalkenyloxy, C1-C18 alkoxy-carbonyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, (d) a monocyclic heterocycle group which is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrazolinyl, hydantoinyl, oxazolinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thioazolidinyl, dioxolanyl, dithiolanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydrooxopyridazinyl, tetrahydrooxapyridazinyl, dihydrooxopyrimidinyl, tetrahydrooxopyrimidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dihydrodithinyl, dithianyl and morpholinyl and which may be substituted by one or members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18alkoxy-carbonyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, or (e) a polycyclic heterocycle group which is selected from the group consisting of thienothienyl, dihydrocyclopentathienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, tetrahydrobenzothienyl, dihydrobenzofuranyl, tetrahydrobenzisoxazolyl, benzodioxolyl, quinolinyl, isoquinolinyl, benzodioxanyl, quinoxalinyl and quinuclidinyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxy-carbonyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, W1 is an oxygen atom or a sulfur atom, W2 is an oxygen atom, a sulfur atom or -NH-, and Y is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (c) C2-C20 alkenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino or (d) C2-C20 alkynyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, provided that the following cases are excluded:
(1) a case where in the formula (I-1), each of R1, R2, R3, R6 and X is hydrogen, and Y is hydrogen or the C1-C20 alkyl which may be substituted, (2) a case where in the formula (I-1), each of R1, R2, R3, R6 and Y is hydrogen, X is acetyl, 3,5-dinitrobenzoyl or p-toluenesulfonyl, (3) a case where in the formula (I-1), each of R1, R2, R3 and Y is hydrogen, R6 is the C1-C20 alkyl which may be substituted, and X is hydrogen or acetyl, (4) a case where in the formula (I-2), each of R1, R2, R3, R6 and X is hydrogen, and Y is methyl, (5) a case where in the formula (I-2), each of R1, R2, R3, R6 and Y is hydrogen, and X is hydrogen, methyl, benzyl, formyl, acetyl, benzoyl, 4-chlorobenzoyl, 3,5-dichlorobenzoyl, 4-nitrobenzoyl, 3,5-dinitrobenzoyl, 4-methoxybenzoyl, 3,5-dimethoxybenzoyl, methylsulfonyl or p-toluenesulfonyl, and (6) a case where in the formula (I-2), R1 is p-toluenesulfonyloxy, each of R2, R3, R6 and Y is hydrogen, and X is hydrogen, acetyl or p-toluenesulfonyl.
or its salt, wherein:
R1 is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, (c) C2-C20 alkenyl, (d) C2-C20 alkynyl, (e) -OSO2R7, (f) halogen, (g) -OCOR7, (h) -NHCOR8, (i) C2-C20 alkoxy, (j) phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro or (k) a saccharose residue, R2 is hydrogen atom or C1-C20 alkyl, R3 is hydrogen or halogen, R4 and R5 together form a single bond, R6 is hydrogen or C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of C1-C20 alkoxy, phenyl and hydroxyl, R7 is C1-C20 alkyl or phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro, R8 is (a) C1-C20 alkyl, (b) phenyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C20 alkyl and nitro or (c) benzyloxy, X is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl furanyl, thienyl, acetoxy, vareloxy, azide and amino, (c) C2-C20 alkenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (d) C2-C20 alkynyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (e) C3-C8 cycloalkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (f) phenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (g) pyridyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (h) furanyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (i) thienyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, C1-C20 alkyl, acetoxy, vareloxy, nitro and amino, (j) formyl, (k) -COR11, (1) -C(W1)W2R11 or (m) -SO2R11, wherein:
R11 is (a) a chain hydrocarbon group which is selected from the group consisting of C1-C18 alkyl, C2-C18 alkenyl and C2-C18 alkynyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxy-carbonyl, carboxyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino and C1-C18 alkyl-substituted amino, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, (b) a monocyclic hydrocarbon group which is selected from the group consisting of C3-C8-cycloalkyl, C5-C8cycloalkenyl and phenyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo, C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxy-carbonyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the anyloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, (c) a polycyclic hydrocarbon group which is selected from the group consisting of naphthyl, tetrahydronaphthyl, indanyl, adamantyl, noradamantyl, norbornanyl and norbornonyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8-cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8-cycloalkenyloxy, C1-C18 alkoxy-carbonyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, (d) a monocyclic heterocycle group which is selected from the group consisting of pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, pyrazolinyl, hydantoinyl, oxazolinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thioazolidinyl, dioxolanyl, dithiolanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, dihydrooxopyridazinyl, tetrahydrooxapyridazinyl, dihydrooxopyrimidinyl, tetrahydrooxopyrimidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, dihydrodithinyl, dithianyl and morpholinyl and which may be substituted by one or members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18alkoxy-carbonyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, or (e) a polycyclic heterocycle group which is selected from the group consisting of thienothienyl, dihydrocyclopentathienyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, tetrahydrobenzothienyl, dihydrobenzofuranyl, tetrahydrobenzisoxazolyl, benzodioxolyl, quinolinyl, isoquinolinyl, benzodioxanyl, quinoxalinyl and quinuclidinyl and which may be substituted by one or more members selected from the group consisting of halogen, C1-C18 alkyl, halo C1-C18 alkyl, C1-C18 alkoxy, halo C1-C18 alkoxy, C1-C18 alkylthio, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C5-C8 cycloalkenyl, C5-C8 cycloalkenyloxy, C1-C18 alkoxy-carbonyl, C1-C18 alkyl-carbonyl, C1-C18 alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18 alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl, W1 is an oxygen atom or a sulfur atom, W2 is an oxygen atom, a sulfur atom or -NH-, and Y is (a) hydrogen, (b) C1-C20 alkyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, (c) C2-C20 alkenyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino or (d) C2-C20 alkynyl which may be substituted by one or more members selected from the group consisting of halogen, hydroxyl, phenyl, C1-C20 alkyl-substituted phenyl, pyridyl, furanyl, thienyl, acetoxy, vareloxy, azide and amino, provided that the following cases are excluded:
(1) a case where in the formula (I-1), each of R1, R2, R3, R6 and X is hydrogen, and Y is hydrogen or the C1-C20 alkyl which may be substituted, (2) a case where in the formula (I-1), each of R1, R2, R3, R6 and Y is hydrogen, X is acetyl, 3,5-dinitrobenzoyl or p-toluenesulfonyl, (3) a case where in the formula (I-1), each of R1, R2, R3 and Y is hydrogen, R6 is the C1-C20 alkyl which may be substituted, and X is hydrogen or acetyl, (4) a case where in the formula (I-2), each of R1, R2, R3, R6 and X is hydrogen, and Y is methyl, (5) a case where in the formula (I-2), each of R1, R2, R3, R6 and Y is hydrogen, and X is hydrogen, methyl, benzyl, formyl, acetyl, benzoyl, 4-chlorobenzoyl, 3,5-dichlorobenzoyl, 4-nitrobenzoyl, 3,5-dinitrobenzoyl, 4-methoxybenzoyl, 3,5-dimethoxybenzoyl, methylsulfonyl or p-toluenesulfonyl, and (6) a case where in the formula (I-2), R1 is p-toluenesulfonyloxy, each of R2, R3, R6 and Y is hydrogen, and X is hydrogen, acetyl or p-toluenesulfonyl.
6. A compound or its salt according to Claim 5, wherein the compound is represented by the formula (I-1) in which R1 is hydrogen, the C1-C20 alkyl which may be substituted, as defined in claim 5, C2-C20 alkenyl or C2-C20 alkynyl, R2 is hydrogen or C1-C20 alkyl and R3 and R6 are each hydrogen and R4 and R6 together form a single bond.
7. A compound or its salt according to Claim 5, wherein the compound is represented by the formula (I-1) wherein R1 is hydrogen, the C1-C20 alkyl which may be substituted, as defined in claim 5, C2-C20 alkenyl or alkynyl, R2 is hydrogen or C1-C20 alkyl, R3 and R6 are each hydrogen, R4 and R5 together form a single bond and X is the C1-C20 alkyl which may be substituted as defined in claim 5 or -COR11 (in which R11 is as defined in claim 5).
8. A compound or its salt according to Claim 7, wherein X is furfuryl or -COR11 in which R11 is furanyl which may be substituted by one or more members selected from the group consisting of halogen, C1-C18alkyl, halo C1-C18alkyl, C1-C18-alkoxy, halo C1-C18alkoxy, C1-C18alkylthio, C3-C8cycloalkyl, C3-C8cycloalkoxy, C5-C8cycloalkenyl, C5-C8cycloalkenyloxy, C1-C18alkoxy-carbonyl, C1-C18alkyl-carbonyl, C1-C18alkyl-carbonyloxy, aryl, aryloxy, arylthio, amino, C1-C18alkyl-substituted amino, cyano, nitro and hydroxyl, where the aryl and the aryl moiety of the aryloxy and of the arylthio are phenyl, thienyl, furanyl, pyridyl naphthyl, benzothienyl, benzofuranyl or quinolinyl.
9. A compound or its salt according to Claim 7, wherein the compound is selected from the group consisting 1,6-anhydro-3,4-dideoxy-2-O-(2-furancarbonyl)-.beta.-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O-(2-furancarbonyl)-3-methyl-.beta.-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-C-ethynyl-2-O-(2-furancarbonyl)-.beta.-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O-(2-furfuryl)-.beta.-D-threo-hex-3-enopyranose, 1,6-anhydro-3,4-dideoxy-2-O-(2-furfuryl)-3-methyl-.beta.-D-threo-hex-3-enopyranose and 1,6-anhydro-3,4-dideoxy-2-C-ethynyl-2-O-(2-furfuryl)-.beta.-D-threo-hex-3-enopyranose.
10. A compound or salt according to claim 5, wherein the compound is represented by the formula (I-1) in which:
R1 is H, -CH3, , Br, I,~OCOCH3, , -NHCOCH3, ,-OCOC4H9-t, , -OCH3, , -CH=CH2, -C~CH, -CH2OCH3,-C2H5, or -(CH2)3CH3;
R2 is H or -CH3;
R3 is H or Br;
R4 and R5 together form a bond;
R6 is H, -CH3 or -CH2OH;
X is H,-COCH2CH(CH3)2,-COCH=CHCH3, , , -CO(CH2)4CH3,-CO(CH2)14CH3,-CO(CH2)7CH=CH(CH2)7CH3,-COCH3, -COCH2Cl, , -CO(CH2)8CH3, -CO(CH2)5Br, , , , , , ,-CO(CH2)18CH3, -COOCH3, , ,-CSNHCH3, -CONHC(CH3)3, ,-CHO-, -(CH2)3CH3, -CH3, , -SO2CH3, , , -CO(CH2)14CH2OH, , -CH2OH or ; and Y is H, -CH-CH2, -CH3, -C~CH, -(CH2)3CH3, -C~CCH2CH2CH3, -CH2OH, -CH2NH2, -CH2OCOCH3, -(CH2)9CH3, -(CH2)17CH3,-CH2N3 or , provided that the followingcases are excluded:
(1) a case where each of R1, R2, R3, R6 and X is H and Y is H,-CH3, -(CH2)3CH3, -CH2OH,-CH2NH2,-CH2OCOCH3, -(CH2)9CH3, -(CH2)17CH3, -CH2N3 or ;
(2) a case where each of R1, R2, R3, R6 and Y is H, X is -COCH3, or , and (3) a case where each of R1, R2, R3 and Y is H, R6 is H, -CH3 or -CH2OH and X is H or -COCH3.
R1 is H, -CH3, , Br, I,~OCOCH3, , -NHCOCH3, ,-OCOC4H9-t, , -OCH3, , -CH=CH2, -C~CH, -CH2OCH3,-C2H5, or -(CH2)3CH3;
R2 is H or -CH3;
R3 is H or Br;
R4 and R5 together form a bond;
R6 is H, -CH3 or -CH2OH;
X is H,-COCH2CH(CH3)2,-COCH=CHCH3, , , -CO(CH2)4CH3,-CO(CH2)14CH3,-CO(CH2)7CH=CH(CH2)7CH3,-COCH3, -COCH2Cl, , -CO(CH2)8CH3, -CO(CH2)5Br, , , , , , ,-CO(CH2)18CH3, -COOCH3, , ,-CSNHCH3, -CONHC(CH3)3, ,-CHO-, -(CH2)3CH3, -CH3, , -SO2CH3, , , -CO(CH2)14CH2OH, , -CH2OH or ; and Y is H, -CH-CH2, -CH3, -C~CH, -(CH2)3CH3, -C~CCH2CH2CH3, -CH2OH, -CH2NH2, -CH2OCOCH3, -(CH2)9CH3, -(CH2)17CH3,-CH2N3 or , provided that the followingcases are excluded:
(1) a case where each of R1, R2, R3, R6 and X is H and Y is H,-CH3, -(CH2)3CH3, -CH2OH,-CH2NH2,-CH2OCOCH3, -(CH2)9CH3, -(CH2)17CH3, -CH2N3 or ;
(2) a case where each of R1, R2, R3, R6 and Y is H, X is -COCH3, or , and (3) a case where each of R1, R2, R3 and Y is H, R6 is H, -CH3 or -CH2OH and X is H or -COCH3.
11. A pharmaceutical composition according to any one of claims 1 to 4, which contains the enopryranose derivative or salt so adapted that 50 mg to 5,000 mg thereof is administered orally or non-orally per day for an adult human.
12. A commercial package comprising a container containing therein the pharmaceutical composition according to any one of claims 1 to 4 or claim 11 and a written matter associated with the container, wherein the written matter states that the pharmaceutical composition can or should be used for suppressing immune system.
13. A commercial package according to claim 12, wherein the written matter states that the pharmaceutical composition can or should be used for treating autoimmune disease or for suppressing a rejection at the time of transplantation of an organ.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP66582/1992 | 1992-02-06 | ||
| JP6658292 | 1992-02-06 |
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| Publication Number | Publication Date |
|---|---|
| CA2087805A1 CA2087805A1 (en) | 1993-08-07 |
| CA2087805C true CA2087805C (en) | 1999-02-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2087805 Expired - Fee Related CA2087805C (en) | 1992-02-06 | 1993-01-21 | Immuno-suppressing agent |
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| Country | Link |
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| CA (1) | CA2087805C (en) |
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